|
A modern tale of
testosterone
Ancient
Greeks described connection between the testes and male vigor. They
noted changes associated with male castration (eunuchs) and men with
shrinking testicles, and postulated on the decline in vigor. Galen
described these findings; in that era, he, or others, prescribed
consumption of animal testes in an attempt to restore vigor—although no
double-blind placebo control data from Athens and the literature of the
time exist in today’s archives. Some of the myths surrounding replacing
vigor with animal gonads do persist: consider Rocky Mountain oysters on
the menus of fine Western restaurants.
Historical
Perspective
Shriveled
testicles, drooping scrotal sacs, change in libido, decreasing muscle
mass, and competition from younger men signals a declining virility.
This decline could accompany the aging process, and be reluctantly
accepted as fate. However, younger men who experienced these changes
challenged physicians and soothsayers to return their manhood.
Testosterone was the hormone was identified.
As extracting
skills improved, British physicians in the 1800s used many different
testicular extracts with reported clinical responses. They even
described cadaveric transplants from younger male corpses into older men
with some success. In 1930s America, some of these transplants were
attempted, using deceased convicts as donors. By 1935, testosterone was
purified, yielding a Nobel Prize for the team accomplishing this feat.
In 1940, JAMA
published the first article describing the clinical utility of using
testosterone to treat symptoms of the “male climacteric.” A subsequent
article in 1944 showed similar results.
From then
until the 1970s, testosterone was given according to subjective criteria
and with generalized dosing regimens. Once testosterone levels could be
measured, it became possible to more accurately assess individual levels
to implement and precisely monitor therapy. With the ability to measure
testosterone came data, showing that testosterone levels decline with
age. Studies found that after age 30, testosterone levels may diminish
an average of 2% annually.
Testosterone
Physiology
Androgen
can be either a natural or synthetic compound, usually a
steroid
hormone,
to stimulate or control the development and maintenance of masculine
characteristics by binding to
androgen receptors.
Androgens are the original
anabolic steroids.
They are also the precursor of all
estrogens.
The major androgen is, of course,
testosterone.
Besides testosterone, other androgens include:
Dihydrotestosterone (DHT): a
metabolite of
testosterone, is produced in the
adrenal cortex. This is a more potent androgen than
testosterone in that it binds more strongly to
androgen receptors.
Testosterone is a steroid hormone produced by the Leydig
cells of the testes. It is an anabolic (or building) hormone. Its
synthesis, like that of many hormones, is the result of a
signal-production-negative feedback loop (commonly seen with other
hormone synthesis regulation), which uses negative feedback to maintain
homeostatic hormone levels.
The hypothalamus
produces gonadotropin-releasing hormone (GnRH), which passes into the
pituitary gland via portal circulation and stimulates the pituitary
gland to secrete leutinizing hormone (LH.) LH is released into
circulation and reaches the testes, where it acts as the stimulus for
testosterone production. Like gonadotropins, testosterone is secreted in
a pulsatile fashion which, in adult men, occurs throughout the entire
day.
As testosterone
levels rise, there is an associated negative feedback effect at the
hypothalamus level, which decreases GnRH production. Much like
temperature regulating the status of a furnace thermostat, this feedback
loop regulates testosterone production. When testosterone levels dip,
GnRH synthesis resumes; and testosterone levels correspondingly are
allowed to rise. This testosterone negative-feedback inhibition at the
hypothalamus level, regulates testosterone’s homeostasis.
Testosterone
exerts its main effect on cells by affecting DNA transcription.
Testosterone can freely enter a cell’s cytoplasm, where it binds to
androgen receptor proteins. Once bound, androgen receptor/androgen
complexes form, which change the androgen receptor’s conformation. The
complex enters the cell’s nucleus, where it can bind DNA receptor sites
and act as a promoter for specific gene transcription. Testosterone can
be converted intra or extra-cellular by 5-alpha-reductase, becoming DHT
and binding the androgen receptor in that form as well. DHT is the more
biologically active form of testosterone. Once bound by either molecule,
the net effect is pro-transcriptional, and moves a cell toward positive
(or anabolic) nitrogen balance and protein synthesis. This effect is not
limited to the sex organs; in fact, it plays an important role in
maintaining general physiologic function. Recall that testosterone has a
negative-feedback inhibition at the hypothalamus level, which regulates
testosterone’s homeostatic function. In 2000, Hayes published an article
in the Journal of Clinical Endocrinology and Metabolism, looked
at the estradiol role in this negative feedback loop. It was found that
estradiol is a potent negative feedback inhibitor of hypothalamic
gonadotropin secretion.1
Slide01
Testosterone’s
effects are body wide. Because about 30% of testosterone is bound to sex
hormone binding globulin (SHBG), it is not biologically available. It is
the 1% to 2% of free testosterone (free T) that is physiologically
active. Its presence is (or lack thereof) manifest in multiple organ
systems, with testosterone associated with retention of desirable values
of actuarial disease risk and with well-maintained body composition. The
impact of falling testosterone levels upon many of these parameters is
examined as part of this presentation.
Aging
The decline
in testosterone levels associated with normal aging is
multi-factorial, with no one event being the most common finding in
a given patient population. These events can be measured as the
levels of serum testosterone begin to change. Studies suggest that
about 20% of men in their 60s, and half of men in the 80s have low
serum testosterone levels.2
Concommintently, metabolic syndrome (MetS), and its conditions of
obesity, type 2 diabetes mellitus, and hypertention increase the
risk of hypergonadism .3,4
Not only MetS impacts men’s health, but
adverse environmental factors are attributed to testosterone
deficiency.5
6
Anatomy
and physiology change. There is a decline in the absolute number of
Leydig cells in the testes; each remaining cell shows a decline in
testosterone production. There is an associated decline in
testosterone synthesis proteins and enzymes, evidenced in aging
Leydig cells. The net result is the presence of fewer cells, lower
production per cell, and loss of previous response to stimulatory
signals.
Additionally,
the pituitary gland loses the ability to coordinate pulsatile LH
secretion patterns and becomes more random. The loss of coordinated
LH pulses—rather than a decline in over-all amount of LH
production—is associated with diminished testosterone production.
Another
factor affecting the functional availability of testosterone is the
age-related increase in SHBG. SHBG levels increase with age,
regardless of intervention, and lower the amount of unbound (free)
testosterone. These proteins "cling" to testosterone. Even though
testosterone may be present, it is not "free" or biologically
available to do its work. Increasing SHBG levels, therefore, reduces
free testosterone to an even greater extent than the reduction seen
in total testosterone. These factors, act additively to lead to
less total testosterone production, and an increase in binding
protein levels, further depressing free/functional testosterone
levels.
Obesity,
however, is associated with decreased SHBG productions, then
increases total T, but decreases free T. Although this might seem
contradictory, other factors exist. Obesity is associated with
increased inflammatory cytokine production and increased
aromatization to estradiol in peripheral fat tissues. Consequently
the pituitary production of gonadotropins is decreased which then
decreases testicular production of T.
7
Diagnosis
Slide02
Men with
testosterone deficiency are often under-diagnosed and undertreated.
The first signs of decline in testosterone are generally slightly
vague: diminished subjective energy levels, increase in
irritability, decline in mood, decline in cognitive performance,
loss of early morning erections. These symptoms often mimic other
conditions. Complaints including infertility, decrease in beard and
body hair, increase in body fat, decrease in muscle mass,
gynecomastia, changes in size or firmness ot testicles, and
osteoporosis should alert the physician to testosterone deficiency.
8
While decreased libido and erectile quality are often the most
frequent findings associated with falling testosterone levels, they
are actually some of the latest symptoms, with other findings
present much sooner.
Often,
individuals and family attribute these symptoms to psychosocial
stressors or “aging” and do not investigate the cause. As
testosterone declines, age-related drops in testosterone levels is
associated with identifiable signs or symptoms: A decline in muscle
mass and strength, decrease of bone mass, increase in body fat,
particularly abdominal and pectoral fat, coronary artery disease
and cholesterol derangement. decline in cognitive skills or
concentration and memory, decline in stamina and exertion
performance, increased frequency of erectile dysfunction, decline in
sex drive and frequency of sexual thoughts, and decreased sense of
overall well-being, perception of energy level and vigor. These
signs and symptoms will be discussed individually to present a
complete picture of the importance of testosterone diagnosis.
The signs and
symptoms of declining testosterone levels have been examined in
validated in two ways: 1. Examining an age-matched population
cohort, correlating findings within a group, and 2. Following
individuals longitudinally, correlating findings to a given
subject’s testosterone levels. Looking at testosterone levels in
this way creates an evidence-based method to evaluate a patient’s
status relative to an age-matched population group and to
himself/herself over time.
A decline in muscle mass and strength.
Loss of muscle volume and tensile strength are hallmarks of aging.
Diminishing testosterone levels directly correlate with a decrease
in the synthesis rate of muscle proteins, formation of contractile
structures and the force-generating capabilities of muscle cells.
Declines in muscle mass also are correlated with increased risk for
falls and fractures. Population studies have pointed out the inverse
relationship between both retention of lean mass (LBM) and gain in
fat mass associated with declining testosterone levels. The
Annewieke
9
study showed a direct correlation between testosterone levels and
lean mass in subjects over age 70, with an inverse correlation
regarding body fat.
Slide03
In addition to
correlating testosterone decline with loss of lean mass, studies
looked at the relationship between testosterone replacement and
a return to a more favorable body composition. Retained muscle
mass and strength are strongly associated with decreased
fall-and-fracture risks—a finding consistent, even after
correcting for bone mineral density. Well-maintained lean mass
is associated with better gait and gait correction, resulting in
fewer falls and fractures, even in patients with osteoporosis.
A study accessing the independent effects of estradiol,
testosterone, and SHBG,researchers concluded that low estradiol
(bioE2) and high SHBG increased the risk of nonvertebral
fractures; low testosterone and high SHBG was also associated
with fracture risk. The strongest association occurred when all
measures were considered in combination.10
Slide04
The
consensus from the literature is that testosterone
supplementation is accompanied by gains in lean mass, across all
age groups. as associated with reduced body fat, with some
preferential fat loss seen on the trunk.
Slide05
Decline in central body fat is associated with a decrease in
waist-hip ratio. Both central adiposity and waist-hip ratio are
independent actuarial risk factors for subsequent development of
coronary artery disease.
Increase in body fat mass, particularly abdominal and pectoral
fat.
Sometimes, gynecomastia, may occur. Decreases in testosterone
also are associated with increasing levels of leptin. Leptin is
a peptide hormone produced by fat cells; its circulating levels
are directly reflective of an individual's fat mass. Adequate
testosterone levels and lean mass are inversely correlated with
leptin levels. Central adiposity is a classic feature of MetS,
and has independently been associated with reduced testosterone
levels.
11Pasquali,
Osuna, Svartber. Svartberg (2004) suggests that waist
circumference is better at predicting testerone levels than body
mass index (BMI)12,
Svartberg, although the inverse relationship of BMI with low T
is very significant.13
Decrease of bone mass.
Studies indicate age and associated declines in testosterone
levels correlate with bone loss in men. Decreased estradiol
and testosterone levels are associated with bone loss in
women—a phenomenon that appears at an earlier age and more
rapidly, compared to men. Up to 30% of men 60 years old and
over may become osteoporotic. One in six will fracture a hip
at some point in his life. Women are hormonally and
statistically more complex than men. Female hormone
replacement studies do not separate the effects of estrogens
and testosterone, but do show benefits of proper overall
hormone replacement programs. An unsupplemented woman
between age 60 and 80 will show a 50% reduction in her
original bone mineral density; one in five will suffer a
vertebral or hip fracture.
Like
the relationship between lean mass, there is a similar
correlation between testosterone levels and bone mineral
density (BMD). In population studies, like the one published
by Annewieke, a direct correlation between BMD and
testosterone levels was demonstrated, with retained
testosterone levels associated with better-maintained BMD
and lower testosterone levels associated with diminished BMD
values. In the Kholsa study, subjects on testosterone
replacement therapy showed increase in bone mineral density
(BMD) across all age groups.14
The Snyder study showed an average of 4.2%
increase in BMD over a 36-month treatment period. Also, it’s
worth noting that average expected bone loss during that
same 36-month period would have been approximately 1% per
year. After a 36-month study, the treatment group would have
shown a greater than 7% improvement, relative to an
untreated group. Also of interest, the subjects in the study
who had the lowest BMD scores were also the ones who had the
largest interval improvements in their BMD. (7)
Slide06
Decline in sex drive and frequency of
sexual thoughts.
Interestingly, this decline precedes declines in actual
performance.
Increased frequency of erectile
dysfunction (ED) in men.
The effects of
testosterone on erectile function and libido have been
well-documented for the treatment of “classically”
hypogonadal men. The Kwan and Skakkeback studies show
improvement on several sexual performance fronts, as
expected. (31)(32) The Hajjar, O’Carroll and Morales
studies demonstrate the same benefits in subjects who
did not meet diagnostic criteria for frank hypogonadism.
These subjects noted improvement in libido and
performance with statistically normal range testosterone
levels. (30)(33)(34)
The prevalence of hypertension in men with ED was found
to be 44% and the incidence of hypogonadism was 30.8% in
men with ED.15
Mulligan found that more men with hypertension have T
levels lower than normal.
Decreased sense of overall well-being,
perception of energy level and vigor.
These types of complaints, along with non-specific
irritability, are frequently the first symptoms
associated with declining testosterone levels - yet,
they are the most often overlooked or incorrectly
attributed to stress or "not being as young as you used
to be." Looking at testosterone and its relation to
measures of mood or well-being, Marin demonstrated
improvement in mood scores with testosterone
supplementation. (13) Cooper published similar findings
with regard to anxiety score (37); Margolese noted that
lower testosterone levels were correlated with the
diagnosis of depression. (38) In studies of sexual
function, mood and well-being, testosterone levels and
supplementation correlate with improved quality of life.
All measures of body
composition:
lean mass, body fat and BMD, and testosterone levels are
positively correlated with a compositional advantage,
based on reviews of endogenous levels in population
studies and longitudinal studies examining outcomes
associated with testosterone replacement therapy. Low
testosterone demonstrated an association to measures
related with higher health risk; intervention reversed
these undesirable findings. Muller et al found that
higher testosterone and SHGH levels in aging males are
independently associated with a higher insulin
sensitivity and a reduced risk of MetS, independent of
insulin levels, and body composition measurement
suggesting that these hormones may protect against the
development of MetS.16
Retained lean mass is associated with increased strength
and coordination, maintained physical function and less
injury from falls. Body fat reduction is associated with
decreased CAD risk and decreased risk for developing
adult onset diabetes (DM II) and metabolic syndrome. BMD
is associated with decreased risk for osteoporosis, and
it has a positive statistical relationship for health
risk in general and as a biomarker for dementia risk.
Decline in stamina and
exertion performance.
A graph of testosterone and growth hormone diminution
can be placed over a graph that shows the percentage of
professional athletes still performing at a given age,
and both graphs have essentially identical shapes.
Similar functional declines are also noted frequently by
other "performance-minded" individuals, such as business
executives and people whose careers demand multi-tasking
or complex problem-solving skills. Research
investigating the effects of GH and IGF-I in
combination at supra-physiological doses of (rh) GH
failed to demonstrate improvements in muscle
performance.17
To test the hypothesis that endogenous testosterone and
GH are important independent, but complementary
regulators of skeletal muscle mass and function, central
obesity , and substrate metabolism into advanced age.
Conclusions that combined administration of
physiological doses of testosterone and rhGH resulted in
substantial gains in lean mass, voluntary muscle
strength, and aerobic endurance, along with reductions
in total and trunk fat. Further research into the
augmentation of androgen and GH-IGF-I can be expected
before using these agents together in clinical practice
for aging.
18
Decline in cognitive skills,
concentration and memory.
Studies show declining testosterone level is strongly
associated with cognitive decline and diminished visual-spacial
memory. In the film “Sleeper,” Woody Allen described the
brain as his second favorite organ, and the same can be
said of testosterone’s favorite organs. The brain is
second only to the heart in terms of abundance of
testosterone receptors and receptor concentration.
Testosterone features prominently in neurologic
literature; it is associated with maintained cognitive
function in the aging brain, lowered dementia risk and
improvements in the neurophysiology of subjects with
preexisting dementia.
Rupprecht, in Trends in Neuroscience, 2003,
discusses the novel physiologic effects of testosterone
on neuronal receptors and receptor metabolism
regulation. This study reviewed testosterone’s
neurocognitive importance and its possible role in
decreasing symptoms of depression, anxiety and panic
disorders.19
Moffat, et al, showed that Alzheimers Disease (AD) risk
is inversely associated with Free Testosterone Index (FTI)—this
association remained after adjustments for age,
education, smoking status, body mass index, diabetes,
any cancer diagnoses and hormone supplement history.
Increases in FTI associated with decreased risk of AD
(hazard ratio = 0.74; 95% CI = 0.57 to 0.96)—a 26%
decrease for each 10-nmol/nmol FTI increase.
Additionally, Moffatt demonstrated that free
testosterone concentrations were lower in men who
subsequently developed Alzheimer disease. Interestingly,
these findings were present before any symptom of AD was
present, either by patient history or clinical exam. The
study was of excellent length with a mean follow-up time
of 19 years, with some patients followed for 37 years.20
Researchers demonstrated
that testosterone reduces neuronal secretion of
Alzheimer’s β-amyloid peptides.21
Others demonstrated that lower androgen levels are
associated with increased plasma levels of Amyloid beta
peptide 40 in older men with memory loss or dementia,
suggesting a sub-clinical androgen deficiency enhances
the expression of Alzheimer's disease-related peptides
in vivo.22
Patients with the APO-E4 allele are at high risk for
development of future AD and have been shown to
demonstrate a concurrent decrease in testosterone
compared to normal controls, even in the absence of any
other demonstrable finding according to Hogervorst.23
Another article by the same author in 2004 discusses the
direct predictive relationship between testosterone
levels and AD risk.24
And in yet another article, lower testosterone levels
were evidenced in AD patients vs. controls in both male
and female patients;elevated SHBG also demonstrated a
positive association; testosterone therapy was
associated with lowered SHBG, and finally, lower
androgen indices in both men and women were associated
with AD.25
29
In all, maintained
testosterone levels carry a significant cognitive
benefit.
Metabolic Syndrome (Coronary artery disease and
cholesterol derangement).
When most people think
about testosterone, the first organ system that
comes to mind is usually the reproductive tract.
But, in fact, the heart (myocardium) is the organ
with the highest concentration of testosterone
receptors. Testosterone should be considered an
active participant in cardiac health. Testosterone
is associated with several effects on cardiac
health. It has been linked with reducing coronary
artery disease (CAD) and hypertension risks, as well
as with improving cardiac function in patients with
preexisting heart disease.
The metabolic syndrome (MetS),
a constellation of cardiovascular risk factors
thought to be linked by insulin resistance, is
characterized by dyslipidemia, hyperglycemia,
hypertension, and central obesity. Current Adult
Treatment Panel (ATP) III guidelines define the MetS
as the presence of three of five determinants:
abdominal adiposity, hypertension, low high-density
lipoprotein-cholesterol, elevated triglyceride
levels, and abnormal fasting plasma glucose (FPG).
26
MetS has been established as a precursor state in
which patients are at a significantly increased risk
of developing cardiovascular disease. Although there
is continuing debate over which components of MetS
should be included, removed, or added, it is
valuable as a concept for epidemiological analysis
and bundling clinical symptoms for risk. However,
recognizing and identifying these cluster of
conditions allows the physician to aggressively
recommend lifestyle changes hoping to prevent
morbidity and mortality. Aging is associated with a
gradual decline in testosterone (T) levels in men.
Epidemiological studies
have shown that low sex hormones are more prevalent
than previously thought.27
28 29 30
Longitudinal studies from the Massachusetts Male
Aging Study (MMAS) and from the Baltimore
Longitudinal Aging Study (BAS) confirm that MetS
increases with aging and is related to hypogonadism.
31
Testosterone itself may have a central or permissive
role in the pathogenesis of the metabolic syndrome
and type 2 diabetes by increasing skeletal muscle
tissue and decreasing abdominal obesity and
nonesterified fatty acids, consequently improving
insulin sensitivity. Abdominal obesity increases
glucocorticoid turnover and production, which
disturbs regulation of the
hypothalamic-pituitary-adrenal axis and may
contribute to mild hypoandrogenism in men. An
imbalance between levels of testosterone and its
metabolite dihydrotestosterone could also
contribute.
This relationship of
hypogonadism to MetS is independent of different
definitions of MetS.
32
In population studies,
low testosterone levels are associated with
increased risk of ACD. Older men treated with
testosterone can show decreases in total cholesterol
and LDL. Low testosterone levels also correlate with
a greater degree of atherosclerotic obstruction when
CAD is present.
Hypertension
associated with hypogonadism
In a cohort study, a
multistage stratified design was used to sample of
2301 racially/ethnically diverse men age 30–79
years. Blood samples were analyzed from 1885 men
with complete data on total testosterone (T), free
T, and SHBG.A strong inverse association was
observed, in both bi-variant and multivariate
analyses, between hormone levels and MetS. The odds
of MetS increased about two-fold with a 1 SD
decrease in hormone levels. The association between
sex hormones and MetS was statistically significant
across racial/ethnic groups. Although the magnitude
of this association was largest among White men,
racial/ethnic differences were not statistically
significant. The strength of the association of sex
hormones with individual components of MetS varied;
stronger associations were observed with waist
circumference and dyslipidemia and more modest
associations with diabetes and elevated blood sugar.
Conclusions were that a robust, dose-response
relationship between sex hormone levels and odds of
the metabolic syndrome in men is consistent across
racial/ethnic groups.
33
Additional cardiac risk
factors demonstrated a relationship to testosterone
levels. In men with preexisting CAD, testosterone
replacement has shown to have clinical efficacy, as
well.
English (2000) found
that men with CAD had lower testosterone levels than
age-matched non-CAD subjects. These findings were
seen in subjects unaware of any underlying disease
and without previous CAD symptoms. The study
controlled for any possible change in testosterone
levels, which may result from a patient knowledge of
a diagnosis or potential diagnosis. (15) A follow-up
study by the same author demonstrated that
testosterone replacement therapy in men with CAD was
linked to an increased angina threshold during
exertion, with accompanying improvement in treadmill
performance/endurance vs. baseline and a decrease in
the degree of ST depression vs. baseline. Angina
profiles improved. Additionally, he found the lower
the baseline testosterone, the greater the degree of
improvement after therapy.34
The Muller, et al, study
was a landmark meta-analysis of the relationship
between testosterone and subsequent risk for CVD.
While there had been some conflicting data in
previous observational studies, Muller’s group
analyzed the data from studies, which included
adjustments for concurrent risk factors so
testosterone was the only identifiable difference
between otherwise matched groups. Their review
included 8,150 men from 11 studies. The data
analysis revealed that in 10 of 11 studies, higher
testosterone levels were associated with lower CVD
risk (including aortic and carotid disease). Men in
the upper third for testosterone level were at
one-fifth the atherosclerosis risk for that of men
in the lower one-third. In a graphic summary, the
66 percentile values are marked, showing a
corresponding reduction in relative risk versus
average testosterone values.35
Slide07
A follow-up study of 400
subjects by the same author was published in 2005.
Muller concluded: “Higher testosterone and SHBG
levels in aging males are independently associated
with a higher insulin sensitivity and a reduced risk
of the metabolic syndrome, independent of
insulin-levels and body composition measurements,
suggesting that these hormones may protect against
the development of metabolic syndrome.”36
This study showed that total testosterone and SHBG
concentrations in the low-normal range
independently predict not only diabetes, but also
the development of the metabolic syndrome in
middle-aged men, independently of BMI and other
factors related to insulin resistance. Calculated
free testosterone levels likewise predicted the MetS,
but not independently of BMI. Men with total
testosterone levels in he lower fourth were 2.3
times more likely to develop the metabolic syndrome
or diabetes. Along the same lines of MetS inquiry,
Laaksonen, et al identify hypogonadism as an early
marker for disturbances in insulin and glucose
metabolism which may progress to MetS or diabetes,
and might even contribute to their pathogenesis.37
SIGNS OF LOW
TESTOSTERONE
A decline in muscle
mass and strength
Decrease of bone mass
Increase in body fat,
particularly abdominal and pectoral fat
Metabolic Syndrome
(coronary artery disease and cholesterol
derangement)
Decline in cognitive
skills, concentration and memory
Decline in stamina
and exertion performance
Increased frequency
of erectile dysfunction
Decline in sex drive
and frequency of sexual thoughts
Decreased sense of
overall well-being, perception of energy level
and vigor
Younger Men
The focus of much of the
research has been directed at cohorts of older men.
The association of hypogonadotrophic hypogonadism
with Type 2 diabetes, but not type 1 diabetes has
been shown in middle-aged patients. A recent
investigation of TT and FT concentrations in men age
18 to 35 years with type 1 diabetes (n 38, mean age
26.45 years)) and type 2 diabetes (n 24, mean age
27.87) showed that men with type 2 had significantly
lower plasma concentrations of TT and FT than type
1. The LH and FSH was lower in the type 2 group
than type 1. The TT and FT showed an inverse
relationship to the BMI. Researchers concluded that
obese type 2 diabetic men were at risk for
hypogonadotrophic hypogonadism and the implications
for reproductive and sexual function require further
study.38
Diagnosis
During physical
examination, consider developmental anomalies such
as cryptorchidism or hypospadias. Palpate both
testes, and ascertain the equality in size,
attachment position, and consistency. Note signs of
Klinefelter syndrome, small or soft testes, and a
eunuchoild body appearance; check for gynecomastia,
facial and body virilization. Physical examination
might not be helpful in making a diagnosis of
testosterone deficiency.
Diagnosis continues
by distinguishing between Primary and Secondary
Hypogonadism. Primary causes are related to
testicular disease and Secondary Hypogonadism
is related to inadequate gonadotropic
stimulation of the testes, possibly because of
pituitary hormones, GH and LHRH.
When ascertaining
possible causes of testicular failure, consider
mumps orchitis, trauma, radiation exposure,
chemotherapy and surgery. Both prescription and
recreational drug use may interfere with
testosterone synthesis (i.e., marijuana, heroin,
methadone, and spironolactone). A history of
paternity indicates that at some point in the
past, testosterone level was probably normal.
The threshold total
testosterone values used when making a diagnosis
of hypogonadism are in dispute. Not only is
there a variation in laboratory references
levels or critical values, but there is also a
lack of consensus regarding guidelines for
treatment goals. To consider hypogonadism as a
diagnosis, there should be documented low
testosterone levels with a consistent report of
symptoms that are attributed to low
testosterone. However, as a general practice
guideline, starting testosterone replacement is
acceptable when there are consistent symptoms
and the total testosterone level is within one
standard deviation above the laboratory lowest
threshold.
Often, it is
difficult to separate signs and symptoms of
testosterone deficiency to other age-related
decline of other hormones or the start of what
will be a chronic condition. Many “hypogonadal”
symptoms are non-specific; diagnostic concerns
are of greater significance when TT levels are
near the threshold value. In those situations,
TT level might not be a true indicator of
testosterone activity, and free testosterone or
SHBG may be more diagnostic.
The normal
physiologic range is not well defined, but the
laboratory reference range is considered to be
300-1,000 ng/dL for total testosterone.
The relationship
between testosterone and MetS leads to new
physical assessments of men or women with
hypogonadism. These are simple office procedures
that can provide trend information over time.
BMI is computed as the ratio of weight to the
square of height (kg/m2). Waist girth is taken
as the average of two measurements taken after
inspiration and expiration at the midpoint
between the lowest rib and the iliac crest.
Waist-to-hip ratio (WHR) is the ratio of waist
girth to the circumference of the hips measured
at the trochanter major.
Now that you feel
comfortable with the research into testosterone
and subjective and physical findings, it is
important to access hypogonadism with objective
data.
Lab Tests:
Testosterone Levels
The establishment of
baseline laboratory parameters allows for the
most efficient therapeutic choices and makes
subsequent evaluation relevant in a specific
context for each individual. Treating the
patient with many symptoms of low testosterone
requires a complete laboratory review as
hypogonadism mimics symptoms of other conditions
and of chronic diseases. The older age of the
patient complaining of these symptoms is another
reason for a comprehensive review before
initiating treatment with testosterone.
One suggested blood
panel is the Anti-Aging Male Panel.39
This analysis include a Comprehensive Wellness
Profile (chemistry, glucose, kidney, liver
function tests, CBC, metabolic pane, lipid
profile, thyroid with TSH, and electrolytes),
DHES-S, total testosterone, free testosterone,
ICF-1, estradiol, and PSA. While all these tests
might seem excessive for the younger man,
research increasingly points to testosterone
levels associated with MetS, CAD, DM, and
osteoporosis; therefore, initial testing can
predict subsequent health problems.
Testosterone analysis
reflects a wide range of normal values. Three
forms of testosterone are found in serum: SHBG
(60-70% of total), albumin-bound (20-30% of
total), and free
(1 – 3% of total). Only albumin-bound and free
testosterone are available to tissues and are
known as “bioavailable.” Age-related declines of
1% per year seem widely accepted, although this
is challenged by research as associations with
chronic diseases co-exist.40
Deciding which
tests to use for assessing a patient’s
testosterone levels is easy: two tests have the
greatest clinical utility. Total testosterone
and free testosterone provide ample information
for appropriate diagnosis and treatment. Total
testosterone measures all forms of testosterone
in a sample, including protein bound and
hormone, which is bound to SHBG. Free
testosterone measures hormone that is unbound
and actively bio-available.
While free
testosterone levels have the most utility,
measuring total testosterone provides additional
information for safety monitoring and
epidemiologic data. There are indices based on
calculations using total testosterone and other
laboratory values: bio-available testosterone
and free androgen index. These calculations have
become less clinically important, given the
availability of free testosterone levels.
Serum testosterone
levels vary during the day and periodic
decreases that fall below the normal range can
occur in otherwise healthy men. In younger men,
circulating testosterone levels are highest in
the early morning and blood should be drawn
before 10 AM. There is less variation in the
circadian release of testosterone in older men.
When low
testosterone levels are identified, additional
testing is needed to rule out other caused of
hypogonadism. Guidelines issued by the American
Association of Clinical Endocrinologist (AACE)
include testing for LH, FSH, prolactin-1,
estradiol levels in men with high BMI, and serum
transferring saturation.
Prostate Specific
Antigen (PSA) measurement must accompany
testosterone levels at the time of an initial
evaluation to screen for any preexisting
prostate disease, direct any prerequisite
work-up of elevated level associated with
prostate disease and use as a baseline for
future program follow-up.
Measuring SHBG does
not provide additional information, which would
alter the clinician’s decision whether or not to
institute therapy or alter dosage algorithm. It
is interesting to note that regardless of
intervention, SHBG levels continue to rise with
age.
Other studies—such
as thyroid hormones, growth hormone (hGH),
leutinizing hormone (LH), dehydroepiandrosterone
(DHEA), blood count, lipid profiles and other
laboratory and metabolic markers (body
composition and bone density)—play roles in
maximizing a Testosterone Replacement Program.
Follow-up evaluation
is necessary on a 3-month, 6-month, then annual
schedule. Stressing the need for patient
compliance with dosing and return office visits
is critical to avoid sub-therapeutic or
supra-physiologic hormone levels. Adherence to
prescribed care will maximize benefit while
minimizing any potential side effect.
The current laboratory custom of
providing testosterone results normalized and
averaged to all men (age 20-70) lacks adequate
precision regarding the assessment of a
patient’s
testosterone levels
relative to an appropriately precise age-matched
cohort. These values offer a glimpse at what
values are statistically associated with best
clinical status and lowest health risk at given
age intervals. Slide08 The
66th percentile values are provided
because of their correlation to literature
reports of reduced disease risks; 33rd
percentile values are provided on the same basis
with regard to elevation of health risk.
Treatment
Symptomatic men
with a TT level less than 300ng/dL may be
candidates for testoerone replacement
therapy. Typical treatment candidates have a
validated low TT and consistent symptoms of
testosterone deficiency, especially sexual
function complaints. The benefits of
testosterone therapy includes improved
libido, sexual function, and quality of
life. Other improvements can be seen over
time including maintenance of cognitive
function, prevention of BMD loss and
osteoporosis, and reduced symptoms
associated with MetS. In older men with
low-normal serum testosterone levels, a
JAMA article (2008) no beneficial
effects on functional mobility, muscle
strength, cognitive function, or BMD.41
Slide09
Testosterone therapy in men with androgen
deficiency improves energy, body composition
and perhaps corrects the hypogonadism
associated with MetS through reducing
insulin resistance.
Studies by Saad42,
and Allen43
showed that testosterone treatment in
elderly men improved waist circumference and
several lipid parameters, and lowered blood
pressure.
|
BRAND NAME |
DELIVERY METHOD |
DOSAGE |
|
AndroGel
Testim |
Transdermal 1% Gel |
5-10 g applied daily in AM |
|
Androderm |
Transdermal Patch |
1-2 patches applied daily
(1 to 10 mg) |
|
Striant |
Buccal |
30 mg twice daily |
|
Delastestryl (T enanthate)
Depo-Testosterone (T cypionate |
Injection, IM |
100 mg weekly or 200mg every 2
weeks, or 300 mg every 3 weeks,
or 400 mg every 4 weeks |
|
Testopel |
Implant, subcutaneous |
2-6 pellets implanted every 3 to
6 months |
Testosterone
supplementation should take place within a
comprehensive milieu, which allows optimal
opportunity to identify and address
underlying pathology as well as to avoid any
missed diagnosis of pretreatment disease.
Acute or chronic conditions present at
initial examination would be treated and
stabilized before preceding with hormonal
therapy.
Delivery Mode and Dosing
After the
decision to augment testosterone levels is
made, the next step is deciding on the
proper means of delivery. There are several
different modes of testosterone delivery,
but the best method varies from individual
to individual and is dependent upon several
factors. Optimally, a testosterone delivery
method should be clinically effective in
correcting the signs and symptoms of
testosterone decline and produce
predictable, reproducible physiologic levels
of testosterone.
Several delivery methods will restore
testosterone levels to within the normal
physiologic range for age-related
hypogonadism. These include transdermal gels
and patches, intramuscular depot injections,
buccal formulations and subcutaneous
implants. Transdermal gels have become
commonly used because of their effectiveness
and convenient application.
Slide10
The
typical starting dose is 1mg/Kg body weight
per week.
At dosage
intervals of greater than one week,
supraphysiologic peaks would be required to
maintain an adequate testosterone trough
level between doses. Once-monthly dosing is
also associated with longer sub-therapeutic
trough times before the following
injection.
An
item of concern associated with larger
testosterone doses at longer intervals is
that testosterone peak levels are an
important determiner of estradiol levels.
The higher the peak level of testosterone,
the greater the associated rate of
conversion to estradiol. Since estradiol is
known to mitigate the effects of
testosterone and diminish clinical responses
to therapy in the face of well-maintained
testosterone levels, this potential result
should be minimized. Maintain lower
testosterone peaks by delivering
testosterone at a weekly dosage interval.
Slide11
An
illustration of the testosterone synthesis
pathway:
Slide12
Given that a
significant contribution to declining
testosterone levels can be associated with
decreases in pituitary production of LH and
loss of coordination of LH release, it is
possible to affect testosterone levels by
attempting to simulate previous LH secretion
patterns with an LH analog: Human Chorionic
Gonadotropin (HCG). Therapy may be
supplemented indirectly by human chorionic
gonadotropin (HGC) administration, which
stimulates testosterone production by the
testes because of concerns regarding
potential hepatotoxicity; oral testosterone
therapy is not current available in the
United States.
HCG contains a
sub-unit that is homologous to LH, providing
an alternative to simple testosterone
replacement, which allows a clinician to
utilize the patient’s own testicular
function to favorably alter testosterone
levels. HCG can be delivered as a
subcutaneous pulse dose that mimics lost
pituitary physiology, which may be
sufficient to stimulate the testicles and
allow return of previous testosterone levels
without requiring any direct testosterone
replacement.
With advancing age, HCG responsiveness
declines, from 95% response rate at age 40
to approximately 50% at age 65. This change
in responsiveness occurs independently of
any intervention. Therefore, over time, HCG
therapy can show a decline in effectiveness
along this curve.
Slide13
When making a decision whether or not to use
HCG therapy, LH levels may be useful.
Elevated LH levels would predict a low
likelihood of success, while normal or low
LH levels offer a more likely prediction for
HCG success. Of note, administration of
“precursor” molecules occurring higher in
the synthesis pathway is not typically
associated with meaningful downstream
alterations in testosterone production
Testosterone can
be converted to estradiol by an aromatase
enzyme. This is a relevant concern in men
because some men seem to have a much more
hard-wired connection between testosterone
and estradiol, so any intervention raising
testosterone levels may concomitantly raise
estradiol levels in an undesired fashion.
Estradiol can act as a testosterone
antagonist and negatively impact the
clinical response to testosterone
replacement therapy.
When choosing a
method of testosterone modulation delivery,
we are faced with several possible paths.
In an ideal
world, there would be a safe and effective
oral product—as oral medication use is
associated with the highest patient
compliance. At present, there is no adequate
product. Testosterone delivered orally
undergoes first-pass metabolism, rendering
it difficult to achieve useful serum levels.
Additionally, much of the oral dose is
converted into circulating
dihydrotestosterone (DHT), creating
supraphysiologic levels of DHT. Using
current oral preparations would also dictate
TID or even six-times/per-day dosing-and is
associated with potential hepatotoxicity.
Testosterone undecanoate is a testosterone
compound given in an oral base, taken up by
the lymph ducts in the intestines; it can
bypass the liver, thus minimizing the
typical side effects. It has, however, an
extremely short half-life, has low (and
frequently unpredictable) bioavailability
from dose to dose; and is not currently
approved by the FDA for use in America. At
present, there are no recommended oral
testosterone formulations. (46).
Androgens (such
as fluoxynesterone, methyltestosterone,
oxandrolone or danazol) are available for
clinical use, but are not appropriate for
long-term testosterone replacement therapy.
Their use is specific for certain disorders
and must be used with great caution since
they can cause an increase in liver enzymes,
blockage of liver drainage pathways, direct
liver damage and even liver tumors. They
also dramatically raise serum LDL
cholesterol, decrease HDL cholesterol and
have been associated with increased risk of
myocardial infarction and stroke.
Testosterone
formulations are also available for topical
placement. These formulations allow
testosterone absorption through the skin—the
therapy of choice for raising testosterone
levels in women. In our experience, there is
only limited application for this delivery
system in men because its produces supra
physiologic serum levels of DHT:
Testosterone is absorbed through the skin; 5
alpha-reductase converts much of the
testosterone to DHT, raising circulating
levels of DHT and increasing the exposure of
prostate and hair follicle cells to DHT
rather than testosterone, which is not as
active in these cells and not as well taken
up. Testosterone patches have also been
associated with other minor disadvantages,
including low obtainable maximum serum
testosterone levels, difficulties with the
skin area needed to apply creams for achieve
therapeutic levels in men and local skin
reactions. Mild-to-moderate reactions occur
in as many as 50% of men using some
formulations of the skin patch, which
studies have shown to produce a 30% - 50%
failure rate, due to intolerance in clinical
applications. The quite small amounts of
testosterone crème required to raise
testosterone levels in women have not been
associated with these problems. Patches may
seem more user friendly compared to
injections, but we have found their use
limited due to the above concerns.
The current standard bearer
for direct testosterone supplementation is
intramuscular (IM) delivery. Depot
formulations of testosterone exist
(suspended in oil), giving predictable
absorption patterns. Excess conversion to
DHT does not occur; at a dosing interval of
one week, there is a well-maintained
sinusoidal pattern to testosterone levels.
Monitoring Testosterone Therapy
Myth:
testosterone is associated with prostate
cancer risk and will cause prostate cancer.
There is, however, a repeated lack of
association between testosterone and cancer
risk, with studies either yielding a null
result or demonstrating an inverse
relationship between testosterone and
prostate cancer risk. Testosterone is
associated with prostate cancer risk, but in
the exact opposite relationship that the
Myth suggests. Benign prostatic hypertrophy
is not eliminated through therapeutic
testosterone therapy.
Once any
testosterone intervention is initiated,
adequate and ongoing follow-up is critical.
Starting testosterone therapy is only the
first step in a replacement program.
Continued monitoring is the hallmark of a
truly safe and successful program. With
testosterone supplementation, patients must
be followed for several possible directly
related side effects:
Hemoglobin and
hematocrit (H/H) may rise in association
with testosterone supplementation. If H/H
rises above normal limits, phlebotomy is
indicated. The condition of sleep apnea
patients may worsen with testosterone
therapy, which may be related to a rise in
H/H or may occur independently. Patients
with known apnea should be followed by the
physician who is managing the apnea.
Direct
testosterone replacement may result in some
degree of testicular atrophy. With
testosterone levels supplemented to normal
physiologic levels, this occurs in
approximately 10%-12% of patients. However,
testosterone levels typically return to
pretreatment levels when therapy ends; yet,
there is a slight chance any suppression of
testicular function may not fully resolve.
Acne may occur;
with physiologic replacement, this is quite
uncommon. Other rare side effects of normal
replacement include fluid retention and
decline in sperm count.
Patient’s
medication list should be reviewed for any
potential drug interactions. While there are
no true drug/drug reactions associated with
testosterone therapy, testosterone levels
can affect other drug clearance rates and
affect levels of anticoagulants.
An
important consideration regarding the
side-effect profile of testosterone therapy
is the possibility of raising estradiol
level, occurring in approximately 10% to 12%
of subjects placed on testosterone
replacement therapy. Since testosterone is
converted to estradiol via an aromatase
enzyme, this side effect can be easily
mitigated via judicious use of aromatase
inhibitors. By inhibiting this enzyme’s
function, testosterone levels can be
maintained while minimizing any concomitant
rise in estradiol level, helping optimize
the testosterone-estradiol relationship.
Testosterone is aromatized to estradiol by
the enzyme aromatase. Estradiol
down-regulates testsosterone receptors,
increases sex hormone binding globulin (thus
decreasing bioavailable testosterone) and
diminishes clinical testosterone response.
This is of particular importance with
maintaining libido and erection quality.
Additionally, a rise in extradiol levels may
produce nipple tenderness, nipple fullness
or even gynecomastia.Slide14
A less obvious
effect of rising estradiol levels is the
“invisible” side effect of a lessened
clinical response, despite adequately
maintained testosterone levels. For some
subjects, no outward side effect may be
discernable, but they will report an
otherwise unsatisfying clinical result.
Tracking pre- and post-therapy estradiol
levels allows objective monitoring to
minimize this possibility. It may be useful
to track testosterone/estradiol ratios,
trying to maximize this result for patients
who have not had the expected response to
testosterone therapy.
The greater the testosterone level; the
greater the rate of conversion to estradiol.
This relationship is not linear, but shows a
geometric increase in estradiol conversion
with increase in testosterone levels. This
is another important reason to monitor
testosterone levels and avoid
supra-physiologic peaks between dosing
intervals.
Slide15
Typically,
estradiol levels should be maintained within
the normal range for men, but if a patient
notes side effects before follow-up blood
can be drawn, or despite apparently normal
estradiol levels, then addressing this issue
empirically is appropriate. For patients who
have a sub-optimal response to treatment and
normal estradiol levels, calculating the
testosterone-estradiol ratio and comparing
pre- and post-therapy values can be a useful
tool in deciding whether or not to institute
measures to lower estradiol.
Anastrozole is
the most commonly used preparation,
administered orally. Anastrozole has a long
serum half-life, enabling dosing to be
started at approximately two times per week.
The typical starting dose of Anastrazole is
0.5 to 1 mg by mouth twice weekly. A newer
agent, letrozole, is also available. It may
be used in an equivalent fashion to
anastrozole, with the conversion rate of
anastrozole-to-letrozole being 2.5 to one –
i.e. 2.5 mgs of letrozole being the
approximate equivalent of 1 mg anastrozole.
It was found that by
administering anastrozole, estradiol levels
were decreased in male subjects. As
estradiol levels were reduced, endogenous LH
levels rose. As a result, testosterone
levels were seen to increase, as shown in
the diagram’s middle portion. This effect
was seen in both men with idiopathic
hypogonadotropic hypogonadism and in normal
men The estradiol effect on LH production
was elucidated by administering Anastrozole,
an aromatase inhibitor, which regulates the
conversion of testosterone to estradiol.
Mauras et al,
examined this phenomenon and looked at the
effect of 0.5 mg versus Anastrozole’s 1 mg
per day, given to community dwelling normal
men.44
They found that both 0.5 mg and Anastrozole
1 mg daily dosing was associated with
similar declines in estradiol levels, and
that both doses were associated with an
approximate 50% increase in testosterone
levels. As seen in the bar graph,
testosterone response was modulated within
the normal range, placing men at
approximately the 60th – 66th
percentile of testosterone range. This is
the same testosterone level reviewed
earlier, which was associated with declines
in disease risk markers and beneficial
clinical outcomes.45
That same study looked at baseline LH levels
and compared them to LH levels after
Anastrozole intervention. Baseline LH levels
rose from 4 IU/L to approximately 15 IU/L.
Peak values increased from approximately 6
IU/L to 10 to 20 IU/L; the frequency of LH
pulses went up from baseline as well. As
discussed about the natural history of
testosterone levels, one of the main
etiologies of the age-related decline in
testosterone levels is related to a decline
in LH production and LH pulsatility. This
Anastrozole study demonstrated a reversal of
both of those findings.
Slide16
Slide17
After intervention with Anastrozole in
normal males, estradiol levels fell,
testosterone levels increased as did mean LH,
the number and amplitude of LH pulses.
In a subsequent study, published in 2004 by
Leder, a longer trial clinical was
undertaken examining long-term response to
Anastrozole as mono-therapy to raise
testosterone levels. Researchers noted a
prolonged and maintained increase in
bioavailable testosterone as well as total
testosterone, with no change in
dihydrotestosterone values. Regarding total
testosterone, pretreatment values averaged
approximately 350ng/ml with post treatment
values averaging between 550 and 600ng/ml.
The same study found a 38% decrease in
estradiol and a 50% decrease in estrone.
Slide18
Slide19
They also demonstrated an approximate 60% -
75% increase in LH production. Noteworthy
in these studies is the estradiol level
modulation, which has taken place completely
within normal laboratory range and
equivalent estradiol values, using Quest
values demonstrating a fall in estradiol
from 25 picogram/ml to approximately 12
picogram/ml. No study results produced
estradiol levels below normal or
testosterone levels above normal in the
studied subjects.
Slide20
In
pharmacokinetic studies, there is an optimal
dosing range of HCG. At doses up to 7,000 IU
per week, there is a fairly dependable dose
response curve. Above 7,000 IU/wk, receptor
saturation may occur, and can be associated
with a corresponding decline in testosterone
response. For some subjects, this receptor
saturation may occur at slightly higher or
lower HCG doses, making individual
monitoring an important follow-up
consideration and keeping HCG’s dose
response curve in mind.Slide21
HCG is best dose twice weekly as daily
administration is associated with a rapid
decline in response and decline in
testosterone levels after the first two
weeks of therapy, and.
Slide22
weekly
dosing is associated with inadequately
maintained testosterone levels.
Slide23
Twice
weekly dosing then, is associated with
well-maintained steady state testosterone
levels and this response is preserved over
time.
One caveat to
treatment of the treatment of andropause
symptoms: test first, then treat. In a
review of prescriptions filled for all
testosterone products in Canada (2007),
comparison to national laboratory data
showed that family physicians wrote 78.4% of
first time prescriptions, and urologists
wrote 3%. Thirty-five percent of patients
had baseline PSA measurement, but less than
1% received ongoing monitoring. Younger men
were more apt to have testosterone levels
measured than PSA. The study noted that 28%
of prescriptions were filled for women, an
off label use for testosterone.46
Conclusion
Findings from the
literature consistently show improvements in
well-being, and specific bone and organ
systems studied. The association of low
testerstone and MetS is particularly
encouraging because of the number of chronic
disease involved with the syndrome. Few
side effects develop in relationship to the
positive outcomes of therapeutic dosing of
testerone. Testosterone itself does not
prolong the aging process, but men can
certainly feel better while growing old.
|
|
