Comparison of long-acting testosterone undecanoate formulation versus testosterone enanthate on sexual function and mood in hypogonadal men.
ABSTRACT To compare the effects of two treatment modalities of testosterone on sexual functioning and mood. Design Forty men were randomized to receive either parenteral testosterone enanthate (TE) or long-acting parenteral testosterone undecanoate (TU) over a period of 30 weeks. Thereafter, 20 men who had received TU and 16 men who had received TE continued with TU and completed another 65 weeks to study longer-term effects of TU.
The following variables of sexual functioning were studied: sexual thoughts and fantasy, sexual interest and desire, satisfaction with sex life, number of erections and ejaculations per week, and number of spontaneous morning erections per week. Also variables related to mood were analyzed.
Improvements in these variables were significant and were of a similar magnitude in the group treated with TU and TE for 30 weeks. Improvements were maintained at the same levels over a period of another 65 weeks when all men received TU. Effects on mood were recorded for 30 weeks, but were more difficult to establish in the study population. There were significant differences in baseline values between the two groups and scores showed wide s.d.
Both TE and TU were effective in improving sexual functions in hypogonadal men. An advantage of TU over TE is its lower frequency of administration and its better tolerability and safety profile.
- SourceAvailable from: Markus Schubert[show abstract] [hide abstract]
ABSTRACT: In an open-label, randomized, prospective trial, we investigated pharmacokinetics and several efficacy and safety parameters of a novel, long-acting testosterone (T) undecanoate (TU) formulation in 40 hypogonadal men (serum testosterone concentrations < 5 nmol/liter). For the first 30 wk (comparative study), the patients were randomly assigned to receive either 10 x 250 mg T enanthate (TE) im every 3 wk (n = 20) or 3 x 1000 mg TU im every 6 wk (loading dose) followed by 1 x 1000 mg after an additional 9 wk (n = 20). In a follow-up study, observation continued in those patients who completed the comparative part and opted for TU treatment (8 x 1000 mg TU every 12 wk in former TU patients and 2 x 1000 mg TU every 8 wk plus 6 x 1000 mg every 12 wk in former TE patients) for an additional 20-21 months. Here we report only the pharmacokinetic aspects of the new TU formulation for the first approximately 2.5 yr of treatment. At baseline, serum T concentrations did not significantly differ between the two study groups. In the TE group, mean trough levels of serum T were always less than 10 nmol/liter before the next injection, whereas in the TU group, mean trough levels of serum T were 14.1 +/- 4.5 nmol/liter after the first two doses (6-wk intervals) and 16.3 +/- 5.7 nmol/liter after the 9-wk interval at wk 30. The mean serum levels of dihydrotestosterone and estradiol also increased in parallel to the serum T pattern and remained within the normal range. In the follow-up study, the former TU patients (n = 20) received eight TU injections at 12-wk intervals, and the TE patients (n = 16) switched to TU and initially received two TU injections at 8-wk intervals (loading) and continued with six TU injections at 12-wk intervals (maintenance). This regimen resulted in stable mean serum trough levels of T (ranging from 14.9 +/- 5.2 to 16.5 +/- 8.0 nmol/liter) and estradiol (ranging from 98.5 +/- 45.2 to 80.4 +/- 14.4 pmol/liter). The present study has shown that 1000 mg TU injected into male patients with hypogonadism at 12-wk intervals is well tolerated and leads to T levels within normal ranges, using four instead of 17 or more TE injections per year. An initial loading dose of either 3 x 1000 mg TU every 6 wk at the beginning of hormone substitution or 2 x 1000 mg TU every 8 wk after switching from the short-acting TE to TU were found to be a adequate dosing regimens for starting of treatment with the long-acting TU preparation.Journal of Clinical Endocrinology & Metabolism 11/2004; 89(11):5429-34. · 6.43 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Androgens are deemed critical for penile-tissue development, growth, and maintenance of erectile function, however, their role in erection, especially in humans, remains controversial. In this review, we summarize information from clinical and animal model studies to provide a comprehensive and rational argument for the role of androgens, or lack thereof, on penile erection ability in humans. The goal of this review is to present the clinical and preclinical evidence available in the literature with regard to testosterone and erectile physiology and engage the reader in this discussion. Ultimately, each reader will have to form his or her own conclusions based on the existing evidence. In humans, androgen-deficiency manifestations are noted in clinical situations such as: (i) inadequate development of the penis; and (ii) loss of erectile function in prostate cancer and benign prostatic hyperplasia patients managed with medical or surgical castration or antiandrogen therapy. Androgen treatment causes: (i) improvement in sexual function in hypogonadal patients treated with androgen supplementation; (ii) improvement in nocturnal penile tumescence in hypogonadal patients treated with androgens; (iii) improvement in erectile function with androgen supplementation in patients who did not respond to phosphodiesterase type 5 inhibitor therapy initially; and (iv) improvement in the well-being, mood, energy, and sexual function in aging men who have testosterone deficiency treated with androgen therapy. In contrast to animals, especially rodents in which the adrenal cortex does not synthesize androgens, the human adrenal is a source of peripherally circulating androgen precursors, thus, complete androgen insufficiency may not be observed in men at a younger age. Furthermore, in light of the concept that a threshold of androgen levels exists in animals and humans below which sexual function is diminished, further contributes to the complexity of understanding androgens role in erections, especially in humans. Nevertheless, based on the preclinical and clinical data available in the literature, to date, we infer that androgens play a critical role in maintaining erectile physiology in humans.Journal of Sexual Medicine 06/2006; 3(3):382-404; discussion 404-7. · 3.51 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: To study the effects of sildenafil on human sleep-related erections according to the state of androgenization, we evaluated the effects of sildenafil on sleep-related erections in hypogonadal men before and during testosterone replacement treatment and in control subjects. We enrolled 24 hypogonadal men and 24 healthy men as a control group. All hypogonadal subjects had very low testosterone levels (<200 ng/dL [6.9 nmol/L]) [corrected] All subjects underwent nocturnal penile tumescence and rigidity monitoring (NPTRM) for 3 consecutive nights and were randomly assigned to consume either 50 mg of sildenafil or placebo 1 hour before bedtime on the second or third night of nocturnal penile monitoring. The hypogonadal subjects were tested twice, first without replacement treatment (H-T) and then after at least 6 months of testosterone replacement therapy (H+T). The subjects of the control group (C) were tested once. The following parameters of sleep-related erections were analyzed: total number of valid erections, total duration of both rigidity greater than or equal 70% and increase in penile circumference greater than or equal 30 mm, maximum rigidity, and maximum increase in penile circumference. NPTRM parameters were reduced in hypogonadal men before testosterone treatment (H-T+P) when compared with control subjects taking placebo (C+P). NPTRM parameters after testosterone (H+T+P) and sildenafil (H-T+S) administration were similar to that of control subjects taking placebo (C+P). When the statistical analysis was restricted to the hypogonadal men before testosterone treatment, sildenafil alone significantly increased NPTRM parameters when compared with placebo (H-T+S vs H-T+P). Testosterone restored normal erections when administered to hypogonadal subjects (H+T+P vs H-T+P); in hypogonadal men, however, the combined treatment (sildenafil plus testosterone) resulted in the maximum positive effect on NPTRM parameters. When the increase from baseline was analyzed, the effects of testosterone plus sildenafil were greater than the sum of the effects of each drug used alone. In conclusion, sildenafil administered at bedtime improves sleep-related erections in hypogonadal men, suggesting that the nitric oxide pathway may be pharmacologically enrolled and enhanced despite low serum testosterone. Furthermore, these data strongly support the idea of a synergic effect on sleep-related erections of sildenafil and testosterone.Journal of Andrology 01/2006; 27(2):165-75. · 2.53 Impact Factor
Comparison of long-acting testosterone undecanoate
formulation versus testosterone enanthate on sexual
function and mood in hypogonadal men
F Jockenho ¨vel, T Minnemann1, M Schubert1, S Freude1, D Hu ¨bler2, C Schumann1, A Christoph1and M Ernst2
Evangelisches Krankenhaus Herne, Wiescherstraße 24, 44623 Herne, Germany,1Klinik II und Poliklinik fu ¨r Innere Medizin, Klinikum der Universita ¨t
zu Ko ¨ln, Kerpener Street 62, 50937 Ko ¨ln, Germany and2Jenapharm GmbH & Co., KG, Otto-Schott-Straße 15, 07745 Jena, Germany
(Correspondence should be addressed to F Jockenho ¨vel; Email: email@example.com)
Objective: To compare the effects of two treatment modalities of testosterone on sexual functioning
Design: Forty men were randomized to receive either parenteral testosterone enanthate (TE) or long-
acting parenteral testosterone undecanoate (TU) over a period of 30 weeks. Thereafter, 20 men who
had received TU and 16 men who had received TE continued with TU and completed another 65 weeks
to study longer-term effects of TU.
Methods: The following variables of sexual functioning were studied: sexual thoughts and fantasy,
sexual interest and desire, satisfaction with sexlife, number of erections and ejaculations per week, and
number of spontaneous morning erections per week. Also variables related to mood were analyzed.
Results: Improvements in these variables were significant and were of a similar magnitude in the group
treated with TU and TE for 30 weeks. Improvements were maintained at the same levels over a period
of another 65 weeks when all men received TU. Effects on mood were recorded for 30 weeks, but were
more difficult to establish in the study population. There were significant differences in baseline values
between the two groups and scores showed wide S.D.
Conclusions: Both TE and TU were effective in improving sexual functions in hypogonadal men. An
advantage of TU over TE is its lower frequency of administration and its better tolerability and safety
European Journal of Endocrinology 160 815–819
Aging is the most robust factor predicting erectile
difficulties. It is obvious that aging per se is associated
with a deterioration of the biological functions mediat-
ing erectile function: hormonal, vascular, and neural
processes. This is often aggravated by intercurrent
disease in old age, such as diabetes mellitus, cardiovas-
cular disease, and use of medical drugs.
Erectile response in mammals is centrally and
peripherally regulated by androgens (1). Severe hypo-
gonadism in men usually results in loss of libido and
potency which can be restored by androgen adminis-
tration. The original insights into the mechanisms of
action of androgens on sexual function indicated that
androgens exert particular effects on libido and that
sleep-related erections are androgen sensitive but
erections in response to erotic stimuli are relatively
androgen-independent (1). There are a number of
recent developments that shed new light on testosterone
treatment of erectile dysfunction (ED) in aging men.
There is growing insight that testosterone has profound
effects on tissues of the penis involved in the mechanism
of erection and that testosterone deficiency impairs the
anatomical and physiological/biochemical substrate of
erectile capacity, reversible upon androgen treatment
(2–4). Several studies have indicated that the adminis-
tration of phospho-diesterase inhibitors type 5 (PDE-5-
inhibitors) is not always sufficient to restore erectile
potency in men, and that administration of testosterone
improves the therapeutical response to PDE-5-inhibitors
considerably (3, 4). There is an increasing insight to
view ED occurring in elderly as an expression of the
ailments of the aging process. Circulating levels of
testosterone are closely related to manifestations of
etiological factors in ED, such as atherosclerotic disease
and diabetes mellitus (5–7). The latter diseases are
correlated with lower-than-normal testosterone levels.
The effects of testosterone on sexual interest and
activity are obvious. But treatment of hypogonadal men
with testosterone leads almost always to unmistakable
changes in mood, self-esteem, and vitality.This testifies
to the profound effects of testosterone that it exerts on
the brain and the mind. Conversely, hypogonadism and
European Journal of Endocrinology (2009) 160 815–819 ISSN 0804-4643
q 2009 European Society of EndocrinologyDOI: 10.1530/EJE-08-0830
Online version via www.eje-online.org
particularly the profound hypogonadism resulting from
androgen deprivation treatment in men with prostate
cancer are associated with loss of vitality and mood
disorders, if not depression. It is reasonable to assume
that a positive mood state has a favorable effect on
Testosterone formulations for (i.m.) injection and s.c.
application as well as for oral and transdermal
administration have been approved for androgen
therapy (8). To date, injectable testosterone esters are
the most commonly used formulations. To increase
serum testosterone levels to the physiological range,
i.m. injections of testosterone enanthate (TE) every 2–3
weeks are required, which lead to supraphysiological
peaks shortly after administration, followed by a sharp
fall in levels thereafter. Testosterone levels before the
next injection are frequently in the hypogonadal range
(9). Unfortunately, marked oscillations in serum
testosterone concentration and short inter-injection
intervals of this treatment regimen are associated with
considerable discomfort for the patients (9). Therefore,
development of longer-acting formulations represents a
major improvement in testosterone therapy (8, 10).
Testosterone undecanoate (TU), an ester with a
fatty acid side-chain of medium length in 17b-position,
is a long-acting formulation for i.m. injection and
requires significantly less frequent injections than other
established parenteral testosterone ester formulations
(8, 11, 12). After the first injection, a second dose is
given 6 weeks later and in the vast majority of patients
an injection every 12 weeks (with variations between
11–13 weeks) maintains plasma testosterone in the
physiological range (8).
This study assessed the long-term efficacy of i.m. TU
for treatment of sexual dysfunction associated with
hypogonadism in men. The first part of the study
consisted of a 30-week comparative testing of i.m. TU
versus standard treatment with i.m. TE. A follow-up
study investigated the longer-term effects of TU.
Patients, who had completed the comparative study,
received now TU for an additional 65 weeks.
The pharmacokinetic aspects of the present study
have been published by our group (11).
Subjects and methods
Study design and patients
The study was designed as an open-label, randomized,
prospective clinical trial (11) to compare testosterone
treatment with the traditional parenteral testosterone
ester, TE, versus the new parenteral long acting TU and
was carried out between October 1998 and February
2002. Forty men were included in the study. Their ages
ranged between 18 and 65 years and their serum
testosterone levels at inclusion in the present study were
!5 nmol/l (normal range 10–30 nmol/l) following
discontinuation of prior testosterone treatment for at
least eight weeks, and, if testosterone pellets had been
used, for 12 months.
Testosterone therapy had not been received by seven
patients previously. To ensure that the patients were
meeting the inclusion criteria, they underwent two
initial screening visits 42 and 21 days prior to
randomization. Only if serum testosterone was
!5 nmol/l on both occasions, patients were eligible
for inclusion. If medical history, physical examination,
and laboratory analysis at screening revealed evidence
of severe physical or mental illness, of alcohol or drug
abuse or of any contraindication against testosterone
treatment (such as severe lower urinary tract symp-
toms, suspected malignancy of the prostate, erythrocy-
tosis, heart/liver/kidney failure), patients were excluded
from participation in the study. All patients gave their
written informed consent for inclusion in the study. The
study protocols were approved by the Ethics Committee
of the University and the State Medical Board, Cologne,
The study medication (TU (Nebido) 1000 mg in
4 ml castor oil) and Testosteron-Depot JENAPHARM
Injektionslo ¨sung (TE 250 mg in 1 ml oily solution)
were manufactured by Jenapharm GmbH & Co., KG,
Jena, Germany. All i.m. injections were administered
into the gluteus medius muscle, starting on day 0. The
first four TU injections were given at two intervals of six
weeks, the following after an interval of nine weeks.
All following injections were given at 12-week in-
tervals (18). TE injections were administered at 3-week
intervals. Every three weeks during the comparison
study, patients presented for blood sampling and
assessment of individual study variables.
The patients were randomly assigned (using the SAS
software) for treatment with either TU i.m. (nZ20) or
TE i.m. (nZ20) for 30 weeks. There were no essential
differences between the two treatment groups regarding
age, body mass index, and baseline serum testosterone
After completing the comparison study, all 20
patients of the TU group and 16 patients of the TE
group agreed to participate in a follow-up study,
wherein all subjects were receiving long acting TU for
an additional 65 weeks. Three out of the four patients of
the TE group not included in the follow-up study with
TU did not consent to be included in a longer-term study
and one patient was excluded because of the study
protocol violations. Patients who had received TE
treatment earlier received the first two TU adminis-
trations with an interval of eight weeks, followed by
intervals of 12 weeks. Examinations during the follow-
up study were performed every three months, whereas
prostate and andrological status were assessed every
The testosterone preparations used in this study were
provided by Jenapharm GmbH & Co KG.
F Jockenho ¨vel and others
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
For the assessment of possible psychosexual effects
a standardized questionnaire published by Behre
co-workers (13) based on standardized questionnaires
(14, 15) was used to assess general mood and sexual
activity, as well as frequency of erections and
ejaculations and number of morning waking erec-
tions, sexual thoughts and fantasies, sexual interest
and desire, satisfaction with sexuality, as well as
questions of general well-being during the past
seven days. These data were collected for three
consecutive days before each clinic visit over the first
30 weeks of the study when the effects of TU were
compared with those of TE and also for a period of 65
weeks when all men received TU. Over the first 30
weeks of the study when TU was compared with TE,
the patients were asked to rate their state concerning
12 different items (sociability, concentration, agitation,
self-confidence, listlessness, dizziness, activation,
depression, fatigue, anxiety, good mood, and aggres-
sivity). The ratings were performed by the patients
using a 10 cm scale with two extremes designated
‘not at all’ and ‘very strong’. The subjects marked a
point between the two extremes. The ratings related to
sexual fantasies, sexual interest, and satisfaction with
sex life were recorded in the same way.
The answers were evaluated by measuring the
distance between the beginning of the line segment
(‘not at all’ and the mark made by the subject,
multiplying this value by 100 and dividing by the
length of the whole line segment, a method resemblinga
Likert-type scale, though points were not fixed.
The study was performed as an open, randomized,
controlled, 2-arm clinical study.
All patients who had taken one of the study prep-
arations and for whom data from the treatment phase
were available were included in the intention-to-treat
The statistical analysis was carried out by Jenapharm.
For this, the software package SAS for Windows NT,
Version 6.12 (Statistical Analysis System, SAS Institute,
Cary, NC, USA) was used.
Explorative and descriptive data analysis
The analysis was performed exploratively and descrip-
tively. All variables investigated within the frame of the
clinical study were included. Missing values were
evaluated as such and were not replaced by estimates.
Confidence intervals (95%) were calculated for selected
parameters. Data were displayed separately by exami-
nation time and treatment group. Confidence intervals
were determined for the difference between the two
treatment groups concerning the individual para-
meters, in order to compare the two treatments.
Table 1 Serum testosterone values (mean GS.D.) before and during administration of parenteral testosterone enanthate (TE) and
testosterone undecanoate (TU).
Weeks06 12 18 243045 6090
Table 2 Parameters of sexual behavior (ratings on sexual thoughts/fantasy, sexual interest/desire, satisfaction with sex life, number of
ejaculations and erections, total and spontaneous morning erections) in patients with hypogonadism at baseline and after 30 weeks of
treatment with testosterone enanthate(TE) and at baseline,after 30 weeks and 95 weeks of treatment with testosterone undecanoate (TU).
Parameter (distance on a
100 mm-VAS in mm)Screening Week 30Screening Week 30Week 95
Sexual interest and desire
Satisfaction with sex life
Number of ejaculations per week (total)
Number of erections per week (total)
Number of spontaneous morning
erections per week
VAS, visual analog scale.
*P!0.05 versus screening. Scores at week 95 not different from scores at week 30.
Testosterone, sexual functions and mood
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
Table 1 presents plasma testosterone values GS.D. over
the study period. Following administration of TE plasma
testosterone levels fluctuate strongly evidenced by the
large SDS of measured values. At baseline, scores of
sexual motivation and performance scores were similar
in both groups.
Intramuscular injections of both TU and TE improved
all assessed parameters on general mood and sexual
activity. There were no significant differences between
the two treatment modalities.
Assessed by a standardized questionnaire, there was a
in total erections and ejaculations (Table 1) per week
without significant differences between the two groups.
These good results were maintained throughout the
treatment with TU for the next 65 weeks. About 50% of
hypogonadal patients in the study had no erections and
ejaculations before testosterone administration. The
the androgen replacement therapy in both treatment
TU improved the ED in another two patients.
Also sexual thoughts and fantasies, sexual interest
and desire, and satisfaction with sex life (Table 2)
significantly increased during testosterone replacement
and continued to be improved significantly in the
follow-up with TU injections given in every 12 weeks.
Among the 12 items of subjective mood assessment,
agitation, self-confidence, activation, good mood and
concentration (Table 3) showed a significant improve-
ment during the treatment and further significant
improvement during follow-up with TU treatment.
The other items, i.e. sociability, listlessness, dizziness,
depression, fatigue, anxiety, and aggressivity (Table 3),
improved too, but not significantly. This tendency was
the same during the follow-up with treatment with TU.
Self-assessment scores of the parameters of well-being
were characterized by high variability. SD values were
especially high in screening data (between 19.3 and
32.3); in data obtained during week 30, SD values were
from 15.6 to 26.9.
This study of the relatively novel parenteral testoster-
one preparation TU compared, in the first instance,
effects on a number of androgen-related parameters of
sexual functions and mental functions with those of the
‘classical’ TE over a period of 30 weeks. The effects of
TU and TE were largely similar. Subsequently, mono-
therapy with TU was given for an additional 65 weeks
when gains in sexual functioning achieved with either
TU or TE over the first 30 weeks were maintained.
There were some differences in the improvement of
mental functions in the first 30 weeks of the study, when
the effects of TU were compared with those of TE. But
these differences were quantitatively small and mostly
based on the poorer initial scores of patients randomly
assigned to the TE group. So, scores of the group treated
with TE were poorer than the group treated with TU but
the groups were dissimilar with regard to baseline
scores preventing reliable conclusions as the superiority
of TU over TE in this regard or the converse.
This study report does not address safety issues of the
two types of parenteral testosterone administration;
these data have been published earlier (16, 17).
Administration of TU every 12 weeks is at least as
efficacious for treatment of sexual complaints of
hypogonadal men as TE. These improvements are
maintained in the longer-term. While being at least as
Table 3 Parameters of general well-being (VAS ratings on 12 items) in patients with hypogonadism at baseline and after 30 weeks of
treatment with testosterone undecanoate (TU) (four doses of 1000 mg) or testosterone enanthate (TE) (10 doses of 250 mg).
Parameter (distance on a
100 mm-VAS in mm) Screening Week 30Screening Week 30
*P!0.05 versus screening.
F Jockenho ¨vel and others
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
effective as the standard injectable formulation, treat-
ment with TU requires only four injections per year
while maintaining serum testosterone levels within the
physiological range. There are data to confirm the safety
and efficacy of long-term TU therapy in hypogonadal
patients treated over a period of more than eight years
(18). TU appears to be a safe modality of testosterone
treatment, because with the presently established
dosage regimen, plasma testosterone levels remain in
the physiological range. With TU, there is almost never
an occurrence of polycythemia as observed in studies
with the more traditional testosterone esters (19–21).
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 research did not receive any specific grant from any funding
agency in the public, commercial or not-for-profit sector.
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Investigation 2008 31
Received 29 January 2009
Accepted 15 February 2009
Testosterone, sexual functions and mood
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160