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Ancient Greeks described
the connection between the testes and male vigor. They noted the finding
associated with male castration and were astute enough to postulate on
the decline in vigor, seen with the age-related decline in a man’s
testosterone level.
Galen described these
findings; in that era, he or others actually prescribed consumption of
animal testes in an attempt to restore vigor—although there are no
double blind placebo control data from the literature of the time.
Historical
Perspective
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 men’s corpses into older men with some success.
In 1930’s America, some of these transplants were attempted, using
deceased convicts as donors. In 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 as an aid
to implementing and precisely monitoring 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
Testosterone is a
steroid hormone produced by the Leydig cells of the testes. 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.
Slide 01
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. As testosterone levels rise, there is an
associated negative feedback effect at the hypothatlamus 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;
testosterone levels correspondingly are allowed to rise.
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 are formed,
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-cellularly by 5-alpha-reductase, becoming
dihydrotestosterone (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 protranscriptional 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.
Testosterone’s effects
are body wide. Its presence is (or lack thereof) is manifested 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.
The decline in
testosterone levels associated with normal aging is multifactoral, with
no one event being the most frequently seen finding in a given patient
population.
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 sex hormone binding globulin (SHBG). SHBG levels increase with age,
regardless of intervention, lowering 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.
The previously mentioned
factors, acting additively, lead to less total testosterone production,
with an increase in binding protein levels, further depressing
free/functional testosterone levels.
Signs &
Symptoms of Declining Testosterone Levels Slide
Slide 08
The signs and symptoms
of declining testosterone levels have been examined in validated in two
ways:
-
Examining an
age-matched population cohort, correlating findings within a group.
-
Following
individuals longitudinally, correlating findings to a given
subject’s testosterone levels.
Looking at testosterone
levels in these ways creates a valid method to evaluate a patient’s
status relative to an age-matched population group and to
himself/herself over time.
Testosterone is an
anabolic (or building) hormone. The age-related decline in testosterone
levels is associated with the following identifiable signs or symptoms:
-
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.
-
Increase in body
fat mass, particularly abdominal fat and pectoral fat.
Sometimes, gynecomastia, (enlargement of breast tissue in men) 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.
-
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 appearing 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 four will suffer a vertebral or hip fracture.
-
Decline in sex
drive and frequency of sexual thoughts.
Interestingly, this decline precedes declines in actual
performance.
-
Increased
frequency of erectile dysfunction in men; diminished sexual response
and pleasure in women.
-
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."
-
Decline in
stamina and exertional performance. A graph of testosterone and
growth hormone diminution can be placed over a graph, reflecting the
percentage of professional athletes still performing at a given age
and having essentially identical shapes. Similar functional declines
also are noted frequently by other "performance-minded" individuals,
like business executives and people whose careers demand
multi-tasking or complex problem-solving skills.
-
Decline in
cognitive skills, concentration and memory.
Studies show declining testosterone level is strongly associated
with cognitive decline and diminished visuospacial memory.
-
Coronary artery
disease and cholesterol derangement.
In population studies, low testosterone levels are associated with
increased risk of atherosclerotic cardiac disease. Older men treated
with testosterone can show decreases in total cholesterol and LDL.
Low testosterone levels also are correlated with a greater degree of
atherosclerotic obstruction when coronary artery disease is
present.
The first signs of
declines 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.
While decreased libido and erectile quality are often the most
frequently associated findings associated with falling testosterone
levels, they are actually some of the latest symptoms, with other
findings present much sooner.
These symptoms are
usually attributed to psychosocial stressors or “aging” and not
investigated. As testosterone levels continue to fall, patients notice
difficulty with maintaining muscle mass and strength—as well as
difficulty handling an increase in body fat, despite a maintained
activity level or exercise regime. Meadowlark Lemon once described this
situation quite aptly, “I run just as hard as I used to . . . it just
takes me longer to get there.” Patients notice lack of progress with
dedicated exercise or realize they have to increase subjective workout
efforts to maintain their body composition.
Testosterone & Body Composition
Population studies have
pointed out the inverse relationship between both retention of lean mass
and gain in fat mass associated with declining testosterone levels.
The Annewieke study
showed a direct correlation between testosterone levels and lean mass in
subjects over age 70, with an inverse correlation regarding body fat.
(1)
Slide 02
The Bross study showed
similar findings, but across a much more broad age range. (2)
In addition to
correlating testosterone decline with loss of lean mass, studies have
been done looking at the relationship between testosterone replacement
and a return to a more favorable body composition.
In two articles by
Tenover, testosterone replacement was demonstrated to increase lean body
mass. Predictably, subjects who began the studies with the lowest
testosterone levels had somewhat greater gains; the group of subjects
under age 50 showed greater improvements than older subjects. (3)
The second Tenover study
demonstrated that patients with an average testosterone level of 400 ng/Dl
(and classically stratified as “normal”) had conformational changes,
evidenced after a relatively brief 12-week period of testosterone
replacement. (4)
The Urban study showed
similar findings, but with a pretreatment testosterone inclusion level
of 480 ng/Dl. This study also noted a significant increase in quadriceps
and hamstring strength. (5)
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.
The findings in Snyder’s
study were consistent with the aforementioned studies. (6)
Slide 03
The consensus from the
literature is that testosterone supplementation is accompanied by gains
in lean mass, across all age groups. The Snyder and Marin studies
demonstrate testosterone supplementation as associated with reduced body
fat, with some preferential fat loss seen on the trunk (central). (7)(8)
Slide 04
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.
Testosterone & Bone Mineral Density
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 (9).
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)
Slide 05
All measures of body
composition:
lean mass, body fat and bone mineral density; 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.
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.
Testosterone & Heart
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.
In a 1987 study by
Chute, this relationship was well-demonstrated, revealing a five-fold
reduction in coronary artery disease (CAD) risk in otherwise normal non-hypogonadal
community dwelling subjects, whose testosterone levels were in the top
quartile vs. those in the lowest quartile. (10)
And in 1992, Khaw’s
prospective study with a 12-year follow-up of 511 men revealed that low
testosterone associated with increased central adiposity. (11)
Additional cardiac risk
factors demonstrated a relationship to testosterone levels.
A 1988 study by Khaw
showed an inverse correlation between testosterone levels and systolic
as well as diastolic blood pressure (BP). His review of 1132 men, ages
30-79, demonstrated that both BP values correlated inversely with
testosterone levels. Even in normotensives, higher testosterone levels
correlated with lower blood pressure readings and subsequent risk for
hypertension development. This relationship was evidenced in all BP
ranges and across all age groups in the study. Khaw additionally noted a
progressive decrease in blood pressure values for each higher quartile
of testosterone level. (12)
Marin, in two studies
published in 1992, showed normalization of testosterone levels produced
decreases in central adiposity, waist-hip ratio, insulin resistance,
total cholesterol and diastolic BP. He described similar associated
results in studies on females. (13)
Marin’s second study
showed similar results, repeating his previous findings and additionally
showing decreased glucose clearance times after insulin clamping. He
concluded that testosterone replacement was associated with improvement
in insulin sensitivity. (8)
Studies by Tenover and
Zmuda demonstrate the impact of testosterone on lipid profiles.
Slide 06
Published in 1992, the
Tenover study revealed results of her treating male subjects (ages
57-76) with intramuscular testosterone replacement therapy. Her data
showed increases in lean body mass, depression of urinary hydroxyproline
excretion (a marker of bone turnover, elevated when net bone loss is
occurring), a significant increase in hematocrit, a decline in total
cholesterol as well as low-density lipoprotein cholesterol. Tenover
demonstrated that maintained testosterone levels were associated with
lower total cholesterol, LDL and risk for CAD diagnosis. (3)
Zmuda, also in 1992,
published a 13-year longitudinal study of 41- to 61-year-old men (age at
enrollment time). This was a “normal” population sample, having an
average total testosterone of 751 ng/Dl at the study’s start and an
average decline in testosterone levels over that 13-year period of 41 ng/Dl.
The relatively small drop in testosterone was associated with a rise in
triglyceride levels and decline in HDL, present after correcting for
body habitus and other lifestyle parameters. (14)
These studies dovetail
nicely to illustrate the impact of testosterone on CAD risk and lipid
profiles.
In men with preexisting
CAD, testosterone replacement has shown to have clinical efficacy, as
well.
English, KM, 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
being informed 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. (16)
In a study published by
Wu and Weng in 1993, a group of 62 men with CAD were examined. The group
had significantly lower baseline testosterone levels than non-CAD
control subjects. After testosterone treatment, the group demonstrated
(a) significant improvement in angina symptoms; (b) ST changes during
ETT electrocardiography in 68% of subjects; (c) improvement in
ambulatory ST segment readings, during Holter monitoring in 75% of the
study patients; (d) baseline testosterone levels were inversely
associated with the extent of coronary artery occlusion on angiographic
imaging at study entry. (17)
In a 1999 study, Webb reported similar
findings, with CAD patients showing a 20% prolongation in time to ST
segment depression on exercise testing.
(18)
Additional studies have
served to reinforce these findings.
1.
By Malkin
in the Journal of Endocrinology, points out the association with
low testosterone levels and risk for coronary artery disease.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12967330
2.
By Bhasin
in Clinics of Infectious Disease. The article acknowledges the
widespread belief that testosterone supplementation increases the risk
of atherosclerosis, but points out actual evidence of this premise is
lacking. The author raises the issue that in epidemiologic studies,
testosterone levels have been inversely correlated to risk for heart
disease and other factors, which predispose to heart disease.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12942389
3.
By
Eckardstein, published in 2003. The article remains neutral overall,
regarding testosterone replacement therapy—finding neither increase nor
decrease risk. Of interest is the article’s discussion and description
of why negative articles on testosterone looking only at HDL miss
important points, regarding cardiac risk. In this case, no associated
risk is also a positive outcome when looking at testosterone therapy; no
harm is a fine result.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12914731
4.
By
Sieminska, published in 2003. The work found that men with coronary
artery disease had significantly lower levels of free testosterone than
men without CAD.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12761451
5.
By Barud,
published in 2002. The article showed a significant inverse correlation
between testosterone level and antibodies to oxidized LDL—and that only
testosterone levels were associated with lowering this risk factor for
heart disease.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12204799
6.
By Wassef,
published in 1998. The work points out that only a few items affect
Lipoprotein (a) in a positive fashion. Lipoprotein (a) is a significant
heart disease risk factor. The author states that niacin compounds,
moderate doses of alcohol, neomycin and androgens are associated with
lowering Lp(a).
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10665339
7.
By Zhao in
the 1998 International Journal of Cardiology. Zhao found that
testosterone levels in patients with heart disease were significantly
lower than in healthy subjects, noting that statistically, low total
testosterone levels are associated with increased risk for diagnosis of
heart disease.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9510490
8.
By
Phillips, published in 1994. The article reveals testosterone levels
correlated negatively with risk factors for heart disease, including
Fibrinogen, Plasminogen, Activator Inhibitor 1 and insulin; it concluded
that in men, low testosterone levels might be a risk factor for heart
disease.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8172848
9.
By
Contoreggi, published in 1990. Another neutral study finds no
significant differences in testosterone, when comparing groups of men
with and without heart disease.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2147671
10.
By
Sewdarsen, in Atherosclerosis, 1990. In their total male patient
population having had myocardial infarction (heart attacks) between ages
30-60, it was found that their testosterone concentration was
significantly lower than in men without a cardiac history.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2242091
11.
By
Srzednicki, published in 1990. It was found that testosterone
concentrations in unstable coronary artery disease were significantly
lower than in men with stable coronary artery disease—and lower still
than those found in healthy controls. Again, this points out an inverse
correlation between testosterone and coronary artery disease risk.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2287567
12.
By
Sewdarsen, published in Atherosclerosis, 1986. It was concluded
that low testosterone levels were a statistical risk factor for future
myocardial infarction.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3729798
The Muller, M. et al study was a landmark
meta-analysis of the relationship between testosterone and subsequent
risk for cardiovascular disease. 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.(19)
http://www.J
Clin Endocrinol Metab.
2003 Nov;88(11):5076-86.
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
cardiovascular disease 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 this graphic summary,
the 66 percentile values are marked, showing a corresponding reduction
in relative risk vs. average testosterone values. (19)
Slide 07
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.” (20)
Testosterone & Brain
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. (21)
Moffat, et al, showed
that 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. (22)
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.
(22)
Gouras GK, et al. They
demonstrated that testosterone reduces neuronal secretion of Alzheimer’s
β-amyloid peptides. (23)
Papasozomenos
demonstrated that testosterone decreases the change of Tao protein
phosphorilation seen in AD plaques. (24)
Gillett, in 2003,
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. (25)
Tan, in 2003, conducted a study, which showed testosterone modulation in
men with AD was associated with significant improvement on MMSE and
other cognitive measures, while the placebo group demonstrated a typical
decline in cognitive status. (26)
Hogervorst, 2003:
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. (27)
Another article by the
same author in 2004 discusses the direct predictive relationship between
testosterone levels and AD risk. (28)
Paoletti, 2004: In male
and female subjects, lower testosterone levels were evidenced in AD
patients vs. controls. Elevated SHBG also demonstrated a positive
association; testosterone therapy was associated with lowered SHBG.
Lower androgen indices in both men and women were associated with AD.
(29)
In all, maintained
testosterone levels carry a significant cognitive benefit.
Testosterone, Erectile Function & Libido
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)
Carani and Jain performed studies on men
with normal pretreatment testosterone levels who presented erectile
dysfunction with positive results in both studies.
(35)(36)
Testosterone & Mood
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.
Testosterone & Prostate Cancer Risk
At some point in most
physicians’ training, they must have met the same spectral urologist,
who traveled from training program to training program, walking the
hallways proclaiming testosterone is associated with prostate cancer
risk. These same physicians-in-training must have been hypnotized by
this urologist and his post-hypnotic suggestion—never go to the
literature and look the topic up. On one level, the mythical urologist
was correct: Testosterone is associated with prostate cancer risk, but
in the exact opposite relationship he proclaimed.
The following list
reflects a review of testosterone and prostate cancer risk. There is 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.
1.
Published
by Cooper in the Journal of Urology. Study showed that
testosterone replacement therapy was not associated with any rise in PSA
or prostate volume. (37)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9649259
2.
By Hoffman
in the Journal of Urology in 2000. Hoffman reported that patients
with prostate cancer and low free testosterone had more extensive
disease. In addition, all men with a biopsy Gleason score of 8 or
greater had a low serum free testosterone. His conclusion was that low
testosterone levels might be a marker for aggressive prostate disease.
(41)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10687985
3.
Asbell in
the Journal of the National Medical Association found no
correlation between PSA and androgen levels in a study of prostate
cancer patients. (42)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11052458
4.
Published
by Rhoden in the New England Journal of Medicine in 2004, a
comprehensive review of 72 prior studies concluded there was no evidence
supporting a causal link between testosterone replacement therapy and an
increase in prostate cancer risk. The following link will be directed to
the literature citation. The full article is available via the NEJM.
(43)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14749457
5.
Carter in
the Journal Prostate in 1995. Carter found no correlation between
testosterone and prostate cancer risk in patients, followed as long as
15 years before any diagnosis of prostate pathology was noted. His
concluded that his data demonstrated that no measurable difference
exists in testosterone levels among men who are destined to develop
prostate cancer in those without disease. (44)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7541528
6.
Heikkila
in Cancer 1999. Heikkila also reached the same conclusion.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10421267
7.
Gustafsson
in the British Journal of Urology. Again, the study failed to
demonstrate a connection between testosterone levels and prostate cancer
risk.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8814852
8.
Zhang in
the Journal Prostate, published in 2002. Zhand found that
patients with prostate cancer were found to have low androgen levels.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12386917
9.
Massengill
published in the May 2003 Journal of Urology. The study revealed
that low testosterone levels were predictive of pathological stage in
patients with prostate cancer.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12686805
10.
Rhoden,
also in the Journal of Urology in December 2003, evaluated
patients with prostatic intraepithelial neoplasia—commonly regarded as a
pre-malignant change in the prostate—and showed no change in PSA or
their tissue status when given testosterone replacement therapy over a
one-year period.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14634413
11.
Chen in
the Journal of Cancer Epidemiology Biomarkers and Prevention.
Chen found that testosterone levels were unrelated to prostate
pathology.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14693730
12.
Hoffman in
the Journal of Urology in 2000. Again, the study found that low
testosterone levels, rather than high, were a marker of prostate
disease. (41)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10687985
13.
Stattin in
the International Journal of Cancer did a pool-to-prospective
study and found there was no evidence to conclude a connection exists
between high testosterone levels and increased prostate cancer risk.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14648709
14.
Gann in
the Journal of the National Cancer Institute in 1996. Gann found
it was not testosterone levels that related to prostate cancer risk, but
rather low levels of Sex Hormone-Binding Globulin in conjunction with
high testosterone levels.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8757191
15.
Hsing in the Journal of the
National Cancer Institute in 2003. The study revealed a connection
between insulin-resistance and the effect of high insulin levels on
prostate cancer risk being a positive association.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12509402
16.
Slater, S. Drugs and Aging,
2000. After 34 studies were reviewed, no data existed to support higher
risk for prostate CA with elevated testosterone levels vs. controls.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11200304
17. Zhang, Prostate,
2002. The work also reported that in patients with prostate cancer,
testosterone levels were lower than in controls.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12386917
18. Gustafsson, Br J Uro, 1996. The study
demonstrated an inverse relationship between dihydrotestosterone levels
and the presence of prostate cancer. His study also demonstrated
further inverse correlation between DHT and tumor stage.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8814852
19. Haapiainen, 1988.
The study revealed higher pretreatment testosterone levels in subjects
with prostate cancer were associated with better survival.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=
Abstract&list_uids=3187401
Lab Tests:
Testosterone Levels
In making the decision
regarding which tests to use for assessing a patient’s testosterone
levels, two tests have the greatest clinical utility. Total testosterone
and free testosterone provide ample information for appropriate decision
making.
Total testosterone
measures all forms of testosterone in a sample, including protein bound
and hormone, which is bound to sex hormone binding globulin (SHBG).
Free testosterone
measures hormone that is unbound and actively bioavailable.
While free testosterone
levels have the most utility, measuring total testosterone as well
provides additional information for safety monitoring and epidemiologic
data.
There are indices based
on calculations using total testosterone and other laboratory values:
bioavailable testosterone and free androgen index. These calculations
have become much less clinically important, given the availability of
free testosterone levels.
Measuring sex hormone
binding globulin (SHBG) does not provide any 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.
This table demonstrates
normal range testosterone levels by decade of life. (51)
Slide 08
The current laboratory
custom of providing testosterone results normed 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.
Of note, these are
testosterone levels relatively well preserved over time, with the 66th
percentile value to age 100 still being above 500 ng/dl.
These values offer a
glimpse at what values are statistically associated with best clinical
status and lowest health risk at given age intervals.
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.
Testosterone Supplementation
Therapy goals are based
on the preceding table and the literature, citing the lowest health risk
values.
Testosterone
supplementation should take place within a comprehensive milieu, which
allows optimizing any opportunity to identify and address underlying
pathology as well as to avoid any mis-association of pretreatment
disease and patient status after treatment.
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.
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.
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
over time is required to avoid sub-therapeutic or supraphsyiologic
hormone levels—and to maximize benefit while minimizing any potential
side effect.
Delivery
Mode
After the decision to
augment testosterone levels has been 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.
Testosterone is
available directly in oral, injectable, topical and implantable
formulations. It may also be supplemented indirectly by human chorionic
gonadotropin administration, which stimulates testosterone production by
the testes.
An illustration of the
testosterone synthesis pathway:
Slide 09
Of note, administration
of “precursor” molecules occurring higher in the synthesis pathway is
not typically associated with meaningful downstream alterations in
testosterone production.
A recap of the
testosterone feedback pathway, with an addition:
Slide 10
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.
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
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)
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 supraphysiologic 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. Slide
11
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.
Testosterone Dosing
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.
Another item of concern
associated with larger testosterone doses at longer intervals:
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.
Slide 12
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).
Human Chorionic
Gonadotropin (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.
Slide 13
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 (“beating a dead horse”
ever harder still yields the same outcome) while normal or low LH levels
offer a more likely prediction for HCG success.
Slide 14
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