A look at the anabolic steroid Testosterone
By by Dana Ohl, M.D. Associate Professor of Surgery University of Michigan
I. Introduction
Androgen use is very prevalent in society. Much of this is due to androgen
abuse among athletes and bodybuilders, where black market androgen abuse has
reached epidemic proportions. Indeed, in various studies of high school boys,
it has been found that 4-12% had used androgens at least once (JAMA 27O:12l7,
1993). Androgens have also been prescribed for many conditions by physicians
throughout the last several decades.
Despite the prevalence of legal and illegal androgen use, the science of
androgen effects has greatly lagged behind the understanding of biological
effects of estrogen and indications for estrogen replacement therapy. Female
oral contraceptives have been in use for many years, but only recently have we
seen studies regarding hormone contraceptive agents in men. Although there are
a few very well-defined clinical syndromes of male hypogonadism which require
androgen therapy, the use in other clinical situations, such as mild
hypogonadism and hypogonadism associated with aging is less well established.
During this lecture, I would hope that some of the mystery of androgen therapy
in older men is overcome.
II. Normal Androgen Physiology
Testosterone is present in very low levels in boys prior to puberty. At
puberty, pulsatile secretion of GnRH causes the anterior pituitary to produce
LH and FSH. Circulating LH induces the Leydig cells of the testis to produce
testosterone, with the resultant development of secondary sex characteristics.
As the level of testosterone rise in the circulation, there is a negative
feedback on the production of GnRH at the hypothalamic level, and LH and FSH
at the pituitary level.
A high intratesticular level of testosterone is an absolute prerequisite for
sperm production. The levels in the seminiferous tubules remains high due to
the proxitimity of production in the Leydig cells, and well as by binding in
the tubules by androgen binding-protein (ABP). This binding to ABP probably
also prevents fluctuation of the levels, by maintaining a reservoir of hormone
immediately available to buffer changes in production. Although testosterone
is the only absolute requirement for sperm production, FSH has a promotional
effect, and quantitatively normal spermatogenesis requires the action of FSH
on the Sertoli cell. When sperm production is proceeding in a quantitatively
normal manner, a peptide hormone called inhibin is released into the
circulation (also by the Sertoli cell) and is responsible for negative
feedback of FSH (but not LH) production by the pituitary.
Circulating testosterone is present in several forms. Testosterone may be
present as a free hormone (not bound to any protein) or bound relatively
weakly to albumin. The majority of testosterone in circulation, however, is
bound to sex hormone binding globulin (SHBC). The testosterone bound to SHBC
is not available for biological activity. The free testosterone and that
weakly bound to alburnin comprise the so called "bioavailable" testosterone
fraction which is responsible for peripheral androgenic effects. Which is the
most important measurement in diagnosing hypogonadism, the total T, or free T
remains controversial.
Testosterone is converted to other clinically important compounds in the
peripheral circulation and/or peripheral tissues. Dihydrotestosterone (DHT) is
produced by reduction through the action of 5 reductase, which is present in
genital tissue, skin and the prostate. DHT is responsible for prostatic growth
and has other trophic effects on the prostatic tissue. Estradiol (E2) is
produced by esterification of testosterone. The rate of conversion of T to E2
can be increased in obese men and in men with liver failure. Elevated levels
of E2 can down regulate the hypothalamic-pituitary-gonadal axis, resulting in
decreased gonadotropin secretion and decreased circulating T levels.
III. Changes in Testosterone Levels With Aging
There is no corollary of the menopause seen in females as men age. The
menopause in women is caused by ovarian failure. Although no such similar
event of complete testicular failure occurs in men, it has been well
established that mean T levels drop progressively with age and the percentage
of men with T levels in the abnormal range increases (J Clin Endocrinol Metab
56:1278, 1983;J Clin Endocrinol Metab 73:1016, 1991). When one looks at the
levels of bioavailable testosterone, probably more accurate measure of the
decreasing androgenic effects, more marked changes may be evident. Other
evidence of a relatively hypogonadal state in older men includes elevated LH,
as well as an exaggerated response of LH to the administration of GnRH (GnRH
stimulation test).
Although T levels drop with aging, it is less clear whether any of the
generalized manifestations of aging, such as impotence, osteoporosis, CNS
changes, are due to the decrease in circulating androgen. Since it is not
established that these age-related changes are due to hormonal deficiencies,
the simple presence of a decline in circulating hormones cannot be taken as de
facto evidence that hormone replacement therapy will be beneficial in
reversing or preventing these changes. An example of this would be in the case
of erectile dysfunction. There are certain cases of impotence where the only
abnormality seen in testing is a low T level, and in such cases, T replacement
therapy may very well be beneficial. However, in the vast majority of older
men, one can also identify a very high prevalence of penile arterial
insufficiency, tissue dysfunction dysfunction resulting in venous leak, and
neuropathic problems, and all of these cases would not be cured simply with
hormonal therapy.
IV. Types of Androgen Replacement Therapy.
A. Oral agents -
Testosterone itself cannot be given orally because in the first pass through
the liver after oral administration, the breakdown is substantial and very
little androgenic effects would be seen. Alkylated forms of testosterone (see
table below) are much more resistant to hepatic metabolism and can exert a
clinical effect when ingested. Alkylated forms of testosterone are weaker than
T itself. The clinical efficacy is further complicated by irregular absorption
and varying degrees of hepatic breakdown on the first pass through the liver.
Therefore, varying results can be seen when giving these agents. Liver
toxicity may be substantial with oral androgens, and such toxicity may range
from an elevation of liver enzymes to development of hemorrhagic liver cysts.
Liver neoplasms have also been reported in men undergoing oral androgen
therapy.
Because of these problems, oral androgen therapy has very little place in the
treatment of hypogonadism.
B. Injectable agents-
Testosterone esters (see table) have certain advantages as injectable agents.
They are relatively resistant to hepatic breakdown, are released slowly from
oil-based carriers, and are hydrolyzed to yield testosterone itself.
Therefore, delivery in a long-acting injection is possible, and the biological
effects of the injected form of T is indistinguishable from the native
hormone. The usual dosage is approximately 100mg. of drug per week is given
and the interval can be varied to smooth out these wide swings, i.e. 100mg.
every week, 200mg every two weeks, 300mg. every three weeks, etc. acting
injection is possible, and the biological effects of the injected form of T is
indistinguishable from the native hormone.
Following a testosterone injection, the serum T level rises to high normal or
supranormal range for the first few days, followed by a progressive drop until
the next injection is administered. The T level may drop below the normal
range during this time. These wide swings may cause varying efficacy from the
treatment.
V. Testosterone patch therapy
There are currently two available testosterone patch therapies, Testoderm and
Androderm. (Please note that Dr. Ohl is a consultant for Alza Pharmaceuticals,
and Smith-Kline Beecham for these two products).
Testoderm is a patch that must be worn on the scrotum. In this location skin
absorption is increased due to the thin nature of the skin and because of this
property of the scrotal skin, permeation enhancers do not need to be placed
into the formulation to achieve adequate drug absorption. The potential
advantages less potential for skin irritation. Disadvantages include the
necessity to shave the scrotal hair and difficulty with adherence of the patch
(which has been partially circumvented with the addition of adhesive strips).
Another potential disadvantage of Testosderm is the high level of 5-reductase
activity in the scrotal skin with the potential of elevation of DHT levels. At
this point, however, there is no evidence that an elevation of peripheral DHT
levels will have any adverse effects on the prostatic tissue. Testosderm is
applied to the scrotum each morning, and comes in 4 and 6 mg dosages.
Androderm is a patch that may be worn anywhere on the body. Because of the
increased thickness of the skin and a relative resistance to absorption of the
testosterone, it is necessary to place permeation enhancers within the drug
vehicle. Because permeation enhancers are present, this patch should never be
worn on the scrotal skin where extreme absorption might be seen. Two patches
(only one dose available) are worn on flat areas of the skin, not overlying
any joints or high movement areas. The pharmacokinetics dictate that Androderm
patches are placed in the evening (see below). Patch sites are rotated on a
weekly basis so a patch is not placed in the same site anytime during the same
week. Advantages of Androderm include non-scrotal application and good
adhesion. Disadvantages include a non-discrete location and potential for skin
reactions.
Both Androderm and Testoderm, when placed properly at the correct time of day,
cause a rise to the mid to upper normal range of serum testosterone in the
morning and a decrease to the low normal range in the evening. Therefore,
patch therapy mimics the diurnal variation of normal testosterone secretion
and appears to be more physiological. Wide swings seen with injection therapy
are not seen. Whether or not this more physiological pattern of delivery is
more beneficial has not been proven.
TABLE 1. Types of testosterone replacement therapy
Oral (Alkylated forms)
Methyl testosterone
Fluoxymes terone
Injectable (Esterified) Testosterone:
Propionate
Cypionate
Enanthate
Undecanoate
Patch therapy (both testosterone)
Testoderm
Androderm
VI. Potential Benefits of Androgen Replacement Therapy
A.Sexual function
It has been thought for years that testosterone effect on sexual function is
mainly through libido. Although libido is certainly increased by the
administration of testosterone in hypogonadal men, there is also some recent
experimental evidence in rats to suggest that there may be peripheral effects
in penile tissue from testosterone also. Nitric oxide is the primary mediator
of penile erection and investigators have shown that nitric oxide synthase in
penile tissue is androgen-dependent (Fertil Steril, 63:1101, 1995). Therefore,
in the hypogonadal state, it is possible that nitric oxide production in
penile tissue may be deficient, with substandard penile smooth muscle
relaxation and a poor quality erection. Thus, we may have both central and
peripheral effects from testosterone on sexual function.
In men who are identified as having a low testosterone (total and or
bioavailable) and have difficulties with erectile function, testosterone
therapy may be tried prior to moving on to more invasive tests or therapies.
In the event that normal sexual function returns with replacement, then
further evaluation is of Testoderm include the hidden site of application and
the lack of the permeation enhancers, leading to unnecessary. However, as
mentioned above, many elderly men with impotence will have multiple factors
leading to their impotence problem and simple hormonal replacement will not
result in return of normal sexual activity in most When a trial of
testosterone is unable to return a man to normal sexual function, but there
are beneficial effects on libido, the wisdom of proceeding on with ongoing
androgen therapy is less well established. The physician in this circumstance
will have to balance the subjective improvement with potential for adverse
effects.
B. Body composition/muscle strength
Androgenic steroids have general effects of making favorable changes in body
composition. Several studies in older men have identified decreased fat mass,
increased lean body mass, and increased strength ( J Clin Endocrinol Metab
75:1092, 1992; Obesity Res 1:245, 1993; J Am Geratric Soc 41:149, 1993).
Supraphysiologic dosages of androgens in normal have been proven to increase
muscle strength,"and act synergistically with exercise in this regard (NEJM
335:1, 1996). Larger, as well as long-term outcomes studies regarding the
effect of androgens on body composition and strength in older men with
hypogonadism are necessary.
C. Osteoporosis
Bone mass does decrease as men age. Very little data exists regarding the
efficacy of testosterone in reversing or arresting these changes. Some small
studies show beneficial effects on bone with androgen therapy (J Clin
Endocrinol Metab 75:1092, 1992; J Am Geratric Soc 41:149, 1993), but more
research in this area is also necessary. There is no long-term data to assure
that androgen therapy will reduce fractures/disability, etc.
D. Cognitive behavior
There is evidence that spatial cognition in older men improves with androgen
therapy (Behav Neurosci 108:325, 1994). Another area that is not studied
terribly well.
VII. Potential Adverse Effects of Androgen Therapy
A. Hepatotoxidty
As mentioned above, the oral, alkylated forms of testosterone can create a
situation of liver toxicity (Semin Liver Dis 7:230, 1987; Liver 42:73, 1992).
Since I believe that these oral agents should never be given, this problem can
in general be circumvented. There is little evidence that other methods of
administration cause liver dysfunction, but I think it is prudent that in men
on testosterone therapy, liver function tests be performed at approximately
six month intervals.
B. Water retention
Androgen therapy can cause water retention, with the fear of exacerbation of
hypertension or inducing or worsening congestive heart failure in older men
undergoing such therapy. Weight gain thought to be due to water retention has
been demonstrated ( J Clin Endocrinol Metab 75:1092, 1992; JAm Geratr Soc
41:149, 1993), but no study has shown clinically significant pathology due to
this retention.
C. Erythropoiesis
Androgens cause an increase in hematocrit. Two~studies showed a rise in
hematocrit between 3.6 and 7.0% in older men receiving T supplementation (J
Clin Endocrinol Metab 75:1092, 1992; J Am Ceratr Soc 41:149, 1993). Typically
this rise in hematocrit, although measurable, is not clinically significant.
Since many older men are also anemic prior to testosterone therapy due to
their hypogonadism and/or aging/nutritional changes, the rise in hematocrit
may be beneficial.
D. Sleep apnea
Sleep apnea may be worsened in men on testosterone therapy (Clin Endocrinol (Oxf)
22:713, 1985). This may be due to changes in tissue surrounding the posterior
pharynx. Therefore, if there is a clinical history of sleep apnea in a man
considered for T therapy, this should be investigated and treated prior to
institution of therapy.
E. Changes in plasma lipoproteins
This area is perhaps one of the more controversial areas in testosterone
replacement therapy. The differences in incidence of atherosclerotic vessel
disease between men and women has been ascribed to hormonal differences. Since
HDL levels begin to drop in males coincident with the rise of testosterone
seen at puberty, the evidence has been compelling. However, a large review of
studies that attempted to compare HDL levels with circulating T levels failed
to reach. the conclusion that T level is correlated with lower HDL (Diabetes
Metab 21:156, 1995). In fact, most of the evidence shows that higher
endogenous T levels are associated with a higher HDL, and presumably a lower
cardiovascular risk.
This data has been interpreted by some clinicians to indicate that
testosterone replacement therapy will cause beneficial changes in HDL.
However, when one looks at multiple studies regarding replacing testosterone-
in- men who are hypogonadal, a mix of results are seen. Administration of
alkylated testosterone derivatives causes a substantial reduction in HDL-C (JAMA
261:1165, 1989). This further adds to the recommendation that these drugs
should not be given. When parenteral T esters are administered in weekly 100
mg injections, no change is generally seen, but there is a significant decline
in HDL when 200 mg injections are given every 2 weeks (Metabolism 42:446,
1993; Ann Intern Med 116:967, 1992; JAMA 261:1165, 1989). Data on patch
therapy is still being generated.
I think it is safe to say that one should view this issue with caution. It
would be prudent to get a fasting cholesterol/HDL profile on all hypogonadal
men in whom androgen replacement therapy is being suggested and then another
profile at three months to look for these potentially unfavorable changes.
F. Prostatic changes
It is clear that without androgens present, prostatic pathology does not
develop. Prostatic cancer and benign prostatic hyperplasia never develops in
eunuchs. Prostatic diseases represent very clinically significant problems in
the elderly and the effect of androgen replacement therapy on the prostate
needs to be very carefully considered.
The prostate increases in size during androgen replacement therapy in older
men (J Clin Endocrinol Metab 75:1092, 1992). Therefore, symptomatic prostatism
may potentially become worse with androgen therapy. Because of this one needs
to take a careful voiding history prior to initiation of therapy to uncover
such problems.
Prostate cancer has never been proven to be associated with androgen
replacement therapy. While there are scattered case reports of development of
prostate cancer while on such therapy it is commonly accepted that prostatic
cancer which is present (and may be occult when considering androgen
replacement therapy) will probably be accelerated by elevation of the serum
androgens. In this way an occult prostatic cancer may become apparent during
therapy. Surveillance for prostate cancer development and growth is essential
during therapy.
G. Infertility
Via suppression of the hypothalamic-pituitary-gonadal axis, administration of
exogenous androgens results in suppression of spermatogenesis. In many cases,
this will lead to complete azoospermia. Indeed, administration of testosterone
as a contraceptive agent has been proven to be effective in recent
multi-center studies (Lancet 336:955, 1993). Therefore, in all men who are
considering treatment of hypogonadism, and in whom fertility is a concern,
exogenous androgens must not be given.
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