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Quality of Life and Sexual Function Benefits of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME)

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  • Private Institute for Urology, Andrology and Sexual Medicine , Hamburg, Germany

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Background: The benefits and risks of long-term testosterone administration have been a topic of much scientific and regulatory interest in recent years. Aim: To assess long-term quality of life (QOL) and sexual function benefits of testosterone replacement therapy (TRT) prospectively in a diverse, multinational cohort of men with hypogonadism. Methods: A multinational patient registry was used to assess long-term changes associated with TRT in middle-age and older men with hypogonadism. Comprehensive evaluations were conducted at 6, 12, 24, and 36 months after enrollment into the registry. Outcomes: QOL and sexual function were evaluated by validated measures, including the Aging Males' Symptom (AMS) Scale and the International Index of Erectile Function (IIEF). Results: A total of 999 previously untreated men with hypogonadism were enrolled at 25 European centers, 750 of whom received TRT at at least one visit during the period of observation. Patients on TRT reported rapid and sustained improvements in QOL, with fewer sexual, psychological, and somatic symptoms. Modest improvements in QOL and sexual function, including erectile function, also were noted in RHYME patients not on TRT, although treated patients showed consistently greater benefit over time in all symptom domains compared with untreated patients. AMS total scores for patients on TRT were 32.8 (95% confidence interval = 31.3-34.4) compared with 36.6 (95% confidence interval = 34.8-38.5) for untreated patients (P < .001). Small but significant improvements in IIEF scores over time also were noted with TRT. Approximately 25% of treated and untreated men also used phosphodiesterase type 5 inhibitors, with notable differences in the frequency of phosphodiesterase type 5 inhibitor prescription use according to physician specialty and geographic site location. Clinical implications: TRT-related benefits in QOL and sexual function are well maintained for up to 36 months after initiation of treatment. Strengths and limitations: The major strengths are the large, diverse patient population being treated in multidisciplinary clinical settings. The major limitation is the frequency of switching from one formulation to another. Conclusion: Overall, we confirmed the broad and sustained benefits of TRT across major QOL dimensions, including sexual, somatic, and psychological health, which were sustained over 36 months in our treatment cohort. Rosen RC, Wu F, Behre H, et al. Quality of Life and Sexual Function Benefits Effects of Long-Term Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME). J Sex Med 2017;XX:XXX-XXX.
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ORIGINAL RESEARCH
ENDOCRINOLOGY
Quality of Life and Sexual Function Benets of Long-Term Testosterone
Treatment: Longitudinal Results From the Registry of Hypogonadism in
Men (RHYME)
Raymond C. Rosen, PhD,
1
Frederick Wu, MD,
2
Hermann M. Behre, MD,
3
Hartmut Porst, MD,
4
Eric J. H. Meuleman, MD,
5
Mario Maggi, MD,
6
Javier Romero-Otero, MD, PhD,
7
Juan I. Martinez-Salamanca, MD, PhD,
8
Thomas Hugh Jones, MD,
9
Frans M. J. Debruyne, MD, PhD,
10
Karl-Heinz Kurth, MD,
11
Geoff I. Hackett, MD,
12
Richard Quinton, MD,
13
Peter Stroberg, MD,
14
Yacov Reisman, MD,
15
Edoardo S. Pescatori, MD,
16
Antonio Morales, MD,
17
Lluis Bassas, MD,
18
Natalio Cruz, MD,
19
Glenn R. Cunningham, MD,
20
and Olivia A. Wheaton,
1
for the RHYME Investigators
ABSTRACT
Background: The benets and risks of long-term testosterone administration have been a topic of much
scientic and regulatory interest in recent years.
Aim: To assess long-term quality of life (QOL) and sexual function benets of testosterone replacement therapy
(TRT) prospectively in a diverse, multinational cohort of men with hypogonadism.
Methods: A multinational patient registry was used to assess long-term changes associated with TRT in middle-
age and older men with hypogonadism. Comprehensive evaluations were conducted at 6, 12, 24, and 36 months
after enrollment into the registry.
Outcomes: QOL and sexual function were evaluated by validated measures, including the Aging Males
Symptom (AMS) Scale and the International Index of Erectile Function (IIEF).
Results: A total of 999 previously untreated men with hypogonadism were enrolled at 25 European centers, 750
of whom received TRT at at least one visit during the period of observation. Patients on TRT reported rapid and
sustained improvements in QOL, with fewer sexual, psychological, and somatic symptoms. Modest improve-
ments in QOL and sexual function, including erectile function, also were noted in RHYME patients not
on TRT, although treated patients showed consistently greater benet over time in all symptom domains
compared with untreated patients. AMS total scores for patients on TRT were 32.8 (95% condence
interval ¼31.3e34.4) compared with 36.6 (95% condence interval ¼34.8e38.5) for untreated patients
(P<.001). Small but signicant improvements in IIEF scores over time also were noted with TRT. Approx-
imately 25% of treated and untreated men also used phosphodiesterase type 5 inhibitors, with notable differences
Received December 14, 2016. Accepted July 1, 2017.
1
New England Research Institutes, Inc, Watertown, MA, USA;
2
University of Manchester, Central Manchester University Hospitals NHS
Foundation Trust, Centre for Endocrinology and Diabetes, Andrology
Research Unit, Manchester, UK;
3
Martin Luther University Halle-Wittenberg, Center for Reproductive
Medicine and Andrology, Halle, Germany;
4
Private Practice of Urology and Andrology, Hamburg, Germany;
5
VU University Medical Center, Amsterdam, The Netherlands;
6
University of Florence, Clinical Physiopathology, Andrology Unit, Florence,
Italy;
7
Hospital Universitario 12 de Octubre, Madrid, Comunidad de Madrid, Spain;
8
Hospital Universitario Puerta del Hierro Majadahonda, Madrid, Spain;
9
Barnsley Hospital NHS Foundation Trust, Barnsley, Barnsley, UK;
10
Andros Mens Health Institutes, Arnhem, The Netherlands;
11
Universiteit van Amsterdam, Amsterdam, The Netherlands;
12
Holly Cottage Clinic, Licheld, UK;
13
Institute of Genetic Medicine, University of Newcastle-upon-Tyne,
Newcastle-Upon-Tyne, UK;
14
Department of Surgical and Perioperative Sciences, Urology and Androl-
ogy. Umeå university, Umeå, Sweden;
15
Amstelland Hospital Amstelveen, The Netherlands;
16
Hesperia Hospital, Servizio di Andrologia, Modena, Italy;
17
Hospital Carlos Haya, Urology Plaza Hospital Civil s/n Malaga, Malaga,
Spain;
18
Fundació Puigvert, Barcelona, Spain;
19
Hospital Universitario Virgen del Rocio, Sevilla, Andalucía, Spain;
20
Baylor College of Medicine, Department of Medicine, Houston, TX, USA
Copyright ª2017, International Society for Sexual Medicine. Published by
Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jsxm.2017.07.004
1104 J Sex Med 2017;14:1104e1115
in the frequency of phosphodiesterase type 5 inhibitor prescription use according to physician specialty and
geographic site location.
Clinical Implications: TRT-related benets in QOL and sexual function are well maintained for up to 36
months after initiation of treatment.
Strengths and Limitations: The major strengths are the large, diverse patient population being treated in
multidisciplinary clinical settings. The major limitation is the frequency of switching from one formulation to another.
Conclusion: Overall, we conrmed the broad and sustained benets of TRT across major QOL dimensions,
including sexual, somatic, and psychological health, which were sustained over 36 months in our treatment
cohort. Rosen RC, Wu F, Behre H, et al. Quality of Life and Sexual Function Benets Effects of Long-Term
Testosterone Treatment: Longitudinal Results From the Registry of Hypogonadism in Men (RHYME).
J Sex Med 2017;14:1104e1115.
Copyright 2017, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Testosterone Replacement Therapy; Hypogonadism; Sexual Function; Quality of Life; Phospho-
diesterase Type 5 Inhibitors
INTRODUCTION
The decrease in serum testosterone (T) associated with
hypogonadism (HG) in men is typically accompanied by a
noticeable loss of sexual desire or libido, decreasing sexual
performance, and adverse changes in mood, energy, and
subjective well-being.
1e7
These common, bothersome symptoms
are the primary reason that increasing numbers of men around
the world currently seek T replacement therapy (TRT), in
addition to other potential clinical benets of treatment on
musculoskeletal and metabolic functions.
8e11
The role of HG in lower quality of life (QOL) and loss of
sexual interest or activity in men is well established. In the Eu-
ropean Male Aging Study,
12
well-dened sexual symptoms,
including loss of sexual desire, decreased frequency of sexual
thoughts, and absence of spontaneous or nocturnal erections,
were associated with lower levels of T in a large population of
3,300 men in eight European countries. Sexual symptoms were
similarly associated with below normal T levels in the Boston
Area Community Health (BACH) study, a large, population-
based survey of 1,389 US men.
1
Nearly 10% of men older
than 45 in the BACH sample had T deciency and low desire
and 15% had low T and erectile dysfunction (ED). An additional
14% had depressed mood symptoms and 15% had loss of
musculoskeletal strength or onset of frailty.
Findings from two recent large randomized placebo-controlled
trials conrmed signicant benets in restoration of sexual desire,
improved well-being, and other QOL benets of TRT. Signi-
cant improvements in sexual function and vitality were reported
in a large multicenter 12-week trial of daily topical TRT in men
with HG 55 years old on average,
13
and moderate improvements
in sexual activity and desire were reported after 52 weeks of TRT
in elderly men with HG in the T-Trial funded by the National
Institutes of Health.
14,15
In the latter study, a slight decrease in
sexual function was noted during the nal month of treatment.
15
The effects of long-term maintenance TRT on sexual function
and QOL have not been adequately evaluated in large
well-controlled studies. Persistent effects of TRT on sexual
function and QOL were reported recently in a single-center un-
controlled study of 261 patients with late-onset HG, all of whom
received T undecanoate (TU) injections for up to 5 years.
16
Clinically signicant improvements and sustained benets of
TRT were noted in this study across multiple domains of sexual
function and QOL, which were apparent in the rst 3 months of
treatment. These benets persisted across all QOL domains over
the average 5-year period of follow-up in this study.
The Registry of Hypogonadism in Men (RHYME) is a pro-
spective, multinational patient registry including a broad age
range of men with diagnosed HG, none of whom had prior
treatment with T, and all patients received extensive medical and
psychosocial evaluation at the time of enrollment.
17
The
RHYME study was designed primarily to evaluate safety out-
comes, including prostate safety and cardiovascular events and
mortality; these results have been reported elsewhere.
18,19
In the
present report, we present the secondary outcomes of the
RHYME on sexual function and QOL symptoms that were
assessed by validated and widely used symptom scales and were
analyzed as secondary outcomes.
17
The present report presents
longitudinal data on sexual function and QOL benets of TRT
in RHYME.
METHODS
RHYME is a prospective multinational patient registry of
treated and untreated men with HG implemented in 25 sites
across six European countries (Germany, Italy, Netherlands,
Spain, Sweden, and the United Kingdom). Countries were
selected to include northern and southern European countries, in
addition to those European countries with established reim-
bursement policies and sufcient numbers of andrology or
urology practices for effective management of patients. Clinical
site investigators included approximately equal numbers of
urologists (n ¼13) and endocrinologists or general physicians
(n ¼12) and were selected based on their experience and
J Sex Med 2017;14:1104e1115
Benets of Long-Term Testosterone Treatment 1105
familiarity with HG management guidelines and adequate
facilities and staff to participate in a large multinational patient
registry.
Eligibility criteria for registry participation included men at
least 18 years old with a diagnosis of HG conrmed by low T
levels on at least two occasions. The determination of low T was
made by the clinical site using local laboratory total T (TT)
values in most cases. Central laboratory assays were made avail-
able only to the data center (New England Research Institutes,
Inc, Watertown, MA, USA) and could not be accessed by site
physicians or study coordinators because of the non-
interventional nature and observational design of the study.
17
Central laboratory assays included TT measured by liquid
chromatography tandem mass spectrometry, SHBG, luteinizing
hormone, and prostate-specic antigen.
Patients were excluded if they had received prior treatment of
any T products or had a history of breast or prostate cancer, high-
grade prostatic intraepithelial neoplasia, radical prostatectomy, or
life expectancy shorter than 24 months as judged by the clinical
site investigator. Patients with major psychiatric disorders, drug
or alcohol abuse, or gender dysphoria also were excluded. All
eligible patients were enrolled consecutively, which decreased
selection bias. Once enrolled, patients and physicians made a
conjoint decision to initiate TRT; overall, 80% of patients chose
to initiate treatment. Patients were not required to record their
reasons for choosing or declining TRT.
Each patient enrolled was scheduled for at least four and up to
ve assessments over a minimum of 2 years starting at baseline
and then the following 3 to 6, 12, 24, and 36 months. Baseline
and follow-up data collection included complete medical history,
physical examination, blood sampling, and patient question-
naires (Figure 1). Data were collected through abstraction of
medical records and a self-administered questionnaire designed
to obtain information on demographic characteristics, lifestyle
factors (eg, smoking, physical activity), and other health infor-
mation. QOL was monitored at repeated visits by the Aging
Males Symptom (AMS) Scale, a validated 17-item QOL mea-
surement that has been used in previous studies of androgen
effects in aging men.
20,21
The AMS sexual symptom scale in-
cludes patient complaints of low desire, diminished potency, and
erection difculties, in addition to decreased beard growth. The
AMS psychological domain covers symptoms of depressed mood,
negative attitude, and irritability, and the somatic scale includes
symptoms of excessive sweating, sleep disturbance, and lack of
physical energy. The somatic scale is composed of seven items,
and the psychological and sexual scales are composed of ve
items each.
20,21
Subscale scores were computed independently
for the sexual, psychological, and somatic subscales of the AMS
20
and the AMS total score for overall QOL impact.
20,22
The In-
ternational Index of Erectile Function (IIEF), a multidimen-
sional scale of male sexual function, was administered at
successive study visits, and subscale scores were computed for the
two primary domains of erectile function (EF) and sexual
desire.
22
Lower urinary tract symptoms were monitored at every
visit by the International Prostate Symptom Score (IPSS); results
for this measurement are reported elsewhere.
18
Additional diagnostic tests or procedures, including prostate
biopsy or ultrasound tests, were requested by the treating
physician in consultation with the patient. This clinical decision-
making was intended to reect real-world clinical practice to
increase generalizability of the RHYME ndings, being consis-
tent with the non-interventional nature of a registry design. A
complete description of the RHYME trial design and method-
ology has been published previously.
17
Figure 1. Results from the Registry of Hypogonadism in Men measurement and visit schedule. AUASI ¼American Urological Association
Symptom Index; BPH ¼benign prostatic hyperplasia; DRE ¼digital rectal examination; ED ¼erectile dysfunction; IIEF ¼International
Index of Erectile Function; LH ¼luteinizing hormone; LUTS ¼lower urinary tract syndromes; PDE-5I ¼phosphodiesterase type 5 inhibitor;
PSA ¼prostate-specic antigen; T ¼testosterone.
J Sex Med 2017;14:1104e1115
1106 Rosen et al
The disposition of the RHYME cohort according to TRT
status is shown in Figure 2. Of the 1,006 patients enrolled, 7
were found ineligible, resulting in an analytic cohort of 999
patients. The treatment 71 patients was terminated during the
study, resulting in a patient retention rate of 92.9% over 3
years of follow-up. Reasons for early termination included
death, loss to follow-up, and withdrawal of consent. Approx-
imately 23,900 person-months were accrued, which repre-
sented 99.6% of the targeted follow-up period. All patients
provided written informed consent before enrollment. Registry
protocols were approved by local ethics committees at each
clinical site.
Statistical Analyses
Descriptive statistics, including mean or median, SD, and
frequency, were used to characterize the pretreatment charac-
teristics of our sample and to assess baseline differences between
those who went on to be treated with T vs those who were not
subsequently treated owing to patient or physician choice of
treatment options. To ensure the maximum opportunity for
capturing the effects of exposure to TRT, we considered par-
ticipants to be in the treatedgroup if treatment was initiated at
any follow-up visit. Conversely, untreated subjects did not
receive TRT at any time during the study.
Longitudinal mixed model analyses evaluated changes in QOL
and sexual function outcomes. These analyses modeled outcomes
according to the effects of TRT assignment and time in treat-
ment, in addition to interaction effects across time. T therapy
was treated as time-varying in the longitudinal model. Using
baseline measured covariates, multivariate modeling was per-
formed to control for confounders. All covariates were entered
into single multivariate models predicting each outcome. Those
with a Pvalue no higher than 0.2 in each model were selected as
nal covariates for the fully adjusted model. Covariates consid-
ered in the analyses included age, country, baseline comorbidity,
modied Charlson index score, duration of HG before
Figure 2. Consolidated Standards of Reporting Trials (CONSORT) diagram and patient disposition in the Registry of Hypogonadism in
Men.
J Sex Med 2017;14:1104e1115
Benets of Long-Term Testosterone Treatment 1107
treatment, body mass index, prior urologic or prostate diseases,
lower urinary tract symptoms, smoking, laboratory measure-
ments (cholesterol, TT, SHGB, luteinizing hormone, and
prostate-specic antigen), and certain medications (for hyper-
tension, diabetes, high cholesterol, ED, psychiatric disorders, and
benign prostate hyperplasia). SAS 9.3 (SAS Institute, Cary, NC,
USA) was used for statistical analyses.
RESULTS
Cohort Characteristics: Treated vs Untreated
Patients
Baseline characteristics of the RHYME participants are listed
in Table 1. The mean age of the cohort at baseline was 59.1 ±
10.5 years and mean baseline TT was 9.5 ±0.5 mol/L. Of the
999 patients enrolled with clinically diagnosed HG, 750 (75%)
received at least one prescription for TRT (treated) and 249
(25%) did not receive TRT in any form (untreated). TRT-
treated and untreated men did not differ in age, type of HG,
or other sociodemographic characteristics at baseline. Car-
diometabolic proles also were similar in the two groups before
TRT. Men who subsequently received TRT were more symp-
tomatic at baseline (mean AMS score ¼35.9 ±11.4 vs 41.4 ±
13.1 for TRT treated vs untreated men). Treated men also had
higher rates of ED before treatment compared with untreated
men (64.4% vs 56.2%), and the rate of other urologic diseases,
including benign prostate hyperplasia and Peyronie disease, were
higher in the TRT group (76.4% vs 67.9%). Gynecomastia was
noted in 11.1% of men in the TRT group before treatment
compared with 6.9% in the untreated group, although similar
rates were observed during the follow-up period (6.6% for
treated vs 7.1% for untreated men). None of the participants had
received prior TRT, as required by the RHYME eligibility
criteria, although frequent use of concomitant medications was
observed, including antihypertensive, antidiabetic, and lipid-
lowering medications (Table 1).
Treatment Effects on QOL and Sexual Function
AMS Total Symptom Score
Changes over time in AMS total symptom scores for treated
and untreated men are shown in Figure 3. Despite higher
baseline scores in the treated group, a decrease of approximately
7 points (11%) was maintained during the follow-up period for
men on TRT compared with 4.5 points (6%) for the untreated
men (Figure 3). For men who received T injections or pre-
scriptions on at least half of their study visits (n ¼566), the
average improvement in QOL scores was even greater to
approximately 8.0 points. Of consistently treated men, those
who began treatment with an injectable formulation showed a
trend toward slightly greater symptom decreases over time (31.9
vs 33.0), despite higher initial scores for the injectable group
(41.0 vs 37.6). Initial treatment with topical fomulations showed
a similar trend, although less pronounced.
Statistical modeling with longitudinal adjustment for cova-
riates demonstrated signicant treatment effects over time, with
signicantly less overall symptom benet in the untreated group;
men receiving TRT showed consistently greater symptom
decreases (lower score ¼fewer symptoms), beginning at 3 to 6
months and continuing for up to 3 years. This difference in
benet between treated and untreated patients was maintained
over time, despite higher baseline or pretreatment symptom
levels in patients subsequently assigned to TRT.
The treatment effect (TRT vs non-TRT) and treatment
time interaction were signicant (P<.001) in multivariate,
longitudinal analyses (Table 2). AMS scores were consistently
lower in the TRT than in the non-TRT condition, and this
difference was maintained throughout the follow-up period
(Figure 3). Treatment effects were similar for men with an initial
diagnosis of secondary HG (n ¼616) compared with the overall
cohort (N ¼999).
AMS Sexual Symptoms
Sexual symptoms were similarly improved in the two groups;
however, patients receiving TRT showed consistently greater
benet over time compared with untreated men (Figure 4).
Sexual symptom scores were lowered from the moderate to the
mild range in the two groups, although a signicant benetin
favor of the treated group was observed (P<.001). Treatment
effect and treatment time interactions were highly signicant
(P<.001; Table 2). A consistent difference in favor of TRT-
treated men was observed throughout the 3-year follow-up
period (Figure 4). Similar trends were observed for men with
an initial diagnosis of secondary HG and for consistent compared
with inconsistent TRT users. Sustained decreases in sexual
symptoms were similarly noted for those who initiated therapy
on injectable compared with topical agents.
AMS Psychological Symptoms Subscale
Signicant improvements in psychological symptoms
(eg, mood, energy) were similarly observed over time in the two
groups (P<.001), although the treated group showed signi-
cantly greater improvement overall in the adjusted model
compared with the untreated men (P<.001; Figure 5). Average
scores for psychological symptoms decreased from 9.4 ±1.2 to
8.1 ±0.6 for the treated group and from 9.1 ±1.1 to 7.8 ±0.9
for the untreated group. A signicant interaction of treatment
over time was observed (P<.007; Table 2).
AMS Somatic Symptoms Subscale
A signicant decrease was similarly observed in the somatic
symptom scores for treated vs untreated men in the adjusted
models and a marked decrease over time was seen in treated and
untreated patients (Figure 6). The two groups showed a decrease
from the moderate to the mild somatic symptom range, with a
change of 2.2 points on average in the treated group compared
with 1 point improvement in the untreated group (Figure 6). A
statistically signicant interaction of treatment by time also was
J Sex Med 2017;14:1104e1115
1108 Rosen et al
Table 1. Baseline characteristics of the Registry of Hypogonadism in Men participants
Baseline characteristic
All subjects combined TRT status
n
Overall cohort,
n (%) or
mean ±SD
Untreated
(n ¼249), n (%)
or mean ±SD
Treated
(n ¼750), n (%)
or mean ±SD Pvalue
Age 999 59.1 ±10.5 59.7 ±11.1 58.9 ±10.3 .30
Age group 999 .27
<60 y 516 (51.7) 121 (48.6) 395 (52.7)
60 y 483 (48.4) 128 (51.4) 355 (47.3)
Type of HG 751 .26
Primary HG (LH 7.6) 135 (18.0) 39 (20.7) 96 (17.1)
Secondary HG (LH <7.6) 616 (82.0) 149 (79.3) 467 (83.0)
BMI (kg/m
2
) 989 30.0 ±5.5 29.4 ±5.1 30.2 ±5.7 .04
Mean (median) time from HG diagnosis
to entry into registry (mo)
999 4.2 (0.4) ±16.6 4.3 (0.7) ±14.5 4.2 (0.3) ±17.2 .93
Past surgeries and therapy 999
Orchiectomy 27 (2.7) 1 (0.4) 26 (3.5) .01
Orchidopexy 18 (1.8) 4 (1.6) 14 (1.9) .76
Pituitary surgery 28 (2.8) 5 (2.0) 23 (3.1) .36
Radiotherapy 17 (1.7) 3 (1.2) 14 (1.9) .46
HG symptoms at time of diagnosis 999
Erectile dysfunction 622 (62.3) 140 (56.2) 482 (64.4) .02
Decreased desire for sex 116 (11.6) 26 (10.4) 90 (12.0) .49
Fatigue, weakness, decreased strength 100 (10.0) 36 (14.5) 64 (8.5) .01
AMS score 975 40.1 ±13 35.9 ±11.4 41.4 ±13.1 <.0001
Infertility 39 (3.9) 18 (7.2) 21 (2.8) <.01
Gynecomastia 979 98 (10.0) 17 (6.9) 81 (11.1) .06
Chronic diseases or comorbidities at baseline 999
Urologic disease*742 (74.3) 169 (67.9) 573 (76.4) .01
Endocrine disease 532 (53.3) 129 (51.8) 403 (53.7) .60
Cardiovascular disorder 515 (51.6) 125 (50.2) 390 (52.1) .60
Pulmonary disease 130 (13.0) 29 (11.6) NA
Psychiatric disease 151 (15.1) 24 (9.6) 127 (16.9) .01
Top 5 concomitant medications at baseline 999
Antihypertensive medications 495 (49.5) 119 (47.8) 376 (50.1) .53
Lipid-lowering medications 391 (39.1) 89 (35.7) 302 (40.3) .20
Antidiabetes medications 257 (25.7) 65 (26.1) 192 (25.6) .88
Erectile dysfunction medications 253 (25.3) 60 (24.1) 193 (25.7) .62
Peptic ulcer medications 180 (18.0) 41 (16.5) 139 (18.5) .48
LUTS severity (based on IPSS score) 980 .87
None to mild (<8) 584 (59.6) 148 (61.7) 436 (58.9)
Moderate (8e19) 308 (31.4) 73 (30.4) 235 (31.8)
Severe (20) 88 (9.0) 19 (7.9) 69 (9.3)
Erectile dysfunction (based on IIEF score) 981 <.01
None to mild (22) 343 (35.0) 104 (43.5) 239 (32.2)
Moderate to severe (<22) 638 (65.0) 135 (56.5) 503 (67.8)
Past prostate biopsy examinations 999 37 (3.7) 18 (7.2) 19 (2.5) <.001
Past DRE 999 774 (77.5) 181 (73.0) 593 (79.1) .05
Abnormal result 774 195 (25.2) 57 (31.5) 138 (23.3) .03
Male kin with prostate cancer 987 56 (5.7) 18 (7.3) 38 (5.1) .19
AMS ¼Aging MalesSymptoms Scale; BMI ¼body mass index; DRE ¼digital rectal examination; HG ¼hypogonadism; IIEF ¼International Index of Erectile
Function; IPSS ¼International Prostate Symptom Score; LH ¼luteinizing hormone; LUTS ¼lower urinary tract symptoms; NA ¼??; TRT ¼testosterone
replacement therapy.
*Includes ejaculatory disorder, erectile dysfunction, Peyronies Disease, BPH, prostatitis and testicular cancer.
J Sex Med 2017;14:1104e1115
Benets of Long-Term Testosterone Treatment 1109
seen for this measurement (ie, fewer somatic symptoms in the
treated group over time). Similar to the psychological symptoms
score, adjusted means showed somatic symptoms to be consis-
tently improved in treated compared with untreated patients,
despite higher baseline scores in the treated group. Of note, a
relatively slight increase in somatic symptoms was observed in
the untreated group during the last year of follow-up compared
with treated men who maintained their improvement over time
(Figure 6).
IIEF EF Domain
EF domain scores showed similar trends in favor of TRT
(P<.001) after multivariate analysis accounting for age, body
mass index, concomitant medications, and other covariates
(Figure 7). EF increased approximately 0.1% per month in the
treated group, with a small but signicant effect on adjusted
means (P<.001; Table 2). A borderline statistically signicant
interaction of treatment and time was noted for EF domain
scores, with a trend toward greater improvement in EF in men
on TRT over time. Overall, mean domain scores for the EF scale
were 18.9 in treated men vs 17.0 in untreated men (Table 2),
despite lower initial EF scores in patients subsequently receiving
TRT (Figure 7).
IIEF Sexual Desire Domain
A similar pattern of positive response to TRT was seen in
results for sexual desire scores, as shown by the sexual desire
domain scores from the IIEF scale (Figure 8). Treated patients
showed a signicant improvement on this measurement during
the rst 6 months of TRT, which was sustained for the following
24 to 36 months. Signicant differences, although small in
magnitude (10% in treated men, 7% in untreated men), were
observed, although the relative improvement during treatment
for the TRT group was highlighted by near-identical mean sexual
desire scores in the two groups before treatment (Figure 8).
Use of Phosphodiesterase Type 5 Inhibitors
Approximately 25% of men in the two groups were regular
users of phosphodiesterase type 5 inhibitors (PDE-5Is) at
enrollment and most continued to use PDE-5Is during the
course of the RHYME. Signicant variations in the frequency of
PDE-5I use were associated primarily with treating physician
specialty (c
2
¼50.8, P<.0001) and clinical site location (c
2
¼
65.6, P<.0001). As shown in Figures 9A and 9B, PDE-5Is
were prescribed more frequently by urologists (35.9%)
compared with endocrinologists or general practitioners (16.1%).
The largest percentage of PDE-5I prescriptions was administered
to RHYME patients in Spain (44.2%), which also had a high
representation of urologic sites (four of ve).
DISCUSSION
The results of this prospective, multinational HG clinical
outcomes registry provide further evidence of sustained and
consistent benets of TRT in improving long-term QOL and
sexual function in a large, diverse cohort of men with HG,
17
ndings in accord with outcomes reported in recent random-
ized controlled trials.
13e15
The consistency of these effects across
trials and studies, treatment groups, and different outcome
measures is robust and compelling. In particular, sexual desire or
activity measures in these studies showed the same signicant,
albeit relatively modest, magnitude of change with treatment. EF
was improved, but only marginally, by TRT, after controlling for
the effects of concomitant medications and comorbidities. Other
non-sexual QOL outcomes showed greater degrees of improve-
ment, despite differences in the types of TRT administered and
study populations.
In general, RHYME participants who received TRT at at least
one treatment visit showed consistent, sustained symptom
improvement compared with untreated patients over the course
of the RHYME. These benets and improvements in psycho-
logical, sexual, and somatic symptoms were evident as soon as 3
to 6 months after initiation of treatment and persisted over the
course of 36 months of follow-up. More modest symptom im-
provements also were noted in RHYME patients not receiving
TRT, which might have been due to non-specic effects of
scheduled contact with medical staff at participating sites or more
specic effects of active management of concomitant medical
conditions (approximately 25% had diabetes and approximately
50% had hypertension) and the use of concomitant medications
(25% were prescribed PDE-5Is and 20% used a-blockers) or
recommended lifestyle changes (eg, decreased stress, weight loss).
Despite similarities in health status and medical management
across the two patient groups, patients on TRT showed consis-
tently greater symptom improvement on all QOL component
measurements. These symptom benets persisted over a strictly
monitored 36-month follow-up period.
It should be noted that treated patients were more symp-
tomatic and had a higher prevalence of ED before treatment, on
average, and were more likely to have concomitant urologic or
Figure 3. Total AMS symptom scores over time: treatment effects
in adjusted longitudinal models. *P<.001 (see Table 2 for complete
longitudinal results). Data are presented as adjusted geometric
mean ±standard error of the mean (negative change ¼improve-
ment). AMS ¼Aging MalesSymptom Scale. Figure 3 is available
in color at www.jsm.jsexmed.org.
J Sex Med 2017;14:1104e1115
1110 Rosen et al
Table 2. Complete longitudinal results
Effect
AMS total score
(n ¼566)*
AMS sexual symptoms
score (n ¼845)
AMS psychological
symptoms score
(n ¼630)
AMS somatic symptoms
score (n ¼859)
§
IIEF erectile function
score (n ¼671)
k
IIEF sexual desire function
score (n ¼904)
{
Change,
%
#
CI
P
value
Change,
%
#
CI
P
value
Change,
%
#
CI
P
value
Change,
%
#
CI
P
value
Change,
%
#
CI
P
value
Change,
%
#
CI Pvalue
TRT 13.6 15.6 to
11.6
<.001 18.8 20.9 to
16.6
<.001 9.4 12.0 to
6.8
<.001 11.9 14.0 to
9.7
<.001 2.5 1.8e3.1 <.001 0.9 0.8e1.1 <.001
Time 0.4 0.6 to
0.3
<.001 0.5 0.6 to
0.3
<.001 0.4 0.6 to
0.2
<.001 0.3 0.5 to
0.2
<.001 0.1 0.0e0.1 <.001 0.0 0.0e0.0 .002
TRT time 0.3 0.1e0.5 <.001 0.4 0.2e0.6 .001 0.3 0.1e0.5 .007 0.3 0.1e0.5 .005 0.1 0.1 to
0.0
<.06 0.0 0.0 to
0.0
.008
TRT at any
visit
GM CI GM CI GM CI GM CI GM CI GM CI
Yes 32.8 31.3e34.4 9.7 9.2e10.3 8.3 7.8e8.9 13.5 12.9e14.3 18.9 17.3e20.4 6.8 6.5e7.1
No 36.6 34.8e38.5 11.5 10.9e12.2 8.9 8.3e9.5 14.9 14.1e15.7 17.0 15.4e18.6 6.0 5.7e6.4
AMS ¼Aging MalesSymptoms Scale; BMI ¼body mass index; CI ¼95% condence interval; GM ¼geometric mean; HG ¼hypogonadism; IIEF ¼International Index of Erectile Function;
TRT ¼testosterone replacement therapy.
*Signicant covariates for total AMS score: visit (P<.0001), treatment visit (P¼.17), BMI (P<.0001), age (P¼.03), country (P<.001), HG type (primary vs secondary; P¼.03), daily hard physical work
(P¼.10), smoking history (P¼.03), self-reported health (P<.001), previous urologic disorder (P¼.04), current psychiatric disorder (P<.001), and psychiatric disorder medications (P<.001).
Signicant covariates for AMS sexual symptoms score: treatment status (P¼.14), visit (P<.001), treatment visit (P¼.004), age (P<.001), BMI (P¼.02), country (P¼.001), months from HG
diagnosis (P¼.11), daily hard physical work (P¼.04), smoking history (P¼.01), self-reported health (P<.001), previous urologic disorder (P<.001), and psychiatric disorder medications (P<.001).
Signicant covariates for AMS psychological symptoms score: treatment status (P¼.02), visit (P¼.0002), age (P¼.01), BMI (P<.001), and HG type (primary vs secondary; P¼.01).
§
Signicant covariates for AMS somatic symptoms score: visit (P<.001), age (P¼.18), BMI (P<0.001), country (P<.001), months from HG diagnosis (P¼.18), daily hard physical work (P¼.17), HG type
(primary vs secondary; P¼.04), self-reported health (P<.001), current psychiatric disorder (P<.001), and psychiatric disorder medications (P¼.006).
k
Signicant covariates for IIEF erectile function score: treatment status (P¼.004), visit (P<.001), treatment visit (P¼.07), age (P<.001), modied Charlson index (P¼.001), country (P<.001), site
specialty (P<.001), daily hard physical work (P¼.08), self-reported health (P<.001), family history of prostate cancer (P¼.18), previous urologic disease (P¼.005), current psychiatric disorder (P¼.10) ,
erectile dysfunction medications (P¼.02), psychiatric disorder medications (P¼.006), and lipid-lowering medications (P¼.02).
{
Signicant covariates for IIEF sexual desire function score: treatment status (P¼.03), visit (P<.001), age (P¼.04), BMI (P¼.05), country (P¼.01), daily hard physical work (P¼.004), self-reported
health (P<.001), family history of prostate cancer (P¼.005), and psychiatric disorder medications (P¼.02).
#
The value presented represents the percentage of change for a 1-U increase in the effect. This is calculated by: (exp[b]e1) 100.
J Sex Med 2017;14:1104e1115
Benets of Long-Term Testosterone Treatment 1111
psychiatric conditions, infertility, or past prostate biopsies. It is
unclear what effect, if any, these concomitant conditions or
medical histories might have had on the outcome of TRT,
although the benets in symptom improvement were clearly
evident despite these baseline differences. Treated patients were
slightly more overweight on average before treatment, although
this difference failed to reach statistical signicance. Differences
between patients treated with injectable TRT and those receiving
topical formulations also failed to reach statistical signicance in
adjusted models.
Large and sustained QOL benets have been reported recently
in a single-center HG treatment registry by Almehmadi et al
16
using the same symptom measures (AMS, IIEF, IPSS) as those
used in the RHYME.
17
Our results are broadly similar and
showed benets similar to those reported in this long-term (ie,
5-year) observational study of long-acting TU injection therapy
in 261 patients with adult-onset HG. Patients in the Almehmadi
et al
16
study were more symptomatic before TRT than RHYME
patients,
17
with AMS total symptom scores higher than 50
before treatment, which improved by at least 20 points over
5 years of TU injections. Moreover, these effects were found to
be reversible when TRT was withdrawn for approximately 18
months and then to largely recover when TRT was
reinstated.
23,24
In contrast, in our RHYME cohort, mean AMS total scores
were lower than 40 before treatment (ie, patients were less
symptomatic), and scores improved by approximately 20% to
25% of baseline values of AMS total and sexual symptoms
subscale scores, in addition to subscale scores on the sexual desire
domain of the IIEF. Similar thresholds of benet have been
established for voiding and male sexual disorders.
25,26
Moreover,
our results were consistent across outcome measurement
domains and individual measurements, although the magnitude
of change associated with TRT in the RHYME was less
Figure 4. Total Aging MalesSymptom Scale sexual symptom
scores over time: treatment effects in adjusted longitudinal models.
*P¼.001 (see Table 2 for complete longitudinal results). Data are
presented as adjusted geometric mean ±standard error of the
mean (negative change ¼improvement). Figure 4 is available in
color at www.jsm.jsexmed.org.
Figure 5. Aging MalesSymptom Scale psychological symptoms:
treatment effects in adjusted longitudinal models. *P¼.007 (see
Table 2 for complete longitudinal results). Data are presented as
adjusted geometric mean ±standard error of the mean (negative
change ¼improvement). Figure 5 is available in color at www.jsm.
jsexmed.org.
Figure 6. Aging MalesSymptom Scale somatic symptoms over
time: treatment effects in adjusted longitudinal models. *P¼.005
(see Table 2 for complete longitudinal results). Data are presented
as adjusted geometric mean ±standard error of the mean
(negative change ¼improvement). Figure 6 is available in color at
www.jsm.jsexmed.org.
Figure 7. International Index of Erectile Function erectile function
score over time: treatment effects in adjusted longitudinal models.
*P<.06 (see Table 2 for complete longitudinal results). Data are
presented as adjusted geometric mean ±standard error of the
mean (negative change ¼improvement). Figure 7 is available in
color at www.jsm.jsexmed.org.
J Sex Med 2017;14:1104e1115
1112 Rosen et al
pronounced than the 50% level of improvement reported by
Almehmadi et al.
16
The higher dysfunctional baseline scores in
that study, extended duration of treatment (5 vs 2e3 years), and
highly consistent application of TRT with scheduled adminis-
tration of long-acting TU injections in the physiciansofce
producing 100% compliance in the study by Almehmadi et al
16
are likely factors accounting for the greater degree of symptom
benet observed in that study compared with ours. In the
RHYME, a broad range of oral, injectable, and topical TRT
formulations was administered for different periods and switch-
ing between formulations occurred. For these reasons, we could
not correlate individual treatment benets to specic formula-
tions of TRT in the RHYME.
Despite different TRT formulations and dosages and switch-
ing between formulations, the present study could conrm the
broad and sustained benets of TRT across major QOL
dimensions, including sexual, somatic, and psychological health,
which were maintained over 36 months in our treatment cohort.
Of note, the most substantial symptom benet was observed in
the somatic symptom domain, which includes seven somatic
complaints related to HG, such as excessive sweating, disturbed
sleep, and physical weakness. Modest, sustained improvements in
lower urinary tract symptoms also were seen in patients on TRT
in the RHYME, as reported elsewhere.
18
We could not show a
statistical advantage for the injectable compared with topical
formulations of TRT on QOL outcomes, although treatment
disconintuations, switching from one TRT formulation or dose
to another, concomitant uncontrolled use of PDE-5Is, and other
factors might have obscured differences between formulations or
dosages. It should be noted that the study was not designed or
powered to compare one form of TRT with another, but to
evaluate the overall risks and benets of TRT.
EF scores showed improvements in the predicted direction,
although the magnitude of improvement in EF was markedly less
than that reported by Almehmadi et al.
16
Patients with adult-
onset HG in that study had average EF domain score improve-
ments higher than 10 points from baseline during the course of
5 years of treatment with long-acting TU injections.
16
Signi-
cant, but more modest, improvements of at least four points in
EF scores were seen during 2 to 3 years of mixed TRT therapy in
the RHYME.
In contrast, the level of improvement in EF scores observed in
the RHYME is similar to results reported recently from the
12-month randomized National Institutes of Health trial
(T-Trials) of topical T in men with HG older than 65 years.
14,15
In this multicenter, randomized placebo-controlled trial,
12 months of topical TRT resulted in consistent, clinically
meaningful improvements in sexual activity and desire, but less
improvement in EF, as measured similarly by the EF domain of
the IIEF.
22
Fewer than 10% of patients in the trial by Snyder
et al
14
received concomitant PDE-5s during the 12-month
period of treatment compared with 25% of patients in the
RHYME, although the amount of improvement in EF scores was
roughly similar across the two studies.
Other studies have reported similar QOL and sexual function
benets of TRT using alternative outcome measurement. For
example, signicant QOL benets of daily topical TRT were
observed with 16 weeks of TRT administration in another recent
double-blinded randomized trial.
13
Signicant improvements in
Figure 8. International Index of Erectile Function sexual desire
scores over time: treatment effects in adjusted longitudinal models.
*P¼.008 (see Table 2 for complete longitudinal results). Data are
presented as adjusted geometric mean ±standard error of the
mean (negative change ¼improvement). Figure 8 is available in
color at www.jsm.jsexmed.org.
Figure 9. Panel shows phosphodiesterase type 5 inhibitor use by specialty. Panel B shows phosphodiesterase type 5 inhibitor use by country. DE ¼
Germany; ES ¼Spain; IT ¼Italy; NE ¼Netherlands; SE ¼Sweden; UK ¼United Kingdom. Figure 9 is available in color at www.jsm.jsexmed.org.
J Sex Med 2017;14:1104e1115
Benets of Long-Term Testosterone Treatment 1113
patients on topical TRT were observed on a new self-report
meausrement of sex drive and energy, in addition to a vali-
dated new hypogonadal energy diary.
13
Based on changes in
these novel measurements, signicant improvements in QOL
and sexual function were observed after 16 weeks of topical TRT
compared with placebo. It is not possible to compare the
magnitude of effects in this study
13
directly with results from the
RHYME or other recent studies
16,24
because of differences in
design, duration of treatment, and outcome measurements used.
Nevertheless, the overall pattern and direction of effects is
similar across all recent TRT trials and registries,
13,14,16
despite
the highly diverse patient populations, including those with
functional(as opposed to classic or pathologic) HG associated
with multiple comorbidities and concomitant therapies, such as
those in the RHYME. Taken together, the present ndings and
those from other recent studies
13,14,16
strongly support the view
that sustained and clinically important benets in QOL (espe-
cially related to sexual and physical function) can be achieved by
TRT in patients with HG irrespective of the hypogonadal eti-
ology and a patients age or health status.
Given the ongoing controversies regarding the overall risk and
benet of TRT,
10,27,28
it is especially important to document
meaningful benets of TRT, as recommended by the Institute of
Medicines report on TRT in 2004.
29
The RHYME study,
unlike other HG registries or uncontrolled observational studies,
provides data for comparison of TRT effects with outcomes for
an untreated group at the same study sites, albeit without
randomization or double-blinded controls. Most importantly,
our data show consistent improvements across measurements,
over time, and across treatment conditions in TRT-treated men
compared with a similar group of patients treated without TRT.
This adds substantial weight to the positive results from recent
large-scale trials and registries showing clinically meaningful,
sustained QOL benets for men receiving TRT by topical or
injection formulations. Further studies are needed to determine
which patients are more or less likely to show sustained QOL
benets with TRT and to examine systematically the use of
combined therapy with PDE-5Is, antidepressant agents, or life-
style changes. In the meantime, our ndings provide strong
support for clinicians who use TRT regularly to improve QOL
and sexual function in middle-age and older patients with HG.
ACKNOWLEDGMENTS
We gratefully acknowledge the outstanding contributions of
the RHYME investigators at the following sites: University of
Florence, Italy, M. Maggi; University Hospital Halle, Germany,
H.M. Behre; VU University Medical Center, Netherlands, E.
Meuleman; Erasmus MC Rotterdam, Netherlands, G. Dohle;
Karolinska University Hospital, Sweden, S. Arver; Manchester
Royal Inrmary, UK, F. Wu; Private Practice of Urology and
Andrology, Germany, H. Porst; Barnsley Hospital NHS Foun-
dation Trust, UK, T.H. Jones; Institute of Genetic Medicine,
University of Newcastle-upon-Tyne, UK, R. Quinton; Sapienza
University of Rome, Italy, A. Lenzi; Royal Free Hampstead
NHS, UK, P.-M. Bouloux; Carlos Haya University Hospital,
Spain, A.M. Morales; Holly Cottage Clinic, UK, G. Hackett;
Urohälsan i Skövde, Sweden, P. Stroberg; University of Parma,
Italy, M. Maggio; Hospital Virgen del Rocio, Spain, N. Cruz;
Ospediali RiunitieAncona, Italy, G. Balercia; Segeberger Kli-
niken, Germany, A. Yassin; Amstelland Hospital, Netherlands,
C. Reisman; Fundació Puigvert, Barcelona, ES Spain, L. Bassas;
Hesperia Hospital, Italy, E. Pescatori; Hospital Universitario
Puerta de Hierro-Majadahonda, Spain, J.I. Martinez Salamanca;
Hospital Universitario 12 Octubre, Spain, J. Romero Otero;
Evangelisches Krankenhaus Herne, Germany, F. Jockenhoevel;
Andros Mens Health Institutes, Netherlands, F. Debruyne.
Valuable technical support was provided by Dr Farid Saad, Dr
Albert Radlmeyer, and Dr Anders Mattern at Bayer. Juli Martha,
Madhavi Kamma, Blandyna Williams, and other New England
Research Institutes research staff also provided valuable technical
and administrative support for the study.
Corresponding Author: Raymond C. Rosen, PhD, New
England Research Institutes, 480 Pleasant Street, Watertown,
MA 02472, USA. Tel: 617-972-3383; Fax: 617-926-0144;
E-mail: RRosen@neriscience.com
Conicts of Interest: The authors report no conicts of interest.
Funding: Support for the RHYME was provided by Bayer
Healthcare.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Raymond C. Rosen; Frederick Wu; Hermann Behre; Hartmut
Porst; Eric J.H. Meuleman; Mario Maggi; Glenn R. Cunningham
(b) Acquisition of Data
Raymond C. Rosen; Frederick Wu; Hermann Behre; Hartmut
Porst; Eric J.H. Meuleman; Mario Maggi; Javier Romero Otero;
Juan Ignacio Salamanca; Thomas Hugh Jones; Frans M.J.
Debruyne; Karl-Heinz Kurth; Geoff Ian Hackett; Richard
Quinton; Peter Stroberg; Yacov Reisman; Edoardo S. Pescatori;
Antonio Morales; Lluis Bassas; Natalio Cruz; Olivia A. Wheaton
(c) Analysis and Interpretation of Data
Raymond C. Rosen, Frederick Wu, Hermann Behre, Olivia A.
Wheaton; Glenn R. Cunningham
Category 2
(a) Drafting the Article
Raymond C. Rosen; Frederick Wu; Hermann Behre; Eric J.H.
Meuleman;Mario Maggi; Glenn R. Cunningham; Olivia A.Wheaton
(b) Revising It for Intellectual Content
Raymond C. Rosen; Frederick Wu; Hermann Behre; Hartmut
Porst; Eric J.H. Meuleman; Mario Maggi; Javier Romero Otero;
Juan Ignacio Salamanca; Thomas Hugh Jones; Frans
M.J. Debruyne; Karl-Heinz Kurth; Geoff Ian Hackett; Richard
Quinton; Peter Stroberg; Yacov Reisman; Edoardo S. Pescatori;
Antonio Morales; Lluis Bassas; Natalio Cruz; Glenn R.
Cunningham; Olivia A. Wheaton
J Sex Med 2017;14:1104e1115
1114 Rosen et al
Category 3
(a) Final Approval of the Completed Article
All authors
REFERENCES
1. Hall SA, Araujo AB, Esche GR, et al. Treatment of symptomatic
androgen deciency: results from the Boston Area Community
Health Survey. Arch Intern Med 2008;168:1070-1076.
2. OConnor DB, Lee DM, Corona G, et al. The relationships
between sex hormones and sexual function in middle-aged
and older European men. J Clin Endocrinol Metab 2011;
96:E1577-E1587.
3. Gray PB, Singh AB, Woodhouse LJ, et al. Dose-dependent
effects of testosterone on sexual function, mood, and visuo-
spatial cognition in older men. J Clin Endocrinol Metab 2005;
90:3838-3846.
4. Brooke JC, Walter DJ, Kapoor D, et al. Testosterone deciency
and severity of erectile dysfunction are independently associ-
ated with reduced quality of life in men with type 2 diabetes.
Andrology 2014;2:205-211.
5. Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D.
Bioavailable testosterone and depressed mood in older men:
the Rancho Bernardo Study. J Clin Endocrinol Metab 1999;
84:573-577.
6. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal
steroids and body composition, strength, and sexual function
in men. N Engl J Med 2013;369:1011-1022.
7. Cunningham GR, Stephens-Shields AJ, Rosen RC, et al.
Association of sex hormones with sexual function, vitality, and
physical function of symptomatic older men with low testos-
terone levels at baseline in the testosterone trials. J Clin
Endocrinol Metab 2015;100:1146-1155.
8. Shores MM, Moceri VM, Sloan KL, et al. Low testosterone
levels predict incident depressive illness in older men: effects
of age and medical morbidity. J Clin Psychiatry 2005;66:7-14.
9. Gannon JR, Walsh TJ. Testosterone and sexual function. Urol
Clin North Am 2016;43:217-222.
10. Hackett G. An update on the role of testosterone replacement
therapy in the management of hypogonadism. Ther Adv Urol
2016;8:147-160.
11. Corona G, Rastrelli G, Maggi M. Diagnosis and treatment of
late-onset hypogonadism: systematic review and meta-
analysis of TRT outcomes. Best Pract Res Clin Endocrinol
Metab 2013;27:557-579.
12. Wu F, Tajar A, Beynon J, et al. Identication of late-onset
hypogonadism in middle-aged and elderly men. N Engl
J Med 2010;363:123-135.
13. Brock G, Heiselman D, Maggi M, et al. Effect of testosterone
solution 2% on testosterone concentration, sex drive and en-
ergy in hypogonadal men: results of a placebo controlled
study. J Urol 2016;195:699-705.
14. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of
testosterone treatment in older men. N Engl J Med 2016;
374:611-624.
15. Cunningham GR, Stephens-Shields AJ, Rosen RC, et al.
Testosterone treatment and sexual function in older men with
low testosterone levels. J Clin Endocrinol Metab 2016;
101:3096-3104.
16. Almehmadi Y, Yassin AA, Nettleship JE, et al. Testosterone
replacement therapy improves the health-related quality of life
of men diagnosed with late-onset hypogonadism. Arab J Urol
2016;14:31-36.
17. Rosen RC, Wu FC, Behre HM, et al. Registry of Hypogonadism
in Men (RHYME): design of a multi-national longitudinal,
observational registry of exogenous testosterone use in
hypogonadal men. Aging Male 2013;16:1-7.
18. Debruyne F, Behre HM, Roehrborn CG, et al. Testosterone
treatment is not associated with increased risk of prostate
cancer or worsening of lower urinary tract symptoms: prostate
health outcomes in the Registry of Hypogonadism in Men.
BJU Int 2017;119:216-224.
19. Maggi M, Wu FCW, Jones TH, et al. Testosterone treatment is
not associated with increased risk of adverse cardiovascular
events: results from the Registry of Hypogonadism in Men
(RHYME). Int J Clin Pract 2016;70:843-852.
20. Heinemann LAJ, Zimmermann T, Vermeulen A, et al. A new
Aging Males Symptoms(AMS) rating scale. Aging Male
1999;2:105-114.
21. Heinemann LA, Thiel C, Assmann A, et al. Sex differences in
climacteric symptomswith increasing age? A hypothesis-
generating analysis of cross-sectional population surveys.
Aging Male 2000;3:124-131.
22. Rosen RC, Riley A, Wagner G, et al. The International Index of
Erectile Function (IIEF): a multidimensional scale for assess-
ment of erectile dysfunction. Urology 1997;49:822-830.
23. Saad F, Yassin A, Doros G, et al. Effects of long-term
treatment with testosterone on weight and waist size in
411 hypogonadal men with obesity classes IeIII: observational
data from two registry studies. Int J Obes 2016;40:162-170.
24. Yassin A, Nettleship JE, Talib RA, et al. Effects of testosterone
replacement therapy withdrawal and re-treatment in hypo-
gonadal elderly men upon obesity, voiding function and
prostate safety parameters. Aging Male 2016;19:64-69.
25. Gotoh M, Homma Y, Yokoyama O, et al. Responsiveness and
minimal clinically important change in overactive bladder
symptom score. Urology 2011;78:768-773.
26. Rosen RC, Allen KR, Ni X, et al. Minimal clinically important
differences in the erectile function domain of the Interna-
tional Index of Erectile Function Scale. Eur Urol 2011;
60:1010-1016.
27. Kava BR. To treat or not to treat with testosterone replace-
ment therapy: a contemporary review of management of late-
onset hypogonadism and critical issues related to prostate
cancer. Curr Urol Rep 2014;15:422.
28. Grech A, Breck J, Heidelbaugh J. Adverse effects of testos-
terone replacement therapy: an update on the evidence and
controversy. Ther Adv Drug Saf 2014;5:190-200.
29. Liverman C, Blazer D, eds. Testosterone and aging. Clinical
research directions. Washington, DC: The National Academies
Press; 2004.
J Sex Med 2017;14:1104e1115
Benets of Long-Term Testosterone Treatment 1115
... IHH patients suffer from multi-causal and multidimensional sexual dysfunction [11,12,15,30,31]. Sexual activity seems to be one of the main concerns for subjects with hypogonadism [12,32]. ...
... p = 0.88), compared to ED in a third of male controls in this study. A small but statistically significant increase in erectile function in a multinational population of middle-aged and older hypogonadal men on TRT was shown by Rosen et al. [31]. In contrast to our study, Georgopoulos et al. noted that GnRHdeficient males on HRT, with testosterone values within the normal range, reported similar erectile function in IIEF as healthy, age-matched individuals when results were adjusted for anxiety and depression (p = 0.127) [29]. ...
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(1) Background: Isolated hypogonadotropic hypogonadism (IHH) is a genetic condition characterized by impaired puberty and fertility. IHH can significantly impact patient health-related quality of life (HRQoL), sexual satisfaction (SS) and mood. (2) Methods: Participants included 132 IHH subjects (89 men and 43 women) and 132 sex- and age-matched controls. HRQoL, depressive symptoms, erectile dysfunction (ED), and SS were assessed in an online survey using the Zung Self-Rating Depression Scale (SDS), 15D instrument of HRQoL (15D), Sexual Satisfaction Questionnaire (SSQ), and 5-item International Index of Erectile Function (IIEF-5). (3) Results: QoL and SS were significantly lower in the IHH group vs. controls. There was a high rate of ED (53.2% vs. 33%, p = 0.008) and depressive symptoms (45.00 ± 17.00 vs. 32.00 ± 12.00, p < 0.001) in patients vs. controls. The age of patients at IHH diagnosis inversely correlated with their overall 15D scores. An alarming non-compliance rate was seen (51.6%). No differences were found between scores of patients receiving hormone replacement therapy (HRT) and untreated subjects in any of the scales. (4) Conclusions: The HRQoL, SS, ED, and depression levels observed in IHH patients, despite HRT, are alarming. Late IHH diagnosis may have a particularly negative impact on HRQoL. More attention should be devoted to HRT adherence and various HRQoL aspects of IHH patients.
... The following domains of the AMS also improved significantly after NTG: Joint pain . NTG showed extensive effects on physical, mental, and sexual symptoms of aging males, similar to those reported in previous studies [17]. Contrary to our expectation, no significant change occurred in the SHIM score, EHS, and AMS-16 domain (morning erection) after NTG. ...
Article
Late-onset hypogonadism (LOH) is generally treated with testosterone replacement therapy. Intramuscular injection of testosterone enanthate is used for LOH in Japan but requires regular painful injections administered every 2-3 weeks at a clinic. Testosterone 2% (AndroForte 2® [AF2]) is available for treating LOH but is expensive because it is imported. We developed a new 2% testosterone gel (NTG) and hypothesized that in patients with LOH, NTG would improve serum testosterone concentrations and Aging Males' Symptoms (AMS) scores compared with AF2. We enrolled men with low levels of serum free testosterone (<11.8 pg/mL) and androgen deficiency symptoms (AMS score >27). The primary endpoint was equivalent change in serum testosterone concentrations with NTG compared to AF2. Secondary endpoints were equivalent change in AMS scores for each question with NTG compared to AF2. Each of AF2 or NTG was administered to the study subjects (23 men aged 42-71 years) for 4 weeks separated by a washout period of 2 weeks. The subjects were randomly divided into men who first received NTG and those who first received AF2. No subject experienced any adverse events throughout the study. Compared with the baseline values of serum testosterone, those following NTG and AF2 treatment were significantly higher and were also significantly higher in the subjects taking NTG versus AF2. NTG administration significantly improved the AMS score, whereas AF2 did not. This initial study has shown that this new NTG formulation may be effective in improving serum testosterone concentrations and also LOH-related symptoms.
... A study conducted by Rosen and cols., which aimed to show the effect of TRT on the quality of life and sexual functions, reported that TRT increases the quality of life and improves the sexual functions of patients. The IIEF and AMS scales gave similar results (25). In the study conducted by Liang and cols., in which they examined the relationship between hypogonadism symptoms and biochemical parameters in aging men, the IIEF-5 and AMS scales were used, and a significant correlation was observed between LH and sex hormone binding globulin and sexual functions (26). ...
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Objective: This study aimed to investigate the frequency of sexual dysfunction and the effect of short-term testosterone replacement therapy on sexual functions in congenital hypogonadism patients. Furthermore, we sought to reveal the consistency of the self-report scales used for the diagnosis of sexual dysfunction and the relationship between biochemical parameters. Materials and methods: The study was conducted on 47 young male patients aged above 18 years who were diagnosed with hypogonadotropic hypogonadism. Short (IIEF-5) and long (IIEF-15) forms of the International Index of Erectile Function and Arizona Sexual Experiences Scale (ASEX) were applied before treatment under the supervision of a physician. The patients' blood pressure, height, and weight were measured, and their luteinizing hormone (LH), FSH, and total testosterone levels were recorded. Patients who started their treatments were called for a follow-up checkup after 6 months. Their blood pressure, height, and weight were measured by reapplying the ASEX, IIEF-5, and IIEF-15. In addition, their LH, FSH, and total testosterone levels in the biochemical tests were rerecorded. Results: In this study, the sexual dysfunction status of patients diagnosed with hypogonadotropic hypogonadism before and after treatment was evaluated using the ASEX, IIEF-15, and IIEF-5 scales. A decrease in sexual dysfunction was observed in all three scales after treatment compared with that before treatment. The IIEF-5 and IIEF-15 scales were found to be uncorrelated in terms of the pretreatment values but were correlated in terms of the post-treatment values. Although a correlation was observed between ASEX and IIEF- 5 before treatment, no correlation was detected between ASEX and IIEF-15. After the treatment, ASEX was found to be correlated with both IIEF-5 and IIEF-15. The results of the scales indicated the correlation in all categories, except the pretreatment results of the IIEF-15 scale. Conclusion: The results of the current study demonstrated a significant improvement in the sexual function of hypogonadism patients undergoing short-term testosterone therapy. The ASEX, IIEF-5, and IIEF-15 scales used in the diagnosis and follow-up of sexual dysfunction were useful for evaluating sexual functions in hypogonadotropic hypogonadism patients.
... 57 Finally, AMS and SF questionnaires include questions assessing mental health and well-being. 32,58 Discussion Quality of life and the entity of hypogonadism are strongly related. Regardless of age of presentation and exact cause, hypogonadic men experience significant deterioration in their well-being. ...
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Hypogonadism has been associated with significant deterioration of well-being. In the aging male, late-onset hypogonadism affects sexual life, mental health, levels of energy, lower urinary tract symptoms and therefore, quality of life may be found significantly deteriorated. Testosterone replacement or supplementation therapy has been found efficient to reverse the adverse effects of hypogonadism and improve quality of life. Scales and questionnaires assessing the general health, urinary symptoms, sexual health, and cognition can provide a thorough assessment of the clinical syndrome, optimize treatment, assist the follow-up, and facilitate referrals to other specialties depending on the chief complaint. A systematic assessment might combine several tools, but the optimal ones and the exact usage is unknown. In this narrative review, we are flipping through the literature presenting the available tools per domain for the assessment of quality of life in men on testosterone replacement therapy and we discuss the optimal usage.
... A similar trial, performed by Tong et al., confirmed the effects of TRT, without increasing potential adverse effects, also in the short-form-12 (SF12) scale analysis of QoL, with an overall increase of 4.4 points from the baseline in patients treated compared to placebo [161]. Finally, in a large multinational study, involving 999 untreated men with hypogonadism, treated with TRT, a significant, rapid and sustained improvement in QoL, assessed via the Aging Males' Symptom (AMS) scale, was reported, up to 36 months after the initiation of treatment [162]. ...
Article
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Testosterone is the most important hormone in male health. Aging is characterized by testosterone deficiency due to decreasing testosterone levels associated with low testicular production, genetic factors, adiposity, and illness. Low testosterone levels in men are associated with sexual dysfunction (low sexual desire, erectile dysfunction), reduced skeletal muscle mass and strength, decreased bone mineral density, increased cardiovascular risk and alterations of the glycometabolic profile. Testosterone replacement therapy (TRT) shows several therapeutic effects while maintaining a good safety profile in hypogonadal men. TRT restores normal levels of serum testosterone in men, increasing libido and energy level and producing beneficial effects on bone density, strength and muscle as well as yielding cardioprotective effects. Nevertheless, TRT could be contraindicated in men with untreated prostate cancer, although poor findings are reported in the literature. In addition, different potential side effects, such as polycythemia, cardiac events and obstructive sleep apnea, should be monitored. The aim of our review is to provide an updated background regarding the pros and cons of TRT, evaluating its role and its clinical applicability in different domains.
... Además, al considerar que la actividad sexual es un tipo de actividad física clasificada de moderada intensidad, con la cual se pueden quemar hasta 85 kCal si se realiza de corta duración (por ejemplo, como subir dos pisos de escaleras), es posible que se presente un beneficio para la salud, así como para la prevención de enfermedad cardiaca, disminución de sus factores de riesgo y mejora de comorbilidades, 4 por lo que es fundamental que los profesionales de la salud consideren la sexualidad como un aspecto a evaluar. 13,14 Dadas las consideraciones señaladas, se decidió realizar este estudio para evaluar el impacto de la actividad sexual en la calidad de vida en pacientes masculinos de 65 a 75 años de edad. ...
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p> Objetivo: evaluar el impacto de la actividad sexual en la calidad de vida en pacientes masculinos de 65 a 75 años de edad. Métodos: estudio transversal analítico, llevado a cabo de marzo a agosto de 2019, en la Unidad de Medicina Familiar No. 58 del Instituto Mexicano del Seguro Social. Se incluyeron pacientes masculinos de 65 a 75 años de edad, la muestra se calculó para poblaciones finitas con muestreo no probabilístico por conveniencia, con un total de 436 pacientes, a los que se les aplicó la Escala de gencat para valorar la calidad de vida y la Nueva Escala de Satisfacción Sexual para valorar el interés sexual, ambos instrumentos validados para población hispana. Resultados: se encontró que 83.4% (364) de los adultos mayores consideraron que las relaciones sexuales activas sí mejoran su calidad de vida, además se reconoció que 85.76% (374) de los pacientes tenían interés sexual y 72.9% (318) de los pacientes con actividad sexual activa se sienten felices. Se identificaron factores de riesgo del desinterés sexual como la insatisfacción con la vida presente, falta de motivación y la percepción de empeoramiento de la salud, entre otros. Conclusión: se determinó que la actividad sexual impactó en la calidad de vida de pacientes en edad adulta.</p
... 11,12 In addition, considering that sexual activity is a type of physical activity classified as moderate intensity, with which up to 85 kCal can be burned if performed for a short duration (for example, like climbing two flights of stairs), it is possible that there is a health benefit, as well as for the prevention of heart disease, reduction of its risk factors and improvement of comorbidities, 4 so it is essential that health professionals consider sexuality as an aspect to evaluate. 13,14 Given the above considerations, it was decided to conduct this study to evaluate the impact of sexual activity on quality of life in male patients aged 65 to 75 years. ...
Article
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p> Objetivo: evaluar el impacto de la actividad sexual en la calidad de vida en paciente s masculinos de 65 a 75 años de edad. Métodos: estudio transversal analítico, llevado a cabo de marzo a agosto de 2019, en la Unidad de Medicina Familiar No. 58 del Instituto Mexicano del Seguro Social. Se incluyeron pacientes masculinos de 65 a 75 años de edad, la muestra se calculó para poblaciones finitas con muestreo no probabilístico por conveniencia, con un total de 436 pacientes, a los que se les aplicó la Escala de gencat para valorar la calidad de vida y la Nueva Escala de Satisfacción Sexual para valorar el interés sexual, ambos instrumentos validados para población hispana. Resultados: se encontró que 83.4% (364) de los adultos mayores consideraron que las relaciones sexuales activas sí mejoran su calidad de vida, además se reconoció que 85.76% (374) de lo s pacientes tenían interés sexual y 72.9% (318) de los pacientes con actividad sexual activa se sienten felices. Se identificaron factores de riesgo del desinterés sexual como la insatisfacción con la vida presente, falta de motivación y la percepción de empeoramiento de la salud, entre otros.</p
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Georgios Tsampoukas,1,2 Karl H Pang,3 Athanasios Papatsoris,2,4 Mohamad Moussa,5 Saiful Miah6 1Department of Urology, The Great Western Hospital, Swindon, UK; 2U-merge Scientific Office, Athens, Greece; 3Institute of Andrology, University College London Hospital, London, UK; 4Department of Urology, Sismanoglio University Hospital of Athens, Athens, Greece; 5Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon; 6Department of Urology, Wycombe Hospital, Buckinghamshire NHS Trust, High Wycombe, UKCorrespondence: Georgios Tsampoukas, Department of Urology, The Great Western Hospital, Swindon, UK, Email tsampoukasg@gmail.comAbstract: Hypogonadism has been associated with significant deterioration of well-being. In the aging male, late-onset hypogonadism affects sexual life, mental health, levels of energy, lower urinary tract symptoms and, therefore, quality of life may be found significantly deteriorated. Testosterone replacement or supplementation therapy has been found efficient to reverse the adverse effects of hypogonadism and improve quality of life. Scales and questionnaires assessing the general health, urinary symptoms, sexual health, and cognition can provide a thorough assessment of the clinical syndrome, optimize treatment, assist the follow-up, and facilitate referrals to other specialties depending on the chief complaint. A systematic assessment might combine several tools, but the optimal ones and the exact usage is unknown. In this narrative review, we are flipping through the literature presenting the available tools per domain for the assessment of quality of life in men on testosterone replacement therapy and we discuss the optimal usage.Keywords: testosterone replacement treatment, quality of life, sexual health, well-being, mental health, lower urinary tract symptoms
Article
Context: The present summary of the European Association of Urology (EAU) guidelines is based on the latest guidelines on male sexual health published in March 2021, with a last comprehensive update in January 2021. Objective: To present a summary of the 2021 version of the EAU guidelines on sexual and reproductive health. Evidence acquisition: A literature review was performed up to January 2021. The guidelines were updated, and a strength rating for each recommendation was included based on either a systematic review of the evidence or a consensus opinion from the expert panel. Evidence synthesis: Late-onset hypogonadism is a clinical condition in the ageing male combining low levels of circulating testosterone and specific symptoms associated with impaired hormone production and/or action. A comprehensive diagnostic and therapeutic work-up, along with screening recommendations and contraindications, is provided. Erectile dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. Along with a detailed basic and advanced diagnostic approach, a novel decision-making algorithm for treating ED in order to better tailor therapy to individual patients is provided. The EAU guidelines have adopted the definition of premature ejaculation (PE), which has been developed by the International Society for Sexual Medicine. After the subtype of PE has been defined, patient's expectations should be discussed thoroughly and pharmacotherapy must be considered as the first-line treatment for patients with lifelong PE, whereas treating the underlying cause must be the initial goal for patients with acquired PE. Haemospermia is defined as the appearance of blood in the ejaculate. Several reasons of haemospermia have been acknowledged; the primary goal over the management work-up is to exclude malignant conditions and treat any other underlying cause. Conclusions: The 2021 guidelines on sexual and reproductive health summarise the most recent findings, and advise in terms of diagnosis and treatment of male hypogonadism and sexual dysfunction for their use in clinical practice. These guidelines reflect the multidisciplinary nature of their management. Patient summary: Updated European Association of Urology guidelines on sexual and reproductive health are presented, addressing the diagnosis and treatment of the most prevalent conditions in men. Patients must be fully informed of all relevant diagnostic and therapeutic options and, together with their treating physicians, decide on optimal personalised management strategies.
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Aims: The aim of this study was to assess cardiovascular (CV) safety of testosterone replacement therapy (TRT) in a large, diverse cohort of European men with hypogonadism (HG). Methods: The Registry of Hypogonadism in Men (RHYME) was designed as a multi-national, longitudinal disease registry of men diagnosed with hypogonadism (HG) at 25 clinical sites in six European countries. Data collection included a complete medical history, physical examination, blood sampling and patient questionnaires at multiple study visits over 2-3 years. Independent adjudication was performed on all mortalities and CV outcomes. Results: Of 999 patients enrolled with clinically diagnosed HG, 750 (75%) initiated some form of TRT. Registry participants, including both treated and untreated patients, contributed 23 900 person-months (99.6% of the targeted) follow-up time. A total of 55 reported CV events occurred in 41 patients. Overall, five patients died of CV-related causes (3 on TRT, 2 untreated) and none of the deaths were adjudicated as treatment-related. The overall CV incidence rate was 1522 per 100 000 person-years. CV event rates for men receiving TRT were not statistically different from untreated men (P=.70). Regardless of treatment assignment, CV event rates were higher in older men and in those with increased CV risk factors or a prior history of CV events. Conclusions: Age and prior CV history, not TRT use, were predictors of new-onset CV events in this multi-national, prospective hypogonadism registry.
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Context: The Testosterone Trials are a coordinated set of seven trials to determine the efficacy of T in symptomatic men ≥65 years old with unequivocally low T levels. Initial results of the Sexual Function Trial showed that T improved sexual activity, sexual desire, and erectile function. Objective: To assess the responsiveness of specific sexual activities to T treatment; to relate hormone changes to changes in sexual function; and to determine predictive baseline characteristics and T threshold for sexual outcomes. Design: A placebo-controlled trial. Setting: Twelve academic medical centers in the United States. Participants: A total of 470 men ≥65 years of age with low libido, average T <275 ng/dL, and a partner willing to have sexual intercourse at least twice a month. Methods: Men were assigned to take T gel or placebo for 1 year. Sexual function was assessed by three questionnaires every 3 months: the Psychosexual Daily Questionnaire, the Derogatis Interview for Sexual Function, and the International Index of Erectile Function. Results: Compared with placebo, T administration significantly improved 10 of 12 measures of sexual activity. Incremental increases in total and free T and estradiol levels were associated with improvements in sexual activity and desire, but not erectile function. No threshold T level was observed for any outcome, and none of the 27 baseline characteristics predicted responsiveness to T. Conclusions: In older men with low libido and low T levels, improvements in sexual desire and activity in response to T treatment were related to the magnitude of increases in T and estradiol levels, but there was no clear evidence of a threshold effect.
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Whether testosterone replacement therapy (TRT) is a lifelong treatment for men with hypogonadism remains unknown. We investigated long-term TRT and TRT withdrawal on obesity and prostate-related parameters. Two hundred and sixty-two hypogonadal patients (mean age 59.5) received testosterone undecanoate in 12-week intervals for a maximum of 11 years. One hundred and forty-seven men had TRT interrupted for a mean of 16.9 months and resumed thereafter (Group A). The remaining 115 patients were treated continuously (Group B). Prostate volume, prostate-specific antigen (PSA), residual voiding volume, bladder wall thickness, C-reactive protein (CRP), aging male symptoms (AMS), International Index of erectile function - erectile function (IIEF-EF) and International Prostate Symptoms Scores (IPSS) were measured over the study period with anthropometric parameters of obesity, including weight, body mass index (BMI) and waist circumference. Prior to interruption, TRT resulted in improvements in residual voiding volume, bladder wall thickness, CRP, AMS, IIEF-EF, IPSS and obesity parameters while PSA and prostate volume increased. TRT interruption reduced total testosterone to hypogonadal levels in Group A and resulted in worsening of obesity parameters, AMS, IPSS, residual voiding volume and bladder wall thickness, IIEF-EF and PSA while CRP and prostate volume were unchanged until treatment resumed whereby these effects were reversed. TRT interruption results in worsening of symptoms. Hypogonadism may require lifelong TRT.
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While US testosterone prescriptions have tripled in the last decade with lower trends in Europe, debate continues over the risks, benefits and appropriate use of testosterone replacement therapy (TRT). Some authors blame advertising and the availability of more convenient formulations whilst other have pointed out that the routine testing of men with erectile dysfunction (a significant marker of cardiovascular risk) and those with diabetes would inevitably increase the diagnosis of hypogonadism and lead to an increase in totally appropriate prescribing. They commented that this was merely an appropriate correction of previous underdiagnosis and undertreatment by adherence to evidence-based guidelines. Urologists and primary care physicians are the most frequent initiators of TRT, usually for erectile dysfunction. Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with possible reduction in frailty and osteoporosis. There remains no evidence that TRT is associated with increased risk of prostate cancer or symptomatic benign prostatic hyperplasia, yet the decision to initiate and continue therapy is often decided by urologists. The cardiovascular issues associated with TRT have been clarified by recent studies showing clearly that therapy associated with clear rise in testosterone levels are associated with reduced mortality. Studies reporting to show increased risk have been subject to flawed designs with inadequate baseline diagnosis and follow-up testing. Effectively they have compared nontreated patients with undertreated or on-compliant subjects involving a range of different therapy regimens. Recent evidence suggests long acting injections may be associated with decreased cardiovascular risk but the transdermal route may be associated with potentially relatively greater risk because of conversion to dihydrotestosterone by the effect of 5α reductase in skin. The multiple effects of TRT may add up to a considerable benefit to the patient that might be underestimated by the physician primarily concerned with his own specialty. This paper will attempt to identify who should be treated, and how they should be treated safely to achieve best outcomes, based on a comprehensive MEDLINE and EMBASE and Cochrane searches on hypogonadism, TRT and cardiovascular safety from May 2005 to May 2015. This revealed 1714 papers with 52 clinical trials and 32 placebo-controlled randomized, controlled trials.
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Objectives: To test the hypothesis that testosterone replacement therapy (TRT) improves the long-term health-related quality of life (HRQoL) of men with late-onset hypogonadism (LOH), as studies have shown that sub-physiological testosterone levels have a negative impact on psychological (e.g. mood, vitality, libido and sexual interest) and physical features (e.g. erectile function and physical strength), all of which contribute to a sense of well-being. Patients and methods: In all, 261 patients (mean age 58 years) diagnosed with LOH were treated with long-acting intramuscular testosterone undecanoate (TU) for up to 5 years. Health quality indicators including the International Prostate Symptom Score (IPSS), the five-item version of the International Index of Erectile Function (IIEF-5), the Aging Males' Symptoms (AMS) scale, and the percentage of patients reporting joint and muscle pain were measured at baseline and at each visit. The means were then plotted over time in parallel with mean total testosterone (TT) levels. Results: Both the mean IPSS and AMS scores fell significantly within the first 3 months and the mean IIEF-5 score and TT levels increased within the first 3 months. All four parameters continued to improve over the course of the trial. The percentage of patients reporting both joint and muscle pain decreased during TRT. Conclusions: This prospective, observational and longitudinal analysis shows a clear improvement in both psychological and physical characteristics as physiological testosterone levels are reached and maintained contributing to an improvement in the HRQoL in men with diagnosed LOH.
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Background/Objectives Long-term testosterone replacement therapy (TRT) up to five years has been shown to produce progressive and sustainable weight loss in hypogonadal men. This study investigated effects of long-term TRT up to eight years in hypogonadal men with different obesity classes.Subjects/Methods From two independent observational registries we identified a total of 411 obese, hypogonadal men receiving TRT in urological clinics. The effects of TRT on anthropometric as well as metabolic parameters were studied for a maximum duration of 8 years, mean follow-up: 6 years. All men received long-acting injections of testosterone undecanoate in 3-monthly intervals.ResultsIn all three classes of obesity, T therapy produced significant weight loss (WL), decrease in waist circumference (WC) and BMI. In patients with class I obesity, mean weight decreased from 102.6±6.4 to 84.1±4.9 kg, change from baseline: -17.4±0.5 kg and -16.8±0.4%. WC in this group of patients decreased from 106.8±7.4 to 95.1±5.3 cm, change from baseline: -10.6±0.3 cm. BMI decreased from 32.69±1.4 to 27.07±1.57, change from baseline: -5.52±0.15 kg/m(2). In patients with class II obesity, weight decreased from 116.8±6.9 to 91.3±6.3 kg, change from baseline: -25.3±0.5 kg and -21.5±0.4%. WC decreased from 113.5±7.5 to 100.0±5.4 cm, change from baseline: -13.9±0.4 cm. BMI decreased from 37.32±1.45 to 29.49±1.71, change from baseline: -8.15±0.17 kg/m(2). In patients with class III obesity, weight decreased from 129.0±5.6 to 98.9±4.8 kg, change from baseline: -30.5±0.7 kg and -23.6±0.5%. WC decreased from 118. 5±5.6 to 103.8±4.9 cm, change from baseline: -14.3±0.4 cm. BMI decreased from 41.93±1.48 to 32.46±1.59, change from baseline -9.96±0.29 kg/m(2).Conclusions Testosterone therapy appears to be an effective approach to achieve sustained weight loss in obese hypogonadal men irrespective of severity of obesity. Based on these findings we suggest that T therapy offers safe and effective treatment strategy of obesity in hypogonadal men.International Journal of Obesity accepted article preview online, 29 July 2015. doi:10.1038/ijo.2015.139.
Article
Objectives: To evaluate the effects of testosterone-replacement therapy (TRT) on prostate health indicators in hypogonadal men, including rates of prostate cancer diagnoses, changes in prostate-specific antigen (PSA) levels and lower urinary tract symptoms (LUTS) over time. Patients and methods: The Registry of Hypogonadism in Men (RHYME) is a multi-national patient registry of treated and untreated, newly-diagnosed hypogonadal men (n = 999). Follow-up assessments were performed at 3-6, 12, 24, and 36 months. Baseline and follow-up data collection included medical history, physical examination, blood sampling, and patient questionnaires. Prostate biopsies underwent blinded independent adjudication for the presence and severity of prostate cancer; PSA and testosterone levels were measured via local and central laboratory assays; and LUTS severity was assessed via the International Prostate Symptom Score (IPSS). Incidence rates per 100 000 person-years were calculated. Longitudinal mixed models were used to assess effects of testosterone on PSA levels and IPSS. Results: Of the 999 men with clinically diagnosed hypogonadism (HG), 750 (75%) initiated TRT, contributing 23 900 person-months of exposure. The mean testosterone levels increased from 8.3 to 15.4 nmol/L in treated men, compared to only a slight increase from 9.4 to 11.3 nmol/L in untreated men. In all, 55 biopsies were performed for suspected prostate cancer, and 12 non-cancer related biopsies were performed for other reasons. Overall, the proportion of positive biopsies was nearly identical in men on TRT (37.5%) compared to those not on TRT (37.0%) over the course of the study. There were no differences in PSA levels, total IPSS, or the IPSS obstructive sub-scale score by TRT status. Lower IPSS irritative sub-scale scores were reported in treated compared to untreated men. Conclusions: Results support prostate safety of TRT in newly diagnosed men with HG.
Article
Testosterone and sexual function are related. Current evidence suggests that testosterone replacement therapy (TRT) may improve sexual dysfunction. Sexual dysfunction in men who are hypogonadal, mixed, or eugonadal have all been examined through numerous studies. The most recent large analysis showed an overall improvement in sexual function outcomes in men treated with TRT. This improvement is difficult to measure and seems to differ based on the baseline hormonal status of the patient at the beginning of treatment.
Article
Background Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established. Methods We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials — the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants. Results Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy–Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups. Conclusions In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.)
Article
Purpose: To determine the effect of testosterone solution 2% on total testosterone level, and 2 symptoms of hypogonadism, sex drive and energy level. Materials and methods: This was a randomized, multi-center, double-blind, placebo-controlled, 16-week study to compare the effect of testosterone and placebo on the proportion of men having a testosterone level within the normal range (300-1050 ng/dL) upon treatment completion, and to assess the impact of testosterone on sex drive and energy level, measured using the Sexual Arousal, Interest, and Drive scale (SAID) and the Hypogonadism Energy Diary (HED), respectively. Males ≥18 years (N=715), with total testosterone <300 ng/dL and at least one symptom of testosterone deficiency (decreased energy, decreased sexual drive) were randomized to 60mg topical testosterone solution 2% or placebo once daily. Results: For study completers, 73% in the testosterone versus 15% in the placebo group had a testosterone level within the normal range at endpoint (p<0.001). Participants assigned testosterone showed greater baseline-to-endpoint improvement in SAID scores (low sex drive subset; p<0.001 versus placebo) and HED scores (low energy subset; p=0.02 versus placebo [not significant at pre-specified p<0.01]). No major adverse cardiovascular or venous thrombotic events were reported in the testosterone group; the incidence of increased hematocrit was higher with testosterone (p=0.04 versus placebo). Conclusions: Once-daily testosterone solution 2% for 12 weeks was efficacious in restoring normal testosterone levels and improving sexual drive in hypogonadal men. Improvement was also seen in energy levels on the HED though not at the pre-specified p<0.01. No new safety signals were identified.