Aging Males and

Testosterone
Text Book Reading
Division of Geriatric Medicine | Department
of Internal Medicine
Teaching Hospital RSUD DR SOETOMO
Surabaya

Dr Stevanus Immanuel S
 Aging Males and
Testosterone

Text Book Reading

Brocklehurst’s Textbook of Geriatric Medicine
and Gerontology 8th edition

Geriatric Medicine
Chapter 84
Frederick Wu, Tomas Ahern

Text Book reading

Outline
Introduction
01 Definition and Clasification of hypogonadism

Age Related in Testosterone

02 Factor that related to Low Testosterone in Elderly

Testosterone Therapy Guideline

03 Recent Guideline and recommendation of Testosterone Therapy

Risk And Benefit

04 Risk And Benefit of Testosterone Therapy

Dr Stevanus Immanuel S
Introduction
Factors that related to Low Testosterone in Elderly
 Aging Males and Text Book Reading

Testosterone
• Aging -> testosterone fall ->physical and
psychological functions, QOL and life span.
• Effects of aging on the hypothalamic-pituitary-
gonadal (HPG) axis-> increasing prevalence of
obesity and chronic illness.
• Still Contoversy -> Benefit still Unclear?
MALE Your Picture Here

HYPOGONADISM
• Male Hypogonadism : low testosterone AND
defcient spermatogenesis
• Categorized into primary and secondary
hypogonadism
 Primary
hypogonadism
• Klinefelter syndrome (47,XXY) -> small testes
• Decreased libido
• Erectile dysfunction
• Poor beard growth, Sparse pubic hair
• Infertility (with azoospermia)
• Tall stature , decreased muscle mass, decreased Your Picture Here

muscle strength
• Gynecomastia
• low bone mineral density (BMD)
• Anemia.
 Secondary Your Picture Here

hypogonadism
• Hypothalamic-pituitary tumor
• Hypothalamic pituitary infltration
(e.g., hemochromatosis)
• Medications
(e.g., glucocorticoids, opioid)
• Brain insult Your Picture Here

(e.g., traumatic injury, irradiation)

• Chronic illness
(e.g., diabetes and HIV infection)
Age Related in Testosterone
Definition and Clasification of hypogonadism
 Age-Related Decrease in 
Testosterone Levels
• In the European Male Aging Study (EMAS):
• Total Testosterone concentrations fell by
0.1 nmol/L (0.04%) per year
• free (not protein bound) testosterone
concentrations fell by 3.83 pmol/L (0.77%)
per year.
• Prevalence :16% -26% of men aged 70 to 79
years and 11% - 22% of men younger than 50
years.
 Other Factors
• Aging leads to multilevel HPG axis
disruption, which is influenced variably by
body weight, acute or chronic illness,
medications, and lifestyle.
• Testicular volume (decreased)
• Leydig cell number (decreased)
• Response to GNRH and LH (decreased)
 Other Factors

• Testosterone concentrations are lower in obese men (BMI > 30

kg/m2) than in lean men (BMI 20-25 kg/ m2), and obese men’s
testosterone concentrations decline more quickly. BUT no increase
LH concentration -> elevated cytokine concentrations and/or insulin
resistance
• Men with chronic illness have lower testosterone levels compared
with healthy men (CVD, DMT2)
• Statin and vitamin D defciency have also been reported
Age-Related Low Testosterone Levels
and Hypogonadism
• (EMAS) Men with low testosterone levels
• Higher BMI
• Lower muscle mass, lower BMD,
• Higher glucose levels
• Lower hemoglobin levels
• Slower walk speeds
• Greater illness prevalence
Age-Related Low Testosterone Levels
and Hypogonadism
• Prevalence of loss of libido increased from 30.6% to 41.1% and that
the prevalence of erectile dysfunction increased from 37.4% to
42.3%
• The BACH study showed that of men older than 50 years, only
20.2% of those with symptoms of hypogonadism had a low total
testosterone level (≤10.5 nmol/L) and of men with a low testosterone
level, only 20.1% reported low libido and only 29.0% reported
erectile dysfunction
• So low testosterone -> Hipogonadism??
LATE-ONSET HYPOGONADISM IS ……
• Presence of three sexual symptoms
• Decreased frequency of morning erection
• Decreased frequency of sexual thoughts
• Erectile dysfunction

• AND total testosterone concentration less than 11

nmol/L and Free testosterone concentration less than
220 pmol/L
Adverse Effects
of Low 
Testosterone 
Levels
Depressive illness Poor physical Frailty
function

But Androgen Therapy -> diabetes and/or

myocardial infarction, increased mortality Diabetes CVD incidence
 Mortality and Testosterone Levels
(Inconclusive)
• Men with age related low testosterone levels, however, tend to have testosterone
levels that are just below range.
• Aging, obesity, and chronic illness -> age-related low testosterone levels, and
these other factors) may be the reason for adverse consequences and not the low
testosterone level
• Prospective studies that found that once the data were adjusted for obesity and
chronic illness, age-related low testosterone levels were not associated with
increased mortality unless a very low testosterone threshold (<8.36 nmol/L) was
used
• The situation differs for men at the upper extreme of age (older than 70 years):
some studies have shown an association between low testosterone levels with
increased mortality and some have not
• EMAS data showed an association between sexual symptoms and mortality that
was independent of testosterone levels.
Testosterone Therapy Guideline
Recent Guideline and recommendation of Testosterone
Therapy
 Testosterone
Therapy
• In the United States, the number of men who received
a prescription for testosterone increased from 1.3
million in 2010 to 2.3 million in 2013, with
approximately 70% of these aged between 40 and 64
years, approximately 15% aged 65 through 74 years,
and approximately 5% older than 75 years.

• A multinational survey of testosterone prescribing

found that between 2000 and 2011, global sales of
testosterone sales increased 12-fold from 115 million
to 1.4 billion U.S. dollars.
 Current guidelines of
International Endocrine Societies
• Use of testosterone therapy for men with aging-related hypogonadism provided
that testosterone levels are confirmed to be low, the patient has features consistent
with hypogonadism, and appropriate screening for disease of the HPG axis is
performed
• Two consecutive testosterone measurements (confirmation)
• Diurnal variation and food intake effect -> Early Morning and fasting state

Low testosterone level due to aging alone is NOT indication for

testosterone therapy
 Current guidelines of
International Endocrine Societies
• Remediable causes of hypogonadism can be treated
specifcally by therapies other than testosterone.
• Dopamine agonist -> Hyperprolactinemia
• Bariatric surgery -> DM 2, severe obesity, or both
• Secondary hypogonadism who desire fertility ->
Antiestrogen, aromatase inhibitor (long-term safety data are
lacking) , gonadotropin therapy, and/or pulsatile
gonadotropin-releasing hormone therapy
 Testosterone
Preparations
• Transdermal and buccal -> daily
administration
• Intramuscular testosterone -> every 3 to 14
weeks.
• Oral testosterone and 17α-alkylated androgen
preparations are not recommended -> liver
toxicity
• Target Therapy (Titrated) -> middle to lower
(midnormal )Reference range.
Risk And Benefit
Risk And Benefit of Testosterone Therapy
 Beneficial Effects
Sexual Symptoms QOL and Mood
• T improves sexual interest,
spontaneous erections, erectile Unclear, with some studies
Dysfunction in hypogonadal men showing beneft and some not

• Testosterone therapy had no such effect in

eugonadal men
In hypogonadal men with
• Studies also have found improvements in depression, however, testosterone
sexual symptoms with testosterone therapy in therapy does appear to have a
older men with a low testosterone level positive impact on mood.
 Beneficial Effects
Frailty and Physical Function
Transdermal testosterone therapy, at a dose of 5
mg daily for 6 month increased : Other RCTs -> not found improvements in
Total lean body mass physical function with testosterone therapy,
Lower limb muscle strength
Self-reported physical function

But did not improve signifcantly objective

physical function except in the subgroups suggesting that treatment may beneft
comprising older (aged ≥75 years) and frailer only frail men with clearly low
men (≥2 Fried frailty criteria) testosterone levels
The Testosterone in Older Men with Mobility
Limitations trial (TOM)
• Recruited 209 men aged 65 years or older with a total testosterone of 12.0 nmol/L
or less.
• Transdermal testosterone therapy, at double the standard replacement dose (10
mg/day) compared to placebo
• Improved lower and upper muscle strength but not physical function.

This study was terminated early by the safety monitoring board, because
of a greater incidence of cardiovascular-related events.
 Beneficial Effects
Bone Health

T increased lumbar spine, Whether these fndings translate into a

but not hip, BMD decrease in fracture incidence remains
to be determined.

A meta-analysis of randomized placebo-

controlled trials that found also that testosterone
therapy improved bone resorption marker
concentrations by approximately 17%
 Beneficial Effects
Metabolic Health

Double-blind, placebo-controlled
RCTs involving testosterone
therapy for men with DM 2
Testosterone levels are and/or metabolic syndrome have
lower in men with DM 2 found no improvement in insulin
resistance (as assessed by
HOMA2-IR) or in glycemic
control (as assessed by
hemoglobin A1c).
Risk
Polycythemia Prostate Cancer

Cardiovascular Health
 RISK - Polycythemia
• The most common adverse effects of testosterone therapy in
older men is polycythemia (hematocrit > 52%).
• Testosterone therapy suppresses hepcidin ->leading to an
increase in hemoglobin of approximately 1 g/dL, increase in
hematocrit of approximately 3%, and a greater than threefold
risk of polycythemia.
• This effect is related to both dose and formulation and can
therefore be minimized with careful monitoring and dose
titration
 RISK - Prostate Cancer
• The effect of testosterone therapy on prostate cancer
incidence is unknown because suffciently powered RCTs
have not been performed

• Testosterone therapy increases prostate-specifc antigen

levels,current data suggest no increased risk of prostate
cancer.
 RISK - Cardiovascular Health
• Still under debate (conflicting data) on cardiovascular safety

• Two retrospective studies found a 39% to 50% reduction in mortality in men with
chronic illness who received testosterone therapy

• a retrospective case control study of 8709 male veterans with a total testosterone
level less than 10.4 nmol/L who underwent coronary angiography observed that
testosterone therapy was associated with a 30% increased risk of mortality,
myocardial infarction (MI), or stroke over the course of 27.5 months

• A meta-analysis subsequently found that testosterone therapy did not increase the
incidence of new major adverse cardiovascular events
 FDA - Urgent joint advisory committee in
September 2014
1. limit the indication for testosterone therapy to those with “classical”
hypogonadism

2. include in the labeling statements regarding the potential for cardiovascular risk,
the need for testosterone monitoring and the lack of establishment of safety or
effcacy of testosterone therapy in age-related hypogonadism.

FDA approved “only for men who have low testosterone levels due to disorders of
the testicles, pituitary gland or brain” and to add information about a “possible
increased risk of heart attacks and strokes.
 CONCLUSIONS
• Testosterone levels fall with aging, leading to LOH in
approximately 2% of men aged 40 to 70 years. ()
deterioration in testicular and hypothalamic function)
• Increased prevalence of obesity and chronic illness, which
affect pituitary gonadotropin release
• Symptoms associated with age-related low testosterone levels
are NONSPECIFIC and are HIGHLY PREVALENT among
even older men
WITHOUT LOW TESTOSTERONE LEVELS
 CONCLUSIONS
• In older men with low testosterone levels, sexual symptoms,
mood, and bone health improve with testosterone therapy.
• In frail older men with low testosterone levels, physical
function can improve with testosterone therapy.
• The effects of T therapy on QOL and metabolic health are
small and/or inconsistent and need to be weighed against the
risks (Erythrocytosis, prostate disease, and cardiovascular
events )
 CONCLUSIONS
• These complex issues make the decision to initiate testosterone therapy
in older symptomatic men challenging and generate the imperative to
establish a formal diagnosis of hypogonadism and to search for an
identifiable cause of HPG axis dysfunction.

• It does appear clear, however, that a low testosterone level in an older

man should be regarded as a biomarker of chronic illness (overt or
occult) and increased mortality and should lead to the use of
appropriate interventions with the aim of improving overall health.
Aging Males and
Testosterone

Dr Stevanus Immanuel S
Thank You
Dr. Stevanus Immanuel Silahooij