Interview
With
Dr.
Michael Scally
Nelson Vergel (NV):
Dr. Michael Scally is a well-known expert on men’s health in general, and
specifically he’s an expert on hormone therapy and issues surrounding
testosterone replacement. Dr. Scally, can you tell us a little bit about your
background?
Michael
Scally (MS): My education includes a
double degree major in chemistry (1975) and
life sciences (1975) from the
Massachusetts Institute of Technology (MIT) Cambridge , MA .
From 1975 to 1980, in the MIT division
of Brain Sciences & Neuroendocrinology, I researched and published
investigations on neurotransmitter relationships. During this time, I entered
the prestigious Health Sciences & Technology Program, a collaboration of
the MIT and Harvard
Medical School .
In 1980,
I was awarded by Harvard Medical
School a Doctorate of
Medicine, MD. In 1983, I completed a
fellowship in anesthesiology at Parkland Southwest Memorial, in Dallas . From 1983 to 1994, I was a private
practice anesthesiologist. In 1984, I set up the first
ambulatory, outpatient, surgery center at Houston .
In
1994,
I became interested in general and
preventative medicine with a focus on endocrinology. I have been active in this
area since that time.
In
1995,
I inquired to Wyeth Pharmaceuticals
about the association between primary pulmonary hypertension and pondimin
(fenfluramine). I came to learn, this inquiry later was used as evidence in the
class-action suit against Wyeth and was instrumental in showing that the known
adverse effects were known to Wyeth but not revealed to the public.
During
1994,
I competed in the Mr. Texas Bodybuilding
Championship, placing second. While exercising, I was approached by a number of
weightlifters on the medical treatment to restore the hypothalamic-pituitary
axis (HPTA) after stopping anabolic steroids (AAS). Many of these same
individuals also used over-the-counter (OTC) supplements.
As
you might know, many bodybuilders are trying to decrease their body fat and
increase their muscle mass as much as they can. And with these two specific
goals in their mind, they were having a hard time because they were taking this
over-the-counter supplement. Within a short time later, I discovered an
over-the-counter weight loss supplement containing an ingredient, tiratricol,
toxic to the thyroid. The reporting of this to the federal agency, MedWatch,
was instrumental in the nationwide seizure of the supplement thus avoiding a
disaster to the public health and welfare. We published our findings in the
peer-reviewed literature, being the first to do so.
This
spurred on my interest in the field of men’s health, particularly in the field
of testosterone and anabolic steroids. I recognized the use of a treatment for
stopping anabolic steroids, both prescription and nonprescription, was without
any scientific support. The accepted standard of care within the medical
community for anabolic steroid-induced hypogonadism is to do nothing with the
expectation the individual will return to normal unassisted. This is proving
not to be the case and now jeopardizes the health and welfare of countless
individuals.
I
developed a treatment for anabolic steroid-induced hypogonadism that has been
published and presented before the Endocrine Society, the American Association
of Clinical Endocrinologists, American
College of Sports
Medicine, and the International Workshop on Adverse Drug Reactions and
Lipodystrophy in HIV. The condition of anabolic steroid-induced hypogonadism is
found in nonprescription and prescription AAS alike. The failure of the medical
community to recognize the importance of anabolic steroid-induced hypogonadism,
particularly in the research setting, is the focus of my recently published
book, “Anabolic Steroids—A Question of Muscle: Human Subject Abuses in Anabolic
Steroid Research.”
NV:
There are lots of misconceptions when it comes to testosterone replacement in
men. Will you tell us, in your opinion, what are the main misconceptions? For
instance, some doctors may think that giving testosterone to somebody with low
testosterone may affect the liver, or may cause cancer of the liver or
prostate.
MS:
There are many misconceptions regarding
anabolic steroids, which include testosterone. You mentioned two of the areas:
liver and prostate cancer. Other areas are enlargement of the prostate or
benign prostate hypertrophy, anabolic steroid dependency, cardiovascular
disease, and addiction.
I believe that many
of the misconceptions come about by the politicization of anabolic steroids. As
far as prescribed medicines are concerned, anabolic steroids are the only group
of drugs with a law specifically aimed at their use. This has led to a lack or
absence of good research. Instead, what the medical community has relied on are
anecdotal and inflammatory reports.
This is probably most
evident in the medical community’s steadfast refusal to accept that anabolic
steroids increase muscle mass and strength. We now know that anabolic steroids
conclusively do increase muscle mass and strength and athletic performance.
As far as liver
effects, use of the oral anabolic steroids has been reported to cause liver
dysfunction and cancer. These reports are primarily in individuals with a preexisting
condition treated for extended periods. The intramuscular injections and
transdermal preparations do not appear to be associated with liver problems,
and routine monitoring is therefore unnecessary. In the thousands of patients
I have treated with testosterone, I never even think about liver problems being
a contraindication, because they just do not come up.
In
non-obstructive benign prostatic hyperplasia (BPH), testosterone replacement
therapy is not a concern. The prostate volumes increase in an inconsistent
manner. As with any treatment, careful monitoring will alert one to a problem.
As far as prostatic
cancer, there is no association. In 2004, a New England Journal of Medicine article
review of over 60 studies on testosterone
replacement therapy concluded that there is no causal or association with
prostate cancer.
NV: But testosterone
replacement seems to be getting more and more mainstream. Ever since the
introduction of gels like Androgel and Testim, more and more doctors feel
comfortable prescribing testosterone. But yet, there are still a lot of fears,
too. Another fear is changes in lipids and cardiovascular risks associated with
testosterone. Can you expand on that a little?
MS:
The available data indicate that
testosterone replacement therapy within the physiologic range by transdermal or
injectable testosterone preparation is not associated with worsening of the
lipid profile. Studies using physiologic replacement doses of testosterone show
no change, or only a slight decrease, in HDL, often with a reduction in total
cholesterol. The oral non-aromatizable anabolic steroids appear to lower
high-density lipoprotein (HDL) levels.
The
belief that testosterone is a risk factor for cardiac disease is based on the
observation that men have both a higher incidence of cardiovascular events and
higher testosterone levels than women do. There is little data for this idea.
Many studies suggest the opposite. There are multiple studies showing a
relation between hypogonadism and an increased cardiovascular risk.
There
is evidence that testosterone replacement therapy may be beneficial for men
with cardiac disease. In a small study, men with chronic stable angina who were
treated with transdermal testosterone replacement therapy had greater angina free
exercise tolerance. Importantly, testosterone replacement therapy has not shown
an increased incidence of cardiovascular disease or stroke.
NV:
There are some data on hypogonadism and increased risks of cardiovascular
events. Is that what you mean? Some people actually become so severely
hypogonadal, they actually may be risking higher incidence of heart attacks and
strokes?
MS: That is correct.
There are numerous studies demonstrating the relationship between low
testosterone levels and adverse cardiovascular events, as well as stroke. Also,
there are case study reports of people who stop anabolic steroids, and then
suffer a heart attack.
In the book that I wrote, one of the studies in the published
literature, looking at the effects of
anabolic steroids in certain populations, for 12 weeks, did
not look at the patients after they stopped the drug. If you want to look
at the effects of these drugs, you need
to see what happens when you stop them. I filed a Freedom of Information Act to
obtain the patient records. One of the patients actually suffered a heart
attack within four weeks of stopping the anabolic steroid. The details,
including the original patient records, of this case are reported in my book.
NV:
Should patients with an increased or elevated prostatic specific antigen (PSA)
avoid testosterone? What role does testosterone replacement therapy (TRT) have
on prostate cancer, if any? Is there a risk of worsening prostate cancer with
TRT?
MS:
You brought up a number of important and
controversial issues. It is generally agreed that TRT with established prostate
cancer is contraindicated.
It is known that
suppression of testosterone levels causes regression of prostate cancer, and it
is now commonplace for men with metastatic prostate cancer to undergo treatment
designed to lower testosterone levels. The question becomes if lowering
testosterone causes prostate cancer to regress, does elevating testosterone
cause prostate cancer to appear?
There are case
reports suggesting that TRT may convert an occult cancer into a clinically
apparent lesion. These studies are wrong. One must be very careful in
attributing causality to testosterone, since over 200,000 men are given a diagnosis of prostate cancer each year, and most
of these cases are first detected by a rise in the PSA level unrelated to
testosterone therapy. Studies have demonstrated a low frequency of prostate
cancer in association with TRT. Despite extensive research, there is no
compelling evidence that testosterone has a causative role in prostate cancer.
There appears to be
no compelling evidence at present to suggest that men with higher testosterone
levels are at greater risk of prostate cancer or treating men who have
hypogonadism with exogenous androgens increases this risk. In fact, prostate
cancer becomes more prevalent exactly at the time of a man’s life when
testosterone levels decline.
Little
evidence exists on the safety of TRT initiation after treatment for primary
prostate cancer. In one very small case series, TRT after treatment of organ
confined prostate cancer produced no adverse effects. There are no large,
long-term studies proving that the risk of recurrence is not affected by TRT.
Personally, I would be reluctant to provide TRT in prostate cancer; treatment
should be left to strict research protocols.
PSA is a serum glycoprotein
made by the normal prostate that is widely used as a tumor marker, because
elevated PSA levels correlate with the risk of prostate cancer. A PSA value
greater than 4.0 ng/mL has been the
standard indication for prostate biopsy since the introduction of this test in
the 1980s.
Testosterone
trials have inconsistently shown a rise in PSA, typically between 0.2 and 0.5 ng/mL. A greater
increase in PSA arouses concern that prostate cancer has developed. It is my
practice to recommend a prostate biopsy in any patient with a yearly PSA
increase of 1.0 ng/mL or more. If the
PSA level increases by 0.75 ng/mL in one year, I
repeat the PSA measurement in three to six months and recommend a biopsy if
there is any further increase.
NV:
Can you explain what polycythemia is and what it means when it comes to
cardiovascular risk and other issues?
MS:
In respect to anabolic steroid-induced
polycythemia, polycythemia is a condition that results in an increased level of
circulating red blood cells in the blood stream. Erythrocytosis is a more
specific term that is used to denote increased red blood cells. People with
polycythemia have an increase in hematocrit, hemoglobin, or red blood cell
count above the normal limits. The reporting of polycythemia is typically in
terms of increased hematocrit or hemoglobin.
Hematocrit
is a blood test that measures the percentage of red blood cells found in the
whole blood. This measurement depends on the number and size of red blood cells.
Normally, for a male, the hematocrit raises up to a level of 52–54 depending on the
reporting laboratory reference range. Polycythemia is considered when the
hematocrit is greater than the upper limit of normal.
Hemoglobin
is the protein molecule in red blood cells that carries oxygen from the lungs
to the body’s tissues and returns carbon dioxide from the tissues to the lungs.
The hemoglobin level is expressed as the amount of hemoglobin in grams (g) per
deciliter (dl) of the whole blood, a deciliter being 100 mL, for adult males: 14–18 gm/dL.
Polycythemia is considered when a hemoglobin level is greater than 18 g/dL in men.
It
is a thickening of the blood. The blood becomes almost like sludge. You would
think that with the increased number of red blood cells, it would carry more
oxygen; but its oxygen-carrying capacity decreases markedly. Without treatment,
polycythemia can be life threatening. Elevation above the normal range may have
grave consequences, particularly in the elderly, since an attendant increase in
blood viscosity could aggravate vascular disease in the coronary,
cerebrovascular, or peripheral vascular circulation. However, with proper
medical care, many people experience few problems related to this disease.
Symptoms of
polycythemia can be none to minimal in many people. Some general and
nonspecific symptoms include weakness, fatigue, headache, itching, redness of
your skin, bruising, joint pain, dizziness, abdominal pain, shortness of
breath, breathing difficulty when you lie down; and numbness, tingling, or
burning in the hands, feet, arms, or legs.
NV: Or when they work out, they turn red.
MS: That can certainly be a symptom of polycythemia.
NV:
Is the incidence of polycythemia related to the route of administration, dose,
duration, and age? Is polycythemia common in replacement doses?
MS:
Yes. It occurs quite frequently in
people who are just on replacement testosterone. Older men appear more
sensitive to the erythropoietic effects of testosterone than young men do. Both
testosterone dose and mode of delivery affect the magnitude of hematocrit
elevation.
The incidence of
testosterone-associated polycythemia may be lower in males receiving
pharmacokinetically steady-state delivery of testosterone formulations, than it
is in receiving intramuscular injections.
In patients using
topical preparations, there is a 5–20 percent
incidence of erythrocytosis. There is an apparent direct relation between
testosterone dosage and the incidence of erythrocytosis. Erythrocytosis occurs
in about 5– 15 percent by patches and in 10–20 percent with gel
preparations depending on the use of 50 mg/day (delivering 5 mg /day) and 100 mg/day (delivering 10 mg/day) during the course of approximately 14 year.
The
most commonly used forms of intramuscular-injectable testosterone esters are
testosterone enanthate and cypionate. Injectable testosterone esters generate
supranormal testosterone levels shortly after injection and then testosterone
levels decline very rapidly, becoming subnormal in the days before the next
injection.
Testosterone
ester injections have been reported to be associated with a higher risk of
erythrocytosis than transdermal testosterone. It is unclear whether the higher
frequency of erythrocytosis observed with injectable testosterone esters is due
to the higher dose of testosterone delivered by the injections or the higher
peaks of testosterone levels. In one study, intramuscular injections of
testosterone enanthate produced an elevated hematocrit over 40 percent.
NV: Is therapeutic phlebotomy a good way
to manage polycythemia?
MS:
Untoward events are unlikely with mild
erythrocytosis of relatively short duration. Therapeutic phlebotomy and blood
donation are overall a safe procedure, the frequency of side effects being low
and their severity weak. Other options include dosage reduction or the
withholding of testosterone. However, these latter options can be problematic
since the patient will experience symptoms of anabolic steroid-induced
hypogonadism.
This
does present a catch-22 for many physicians. Because the half-life of the red
blood cell is approximately 120 days,
it might be a considerable length of time, more than three months or longer, to normalize the hemoglobin or hematocrit upon
TRT cessation. But, the problem of anabolic steroid-induced hypogonadism
symptoms complicated matters.
Many
a times, an attempt will be to maintain TRT while simultaneously performing a
therapeutic phlebotomy. Because of the increased erythro-poiesis, production of
red blood cells, it feels like the proverbial chasing one’s tail. In a number
of therapeutic phlebotomies, the units of the blood that have to be taken off
are clearly quite excessive; and we do not want to do that too quickly. It may
come to be three, four, or even five pints of blood that have to be taken off.
In order to get a good hold
on the problem of polycythemia, it will be necessary to discontinue TRT. What
we have done again, in our protocol, is that we have stopped the testosterone,
thereby removing the cause of the increased red blood cell production, treat
them with the HPTA protocol that prevents the hypogonadism, and have the
therapeutic phlebotomy done. They are able to get the hemoglobin or hematocrit
down to the normal level, do not go through the adverse effects of the hypogonadism;
and then, at the other end, be able to start the testosterone therapy again. As
far as we can determine, no testosterone associated thromboembolic events have
been reported to date.
NV:
I am actually surprised how many patients are out there that do not have their
physician following up their hematocrit when they are put on testosterone or
anabolics for wasting syndrome. It is something that the physician should be
looking out for and measuring.
MS:
The hemoglobin and hematocrit is part of
the routine laboratory follow-up for anyone on TRT. If a patient complains of
any of the symptoms we describe for polycythemia, a hemoglobin and hematocrit
should be checked. One of the confounding problems is the symptoms tend to be
nonspecific.
NV:
Can you say something about the prophylactic use of finasteride or dutasteride
to avoid DHT-related problems like prostate enlargement or hair loss? Is there
a role for the use of finasteride or dutasteride to prevent the possible
increase of hair loss with TRT?
MS:
Finasteride and dutasteride are 5-alpha
reductase inhibitors. 5-alpha reductase comes in two forms, type 1 and type 2, and is
responsible for the conversion of testosterone into DHT. Finasteride inhibits
type 2 only while dutasteride inhibits both forms.
Finasteride
comes in two doses depending on whether the indication is for hair loss or
benign prostate hypertrophy. Propecia, 1 mg, is for hair loss.
Proscar, 5 mg, is for prostatic
hypertrophy.
DHT has been shown to
be important in the development of hair loss or male pattern baldness. I am
unaware any studies indicating a worsening of hair loss or male pattern
baldness, though this possibility has not been carefully studied. There are
anecdotal reports. The prophylactic use of these drugs is an individual decision
after weighing the risks and benefits.
DHT
is also important in prostate health. It is thought an overabundance of DHT may
be important in benign prostatic hyperplasia (BPH) and prostate cancer.
Dutasteride provides greater suppression of DHT than finasteride does, thereby
underlying the hypothesis that inhibition of both type 1 and type 2 would provide
correspondingly greater protection than inhibition of type 2 alone.
However,
significant side effects of finasteride use include reduced volume of ejaculate,
erectile dysfunction, loss of libido, and gynecomastia. This will prevent many
from their use.
Some
people think that DHT will affect lean body composition. DHT does have a higher
affinity for the androgen receptor. But the enzyme that converts testosterone
into DHT is not located in the muscle. There is no evidence for these drugs to
effect muscle mass.
NV:
What about other issues related TRT, such as to increased estrogen levels and
gynecomastia?
MS:
A small number report breast tenderness
and swelling. Fluid retention is uncommon and generally mild, but TRT should be
used cautiously in men with congestive heart failure or renal insufficiency.
After confirmation of elevated estrogen, estradiol, levels, this can be treated
with either an aromatization inhibitor or estradiol receptor blocker. This must
be done very carefully as any prolonged reduction in estradiol levels runs the
risk of causing osteoporosis.
Exacerbation
of sleep apnea or the development of sleep apnea has been associated with TRT
who have other identifiable risk factors for sleep apnea. The mechanism appears
to be central mediated rather than by means of changes in the airway. Other
side effects include acne, oily skin, increased body hair, and flushing.
Hypertension has rarely been reported.
Of
course, the adverse effect I am most concerned with is androgen-induced
hypogonadism, which occurs in one hundred percent of individuals stopping TRT,
the variables being the duration and severity.
On
testosterone replacement therapy, for those without organic hypogonadism, those
with late onset of hypogonadism, the only thing that I always caution about is
that people should not be on testosterone replacement therapy, year after year
after year, without stopping every 12–18 months
to restore the axis, to make sure the function is still there. The longer you
are on testosterone, the harder it is going to be to come off testosterone.
NV:
In your opinion, can you tell us a little bit about the different options for
TRT? Have you seen any difference in using gels versus injections? Is there any
advantage or disadvantage to using either one?
MS:
Injectable, transdermal, buccal, and
oral testosterone formulations are available for clinical use. These forms of
treatment differ in several key areas.
Oral preparations
include methyl testosterone and fluoxymesterone, which are rarely prescribed
because of their association with substantial liver toxicity. In Europe , there is an oral preparation of testosterone undecanoate,
Andriol. It has a poor history of bioavailability.
Recently, the FDA
approved a buccal preparation of testosterone, Striant. Striant requires
administration twice a day. It is used little at this time.
Transdermal
testosterone is available as a patch, Testim, and gel, Androgel. Daily application
is required for each of these. They are designed to deliver 5–10 mg of testosterone a day. The advantages include ease of use and
maintenance of relatively uniform serum testosterone levels over time. Skin
irritation in the form of itching and redness is a frequent adverse effect of
Testim with reports as high as 60–70 percent. This is
uncommon with Androgel. Inadequate absorption through the skin may limit the
value of transdermal preparations in some persons. A common problem is the low
dose preparations provide inadequate serum testosterone levels. This is also
seen with the high dose.
The topical have
become, by far, the most-used products in the last decade or so, approaching a
billion dollars in sales. Androgel is the biggest product of the topical.
If the patient is not
too scared of doing injectables, oil-based testosterone ester preparations are
available. The most commonly used injectables are Delatestryl or testosterone
enanthate and depo testosterone or testosterone cypionate. In my practice, the
typical dose is between 100 and 150 mg/week. The peak serum levels occur in 2–5 days after injection, and a return to baseline is usually observed
10 days after injection. In this manner, adequate serum levels are
maintained. Intramuscular injections of testosterone can cause local pain,
soreness, bruising, redness, swelling, and possible infection.
NV:
Most doctors prescribe 1-cc of 200 mL of testosterone every two weeks.
Can you describe the problems with this schedule, if any?
MS:
This is a problem that is seen much more
often than necessary. Many doctors use a typical dose is 100 mg/week or 200–300 mg every two to three weeks.
Within
7–10 days after injection, the serum testosterone levels are low to
abnormally low. This is described as a “roller coaster” effect, characterized
by alternating periods of symptomatic benefit and a return to baseline symptoms,
corresponding to the fluctuations in serum testosterone levels. This can be
discovered by having the testosterone level checked within 24 hours prior to injection.
NV:
Can you talk to us a little bit about compounding pharmacy products? In
particular, when using testosterone gels with concentrations higher than 1 percent for reaching total testosterone blood levels above 500 ng/L. Have you had any experience
with the compounding industry?
MS:
I have had some experience with the
compounding industry. Compounding pharmacies are very capable at providing
higher concentrations of transdermal testosterone preparations. Because of
this, they are able to supply a transdermal product in small volumes. They also
tend to be less expensive than commercially available pharmaceutical
testosterone replacement options.
NV:
Do you think it is advisable to get your testosterone levels rechecked after a
few weeks of starting any of the therapies?
MS:
My protocol is that once I start a
patient on testosterone, I check the testosterone level 4–6 weeks after
initiating TRT. In patients using topical preparations, I recommend testing
within 4–6 hours after application. Those using injectables of testosterone
esters, I recommend testing within 24 hours before their next scheduled injection.
NV:
Do you have any preference between the free testosterone and total testosterone
test?
MS:
In the monitoring of the patient on TRT,
I utilize the total testosterone. The initial evaluation of a patient might
include the use of free testosterone or bioavailable testosterone. In a
symptomatic individual, the total testosterone can be normal but the free or
bioavailable testosterone abnormal.
Testosterone
circulates in three forms. Testosterone circulates in a free or unbound state,
tightly bound to SHBG, or weakly bound to the blood protein albumin.
Bioavailable, non-SHBG, testosterone includes free testosterone and
testosterone that is bound to albumin but does not include SHBG -bound
testosterone.
Examined changes over
time have demonstrated a decrease in the total testosterone and an increase in
SHBG levels. Because of this, the total testosterone might be normal, whereas
the free or bioavailable testosterone is abnormal. If these alternative methods
are used to diagnose hypogonadism, their utility during TRT is limited.
I would caution about
the assay methodology used to calculate the free or bioavailable testosterone.
The methods used to conduct the measurements vary in their accuracy,
standardization, the extent of validation, and the reproducibility of results.
Bioavailable
testosterone is measured or calculated in several ways. SHBG bound testosterone
can be precipitated with ammonium sulfate and the remaining testosterone is
then taken as the bioavailable.
Measures of free
testosterone (FT) are controversial. The only standardized and validated
method is equilibrium dialysis or by calculating free testosterone levels based
on separate measurements of testosterone and SHBG. Other measures of free
testosterone are less accurate.
NV: And your goal is usually to have
patients above what level?
MS: I like their total testosterone trough or lower level to be in
the 500–700 range, normal being 300–1,000 ng/dL.
NV:
Besides checking of the initial T level, can you elaborate on the monitoring
during TRT?
I recommend a
periodic follow-up of patients receiving replacement testosterone therapy at
the interval of three months during the first year of treatment. Afterward,
patients are followed up every six months. It is important to do a review of
systems to ensure the relief of the complaining symptoms as well as no
worsening or new symptoms.
In addition to the serum
total testosterone, I routinely monitor the basic chemistry profile, which
includes liver function, kidney function, electrolytes, glucose, lipid panel,
and hemoglobin or hematocrit. At three months, I will often include estradiol and DHT levels.
If
the patient is older than 50 years,
I include the PSA. The role of digital rectal examination (DRE) and PSA in
detecting early, clinically significant, prostate cancer is controversial. I
discuss this with each patient and allow them to decide on their use.
NV:
How about the new non-steroidal androgens that are in the pipeline? Can you
tell us what you have read about them?
MS:
They are called SARM: selective androgen
receptor modulators. They are going to become more and more popular. The
closest SARM that is coming to the market, and it is years away, is called
ostarine. It is being developed by GTx, Inc. Ligand Pharmaceuticals has a SARM
in early phase of development. They are both traded on the NASDAQ Exchange.
The
initial studies are being done in cancer patients. The data collected is change
in muscle mass and strength. The clinical outcome being measured is the six-minute
walk test.
My
feeling on this is that we have a long way to go before these things come to
market. If they come to market within the next 5–10 years, we will be lucky. As far as I know, these are the only
SARMs in human clinical trials.
NV:
I have also heard that SARMs may not have any influence on sexual function,
only on lean body mass and maybe some functional capacity. They are really not
replacement of testosterone. Are they?
MS:
From the initial studies, these are
meant to take the place of anabolic steroids, not testosterone. There are no
indications SARMs are being developed as TRT. The data from both animal and
human studies is that they act similarly, if not identically, to anabolic
steroids. They act through the androgen receptor. They do cause HPTA
suppression.
Even though they have
the same effect, they will be able to be marketed without that name “anabolic
steroids.” This would be an obvious advantage in their marketing. It should be
noted that these drugs, SARMs, have already found their way into the
nonprescription or illicit market.
NV:
Can somebody on testosterone replacement become less fertile? If a man wants to
impregnate his wife after, let us say, a year of testosterone replacement, is
there any risk for that man to become less fertile to his wife?
MS:
Testicular size and consistency often
diminish, and men should be advised that fertility would be greatly compromised
during testosterone replacement therapy because of downregulation of LH and
FSH.
The
general rule is they will become less fertile. But you cannot depend on its use
as a fertility drug. And that is where we come in with contraceptive studies.
We have many, many contraceptive studies that use testosterone cypionate at 200 mg a week and find that, yes, it decreases fertility. But there is
still a subset of men that still produce sperm that are fertile.
NV:
Are these men good candidates for a protocol to reset their HPGA?
MS:
We have had many men who come to the
clinic with the actual complaint that they were using anabolic steroids, or
they were using testosterone, and they now want to get their wife pregnant.
Although many will return to normal after stopping TRT, this period can be lengthy.
The
amazing thing to me is that the number of people that come to me, who have seen
the doctor, who are either non-prescription or prescription anabolic steroid
users, testosterone with or without combination of anabolic steroids, who have
the problem of infertility; and their doctors have no idea what to do, except
to do nothing. But on top of this are all the psychological problems and
effects that come along with doing nothing as a consequence of anabolic
steroid-induced hypogonadism. The HPTA protocol has restored fertility as well
as decreased the time substantially.
NV: Can you expand about resetting the
HPGA?
The
word resetting is a misnomer, though recent studies published in the New
England Journal of Medicine (NEJM) do indicate this possible. In 2007, the NEJM reports on the
resetting of the HPTA after TRT for adult onset idiopathic hypogonadism. This
is the first report demonstrating HPTA plasticity in adulthood. The term I
prefer is HPTA functionality and restoration.
There are clear
conditions under which testosterone requires administration for life-long
treatment. However, there are increasing numbers of individuals being treated
with TRT who do not fall under these disorders. TRT is being prescribed more
and more for late onset hypogonadism. This is called by many other names,
including andropause, androgen deficiency of the aging male, and others.
There
are no consequences of the decline in serum testosterone with age that are
known with certainty. Several parallels exist between the effects of aging and
those of hypogonadism, which suggest that the decline in serum testosterone
might be a cause of several effects of aging. Since the long-term effects of
androgen treatment for late onset hypogonadism or andropause are not
well-known, I discontinue therapy on an approximate annual basis to ensure HPTA
normalization—functionality. This allows the patient the autonomy to stop
therapy should the need arise.
What
is clear is that upon stopping testosterone or anabolic steroids, a period of
anabolic steroid-induced hypogonadism ensues. This occurs in one hundred
percent of individuals stopping testosterone. The only variables are the
duration and severity. The duration of hypogonadism, or the severity of
hypogonadism, is typically related to the anabolic steroid drug, dose, and
duration.
In other words, one
person that is on testosterone for an entire year; they may come back to normal
within 1 or 2 months. Another person may take 12, 18 months, or even 3 years
to come back to normal. The best studies we have on this are contraceptive
studies with testosterone for over a year. And what we find in those studies is
that it may take up to three years
for a person to return to normal.
If
they have been taking those anabolic steroids to improve their body composition,
increase the lean body mass, and decrease the body fat, that all goes back to
normal after stopping anabolic steroids. But you are also going to be exposed
to the other adverse effects of hypogonadism, which include adverse
psychological and cardiovascular effects. Some of the adverse psychological
effects are depression, decreased cognitive abilities, insomnia, decreased
libido, and erection dysfunction. More significantly, after cessation adds the
comorbid condition of hypogonadism to their already existing chronic illness.
AAS,
including testosterone, licit and illicit, administration induces a state of
hypogonadism that continues after their cessation. All compounds classified as
androgens or anabolic steroids cause a negative feedback inhibition of the
hypothalamic-pituitary testicular axis, suppress endogenous gonadotropin
secretion, and as a consequence serum testosterone.
The symptoms of AIH
are identical to classical hypogonadism. This problem prevents many of
discontinuing testosterone or anabolic steroids. As we have said, there are
many reasons for stopping testosterone, including polycythemia, gynecomastia,
and other issue as compliance, affordability, and changing life style.
The
accepted standard of care within the medical community for anabolic steroid
induced hypogonadism is to do nothing with the expectation the individual will
return to normal unassisted. But the literature shows this not to be the case.
AIH is critical
toward any planned use of AAS or similar compound to effect positive changes in
muscle mass and muscle strength as well as an understanding for what has been
termed anabolic steroid dependency. The further understanding and treatments
that mitigate or prevent AIH could contribute to androgen therapies for wasting
associated diseases and stopping nonprescription AAS use.
NV: What is used for restoring the hormonal axis?
MS:
A combination of three drugs. The
individual use of HCG, clomiphene citrate, and tamoxifen is well-known,
well-accepted, and well-tested standards of care treatments in peer-reviewed
medical literature for diagnostic testing for underlying pathology of
hypogonadism. The HPTA protocol uses the medications human chorionic
gonadotropin, clomiphene citrate, and tamoxifen.
The first phase of
the HPTA protocol examines the functionality of the testicles by the direct
action of HCG. HCG raises sex hormone levels directly through the stimulation
of the testes and secondly decreases the production and level of gonadotropin
LH. The increase in serum testosterone with the HCG stimulation is useful in
determining whether any primary testicular dysfunction is present.
This
initial value is a measure of the ability of the testicles to respond to
stimulation from HCG. Demonstration of the HPTA functionality is an adequate
response of the testicles to raise the serum level of T well into the normal
range. If this is observed, HCG is discontinued. The failure of the testes to
respond to an HCG challenge is indicative of primary testicular failure. In the
simplest terms, the first half of the protocol is to determine testicular
production and reserve by direct stimulation with HCG. If one is unable to
obtain adequate (normal) levels successfully in the first half, there is little
cause or reason to proceed to the second half.
The
second phase of the HPTA protocol, clomiphene and tamoxifen, examines the
ability of the hypothalamic-pituitary axis to respond to stimulation by
producing LH levels within the normal reference range. The clomiphene citrate
challenge differentiates secondary hypogonadism. Clomiphene is an antiestrogen,
which decreases the estrogen effect in the body. It has a dual effect by
stimulating the hypothalamic pituitary area and it has an antiestrogenic
effect, so that it decreases the effect of estrogen in the body. Tamoxifen is
more of a strict antiestrogen; it decreases the effect of estrogen in the body,
and potentiates the action of clomiphene. Tamoxifen and clomiphene citrate
compete with estrogen for estrogen receptor binding sites, thus eliminating
excess estrogen circulation at the level of the hypothalamus and pituitary,
allowing gonadotropin production to resume. Administering them together
produces an elevation of LH and secondarily gonadal sex hormones. The
administration of clomiphene leads to an appropriate rise in the levels of LH,
suggesting that the negative feedback control on the hypothalamus is intact and
that the storage and release of gonadotropins by the pituitary is normal. If
there was a successful stimulation of testicular T levels by HCG, but an
inadequate or no response in LH production, then the patient has
hypogonadotropic, secondary, hypogonadism.
In
the simplest terms, the second half of the protocol is to determine
hypothalamo-pituitary production and reserve with clomiphene and tamoxifen. The
physiological type of hypogonadism—hypogonadotropic or secondary—is
characterized by abnormal low or low normal gonadotropin (LH) production in
response to clomiphene citrate and tamoxifen. In the functional type of
hypogonadism, the ability to stimulate the HPTA to produce LH and T levels
within the normal reference range occurs.
There
is a dearth of good studies in anabolic steroids, both while you are taking
them and after you stop them, I think this is going to be something that we are
going to need to look at in the future. In fact, we are going to plan on
looking at it in our proposed clinical studies that we have with our company
for the prevention of anabolic steroid-induced hypogonadism.
Dr Michael Scally can be contacted at mscally@alum.mit.edu. His book “Anabolic
Steroids - A Question of Muscle: Human Subject Abuses in Anabolic Steroid
Research” is available on Amazon.com