International Journal of Urology (2007) 14, 981–985 doi: 10.1111/j.1442-2042.2007.01882.

x,

Review Article

Recent trends in the treatment of testosterone

deficiency syndrome
Bum Sik Hong and Tai Young Ahn
Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

Abstract: Testosterone deficiency syndrome (TDS) is defined as a clinical and biochemical syndrome associated with advancing age and is
characterized by typical symptoms and deficiency in serum testosterone levels. TDS is a result of the interaction of hypothalamo-pituitary and
testicular factors. Now, treatment of TDS with testosterone is still controversial due to a lack of large, controlled clinical trials on efficacy. The risks
of treatment with testosterone appear to be minimal, although long-term studies on the safety of testosterone therapy are lacking. The aim of
the therapy is to establish a physiological concentration of serum testosterone in order to correct the androgen deficiency, relieve its symptoms
and prevent long-term sequelae. All of the available products, despite their varying pharmacodynamic and pharmacokinetic profiles, are able to
reach this goal. Newer testosterone patches seem not to cause severe skin irritation. Testosterone gels minimize the skin irritation while
providing flexibility in dosing and a low discontinuation rate. Oral testosterone undecanoate (TU) is free of liver toxicity. Recent formulation of oral
TU markedly increased shelf-live, a major drawback in the older preparation. Producing swings in testosterone levels rising rapidly to the
supraphysiological range is not the case with the new injectable long-acting preparation of TU. To be able to rapidly react and stop treatment in
cases where side-effects and contraindications are detected , the short-acting transdermal and oral delivery modes have certain advantages.
However, there is no evidence that the use of an injectable long-acting TU in men with TDS has limitations in clinical application for this reason.
The use of dehydroepiandrosterone is still controversial because of a lack of well designed long-term trials, although some recent studies
suggest positive effects on various body systems. Only a few studies have been carried out to investigate the effect of hCG (human chorionic
gonadotropin) in TDS with some positive results on various body systems.

Key words: androgen deficiency, testosterone, testosterone deficiency syndrome.

Introduction
It has been well recognized that the level of peripheral testosterone
decreases over the lifespan in a significant percentage of the aging male
population.1,2 Testosterone is a vitally important factor for homeostasis
in a number of organ systems.3 Testosterone deficiency syndrome in
aging males has been found to be associated with various pathological
conditions including sexual dysfunction such as decreased libido, dis-
integration of smooth muscle and nitric oxide synthase-containing
nerves within corpus cavernosum.4–10
The decline in androgen production that occurs in the aging male
population has been designated with an assortment of names that reflect
a variety of opinions. Those are male climacteric, male menopause,
andropause, androgen decline in the aging male (ADAM), partial
androgen decline in the aging male (PADAM), and late onset hypogo-
nadism (LOH). However, true andropause exists only in those men who
have lost testicular function, due to disease or accidents, and those with
advanced prostate cancer who are subjected to medical or surgical
castration. ADAM and PADAM represent a significant improvement,
nevertheless because testosterone decline can be apparent in the early
ages, it appears more fitting not to incorporate ‘aging male’ in the
description of T decline. Late-onset hypogonadism and symptomatic
late onset hypogonadism (SLOH) gained favor recently. It carries,
however, significant drawback. The term hypogonadism has been used
synonymously with pathological T dysfunctions of the hypothalamic-
pituitary-testicular axis, which generally require specialized investiga-
tions. Thus, Morales suggested to name T decline as testosterone
Correspondence: Tai Young Ahn, Department of Urology, University of
Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-dong,
Sonpa-gu, Seoul 138-736, Korea. Email: tyahn@amc.seoul.kr
Received 31 May 2007; accepted 18 July 2007.
deficiency syndrome (TDS) due to its simplicity, clarity, and respect for
physiological principle.11–16
When TDS causes pathological conditions, the physiological or
mental syndrome is often called symptomatic TDS (STDS). Testoster-
one supplementation has the potential to counteract the signs, symp-
toms, and health risks of TDS, thereby promoting successful male
aging, but the issues of how and when to treat are complex. Irrational
use of testosterone entails significant risks. The clinical implications of
TDS in aging male population are different from the consequences of
cessation of ovarian function in aging women. However, it is also
recognized that STDS is largely underdiagnosed and undertreated.17,18
Allowing the elderly to keep an active and productive lifestyle, the most
urgent issues and misunderstanding with STDS management are its
clinical implications, diagnosis, and monitoring in daily practice.
Definition and clinical feature of TDS
According to International Society of Andrology (ISA), International
Society for the Study of the Aging Male (ISSAM) and European
Association of Urology (EAU) recommendations, TDS is defined as ‘a
clinical and biochemical syndrome associated with advancing age and
characterized by typical symptoms and deficiency in serum testoster-
one levels’. They also clarified that TDS may result in significant
detriment in the quality of life and adversely affect the function of
multiple organ systems.19 Clinical features of TDS include negative
effects on body composition, bone mineral density (BMD), sexuality,
the skin, and the central nervous system. TDS may encompass numer-
ous, sometimes vague and non-specific symptoms and signs: a
decreased sense of well-being; a decrease in muscle mass, strength,
energy; reduced virility, libido, and sexual activity; an increased fre-
quency of impotence; and increased sweating, mood changes, fat mass,

© 2007 The Japanese Urological Association 981

BS HONG AND TY AHN
dry skin and anemia.11,17 However, these signs and symptoms often do
not present at the same time and may escape physicians’ suspicion of
TDS, because changes in mood , libido, sexual functions, and BMD can
not be easily related to decreased testosterone level in a routine clinical
setting. Tardy and vague progression of these symptoms and signs
entail a patient’s unawareness of their manifestation, more frequently,
large portions of patients may not consider them as a disease to be dealt
with, but a part of the aging process.17 This point has escalated the need
for suitable questionnaires as tools for screening and treatment
outcome measurements.12 However, many physicians treating aging
men and consequently accepting the existence of TDS are skeptical
about the accuracy of the clinical diagnosis because its manifestations
are not specific.20 In addition, conditions such as depression or
hypothyroidism exactly mimic the symptomatology of TDS.21 There-
fore, biochemical findings that may indicate a possible abnormality in
hormone levels are a crucial part of TDS diagnosis. Unfortunately,
most appropriate biochemical assays, which should be reliable and
reproducible, do not appear to be accurate enough diagnostically, and
the normal ranges for serum testosterone remain undefined.
Biochemical diagnosis of TDS
Much debate exists in published reports as to which laboratory analyses
represent the appropriate assessment of the man with symptoms con-
sistent with hypogonadism. Biochemical parameters assessing andro-
gen deficiency includes total testosterone, free testosterone, calculated
free testosterone, bioavailable testosterone, and free androgen index.17
Measurement of total serum testosterone level is a basic laboratory
evaluation, however, results have been found to be misleading when
SHBG is elevated. Therefore, a more appropriate test is the determina-
tion of bioavailable testosterone (more expensive and not universally
accessible) though a simple measure of total T is sufficient to confirm
the diagnosis of STDS under most circumstances.18 Calculation of free
testosterone based on serum levels of testosterone and SHBG increases
diagnostic accuracy in assessing the degree of androgenecity in a
cost-effective manner. A free automatic calculator can be found at:
http://www.issam.ch22
Measurement of serum testosterone level is recommended to be
carried out in the morning considering circadian rhythm of testosterone
production by the testicles. According to ISA, ISSAM and EAU rec-
ommendations, total serum testosterone levels below 8 nmol/L
(231 ng/dL) or free testosterone below 180 pmol/L (52 pg/mL) indicate
hypogonadism and testosterone supplementation may be appropriate
following exclusion of alternative causes. Total testosterone levels
above a threshold of 12 nmol/L (346 ng/dL) or a free testosterone level
above 250 pmol/L (72 pg/mL) is commonly regarded as normal.19
However, laboratory tests show very large intra-individual variability
within a relatively short time; indeed , an individual can easily have
values in and out of the normal eugonadal range from week to week.13
Therefore, if testosterone levels are below or at the lower limit of
normal male values, repeated measurement is anticipated. The equivo-
cal laboratory results should be followed up by calculation of free
testosterone from total testosterone and SHBG concentrations
(http://www.issam.ch) or by measurement of free testosterone levels by
the dialysis method , or bio-available testosterone by the ammonium
sulfate precipitation method.18 Along with intra-individual fluctuations,
laboratory to laboratory fluctuation is also significant depending on the
methods and/or the assay kits used. This phenomenon urges each insti-
tution to make strict quality control of the assays to be used and to
establish their own normal ranges in each laboratory.23
982
Testosterone substitution
Testosterone is commercially available in different delivery forms such
as injectable, oral, buccal, transdermal, and subdermal preparations.
Injectable testosterone esters, such as testosterone propionate, testoster-
one cypionate, testosterone enanthate, and testosterone undecanoate,
can be administered intramuscularly to avoid the hepatic first pass
effect. Conventional parenteral testosterone preparations are far from
ideal.23 T enanthate and cypionate, at a dose of 200–250 mg/2 weeks
are the common formulations. They yield transient supraphysiological
levels the first 2–3 days after injection, followed by a steady decline to
subphysiological levels 4–6 days prior to the next injection. This phe-
nomenon is known as the ‘roller coaster effect’.24–27 The transient
supraphysiological levels may increase the frequency of side-effects,
such as polycythemia.28,29 Many men dislike these wide swings of
testosterone levels which certainly influence performance, mood and
sexual function as well.24
This, however, is not the case with the new long-acting preparation
of testosterone undecanoate.30 Parenteral testosterone undecanoate is a
new treatment modality for testosterone substitution. In contrast to
other injectable testosterone esters, the kinetics for side chain cleavage
of the saturated aliphatic fatty acid undecanoic acid with 11 carbon
atoms turned out to be considerably longer permitting much longer
injection intervals.31,32 After adequate loading most patients are well
substituted with a dose every 12 weeks. The resulting plasma testoster-
one levels are almost always in the physiological range, so the so called
‘roller coaster effect’ is rarely experienced by patients.29,30 Also side-
effects of supraphysiological testosterone levels, such as polycythemia,
are only rarely observed.33
Injectable testosterone undecanoate (Nebido: 1000 mg testosterone
undecanoate in 4 mL castor oil) has long-term kinetics, sustained close
mimicking of eugonadal testosterone serum levels without supra- or
subphysiological serum concentrations. The generally recommended
dosage scheme is the second injection 6 weeks after the first one fol-
lowed by further injections every 12 weeks. With this, administration
intervals are drastically reduced in comparison to conventional intra-
muscular injectable testosterone preparations. In hypogonadal patients
with erectile dysfunction (ED), 58% of the patients responded to this
injectable testosterone undecanoate alone.34
However, to be able to rapidly react and stop treatment, when side-
effects and contraindications emerge, the advice is given not to use the
long-acting injectable and testosterone implants in TDS, and favor the
short-acting transdermal, oral and buccal delivery modes.18 These
routes are convenient and can be applied by the patient himself. Test-
osterone patches imitate the circadian production of testosterone.35,36
However, there has been no evidence indicating any therapeutic advan-
tages of mimicking the circadian rhythm.18 Sometimes testosterone
patches lead to skin irritation, which occasionally can be severe.
Recently, testosterone gels minimize these problems. With application
of 5–10 g gel (50–100 mg testosterone) per day on the skin, serum
levels of testosterone, dihydrotestosterone (DHT) and estradiol are
established that are well within the normal range.37,38 Application to a
large area seems to lead to higher levels than the application of the
same amount to a small area. The compliance of the patients treated
with gel proved to be markedly better, and considerably fewer cases
of skin itching have occurred. As application of the gel is simple,
very practicable for the patient and replaces painful intramuscular
injections.
Oral testosterone undecanoate is coabsorbed with the lipophilic
solvent from the intestine into the lymphatic system thereby circum-
venting first-pass inactivation in the liver. Therefore, it is free of liver
© 2007 The Japanese Urological Association

toxicity. Recent preparation of testosterone undecanoate in a mixture of
castor oil and propylene glycol laurate represented high stability at
room temperature so that solved the problem of inconvenient storage
observed in older preparations.18 In Korean male patients with a
decreased level of serum total testosterone (<2.8 ng/mL) or free test-
osterone (<13 pg/mL), oral form of testosterone, testosterone unde-
canoate (Andriol, NV Organon, the Netherlands) was tried. Patients
were given oral testosterone undecanoate 160 mg daily for 3 weeks.
The dosage was then decreased to 80 mg daily and changes in symp-
toms were assessed at every visit. After 3 months, serum tests, includ-
ing testosterone, were repeated. The score of the Korean Andropause
Questionnaire changed from 56.2 ⫾ 21.7 at baseline to 52.9 ⫾ 21.3
(P = 0.03) after 3 weeks, to 49.3 ⫾ 19.3 (P = 0.03) after 8 weeks, and
to 46.5 ⫾ 25.6 (P = 0.028) after 12 weeks. With respect to sexual
function, mean IIEF scores were 37.2 ⫾ 19.6 at baseline and
38.7 ⫾ 19.2 and 40.2 ⫾ 22.0 (P = 0.033) after 3 weeks and 12
weeks, respectively. Serum total testosterone increased from
2.13 ⫾ 1.20 ng/mL at baseline to 6.04 ⫾ 3.08 ng/mL (P = 0.005) after
12 weeks, and free testosterone was marginally significantly changed
from 8.60 ⫾ 2.25 pg/mL to 11.40 ⫾ 3.81 pg/mL (P = 0.13). However,
there were no significant adverse reactions that led to the cessation of
the administration of oral testosterone.39
The safety and efficacy of alternative supplements, such as dihy-
drotestosterone, dehydroepiandrosterone, androstenediol, androstene-
dione, and hCG (human chorionic gonadotropin), are questionable in
the published research. Because of the lack of long-term human trials
the efficacy of DHEA is still controversial, though the widespread
practical experience and a series of recent studies suggest positive
effects on various body systems.40 Only a few studies tried to investi-
gate if hCG administration may be effective in age-related androgen
deficiency. They showed some positive results of hCG on muscle mass,
osteoblastic collagen formation, and lipids.41,42
Therapeutic effect
Sexuality
In a recent study, testosterone supplementation enhanced sildenafil
efficacy in sildenafil non-responders with hypogonadism.43 A daily
dose of 1% testosterone gel (1%) to 100 mg sildenafil for 12 weeks
showed significantly enhanced erectile function compared to the
placebo group.44 A combination therapy of oral testosterone unde-
canoate and sildenafil showed improvement in erections, a significant
increase in IIEF scale and increased sexual contacts in sildenafil non-
responders with diabetes mellitus type II.45 Likewise in a prospective,
placebo-controlled study with patients characterized by sildenafil
refractory, arteriogenic ED, normal sexual desire and testosterone in the
lower quartile of the normal range, a significant improvement in erec-
tile function domain score at IIEF was observed in the patients group
treated with transdermal testosterone.46
Bone mineral density
The prevention of osteoporosis in men is strongly warranted , because
it is a common cause of morbidity, mortality and health care expendi-
ture. One in eight men older than 50 years will experience an
osteoporotic fracture. The association between low testosterone and
low bone mineral density (BMD) has been established.47,48 In men with
idiopathic osteoporosis, lower levels of estradiol, higher levels of sex
hormone binding globulin and a decreased free androgen index have
been reported.49 In a previous study with 83 hypogonadal men,
© 2007 The Japanese Urological Association
Testosterone deficiency syndrome
bioavailable testosterone, body mass index (BMI), and physical activi-
ties were significant predictors of femoral neck BMD.50 The ability to
aromatize testosterone to estradiol is considered to be an important
factor maintaining healthy bone metabolism in aging men according to
a longitudinal study with 200 elderly men in which the ratio between
serum estradiol and serum testosterone as an indirect measure for
aromatase activity was decreased in osteoporotic men.51 A testosterone
patch in a randomized , placebo-controlled double blind study showed
that the lower the pretreatment serum testosterone concentration, the
greater the outcome of testosterone therapy on lumbar spine bone
density.52
Muscle strength and body composition
A significant increase of fat-free mass of the cross-sectional area of the
triceps arm muscle and the quadriceps leg muscle when testosterone
enanthate (100 mg/week, im injections) was given to hypogonadal
men.53 A series of studies reported that testosterone supplementation
showed a positive effect on muscle status, strength, and body compo-
sition in hypogonadal patients. Testosterone enanthate administration
(100 mg/week for 18 months) led to a decrease in body fat and subcu-
taneous fat and an increase in lean muscle mass in a study with
acquired hypogonadal men.54
Contraindications and side-effects
Substitution treatment with testosterone is characterized by great safety
and a paucity of side-effects. There are only a few contraindications and
the side-effects are usually non-serious and reversible. According to
ISA, ISSAM and EAU recommendations, testosterone administration
is absolutely contraindicated in men suspected of or having carcinoma
of the prostate or breast. Men with significant polycythemia, untreated
sleep apnea, severe heart failure, severe symptoms of lower urinary
tract obstruction evidenced by high scores in the International Prostate
Symptom Score, or clinical findings of bladder outflow obstruction
(increased postmicturition residual volume, decreased peak urinary
flow, pathological pressure flow-studies) due to an enlarged , clinically
benign prostate should not be treated with testosterone. Moderate
obstruction represents a partial contraindication. After successful treat-
ment of the obstruction, the contraindication is lifted.19
Several reports indicate that testosterone can exacerbate prostate
cancer by converting occult microscopic loci into clinically apparent
lesions.55,56 However, the causality between high testosterone and the
progression of preclinical to clinical cancer is still being discussed
controversially. Several prospective studies of testosterone replacement
therapy gave a similar prevalence rate of prostate cancer (1.1%) in
testosterone-treated men compared to the general population.57 Even in
hypogonadal men with high grade prostatic intraepithelial neoplasia
(PIN), testosterone supplementation did not augment the risk of pros-
tate cancer in a comparative 1-year study.58 Because testosterone is
known to stimulate erythropoietin in the kidneys and have a direct
action on the erythropoietic stem, testosterone supplementation can
cause a rise in red blood cell mass and hemoglobin levels.59 A wide
range of risk for erythrocytosis has been reported with 3–15% for
transdermal applications and 44% for injections.57 Extra-normal
supplementation of testosterone can entail an aggravation of cardiovas-
cular diseases.18 Testosterone replacement therapy has been reported to
worsen sleep apnea increasing the total number of disordered breathing
events.60
983
BS HONG AND TY AHN
Monitoring
Prerequisite test before initiating testosterone supplementation should
include the prostate-specific antigen (PSA) and a digital rectal exami-
nation (DRE) in men older than 45 years. For monitoring purposes,
quarterly intervals are recommended for the first 12 months followed
by a yearly investigation. DRE in combination with the determination
of PSA has been found to have a positive predictive value of 49%.
Prostate biopsy is warranted in cases where PSA is higher than
4 ng/mL or abnormal DRE. Though the negative behavioral patterns
during adequate testosterone supplementation are rare, proper monitor-
ing of mood and behavioral changes are required. When hematocrit is
elevated during the therapy, dosage reduction or cessation of treatment
should be considered according to the severity.
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