Testosterone is responsible for normal growth and development of male
sex organs and maintenance of secondary sex characteristics. It is the
primary androgenic hormone.
When the testes fail to
produce normal levels of testosterone, testosterone deficiency results.
Hypogonadism is caused by primary testicular failure. Testosterone
levels are low and pituitary gonadotropins are elevated. In
hypogonadism, there is inadequate secretion of pituitary gonadotropins.
In addition to a low testosterone level, LH and FSH levels are low or
low-normal. The development of hypogonadism after puberty frequently
results in complaints such as diminished libido, erectile dysfunction,
infertility, gynecomastia, changes in body composition, reductions in
body and facial hair, and osteoporosis. Hypogonadal men report higher
levels of anger, confusion and depression.
There are now a variety of
products available to treat testosterone deficiency. Successful
management of testosterone replacement therapy requires appropriate
evaluation and an understanding of the benefits and risks of treatment.
Proper Diagnosis of Testosterone Deficiency
There are many causes of
testosterone deficiency, a medical history, physical exam, and the
proper laboratory evaluation are imperative. The medical history should
be questions regarding abnormalities at birth, the current status of
sexual function and secondary sexual characteristics, such as beard
growth, muscular strength, and energy level. Hypogonadal men have
statistically significant reductions in the incidence of nocturnal
erections, the degree of penile rigidity during erection, and the
frequency of sexual thoughts, feelings of desire, and sexual fantasies.
Furthermore, alterations in body composition, changes in adipose tissue,
increases in percent body fat and reduction in muscle mass, are
frequently seen in hypogonadal men.
Proper Labs should be
drawn to determine a diagnosis. The following levels should be drawn in
the morning. FSH, LH, SHBG, Total and Free Testosterone, Estradiol and
The Clinical rational for Testosterone Replacement Therapy
should in theory approximate the natural, endogenous production of the
hormone. The average male produces 4-7 mg of testosterone per day in a
circadian pattern, with maximal plasma levels attained in early morning
and minimal levels in the evening.
The clinical rationale for
treatment of testosterone deficiency may include:
- increasing bone density
-enhancing body composition by increasing muscle strength and reducing
-improving energy and mood
-improving libido and erectile function
Types of Testosterone Replacement Therapy
replacement therapy produces and maintains physiologic serum
concentrations of the hormone and its active metabolites without
significant side effects or safety concerns. Several different types of
testosterone replacement are currently marketed, including tablets,
injectables, sublingual, transdermal, and Pellet insertion.
Oral agents may cause
elevations in liver function tests and abnormalities at liver scan and
biopsy. Both modified and unmodified oral testosterone preparations are
available. Unmodified testosterone is rapidly absorbed by the liver,
making satisfactory serum concentrations difficult to achieve. Modified
17-alpha alkyltestosterones, such as methyltestosterone or
fluoxymesterone, also require relatively large doses that must be taken
several times a day.
Testosterone cypionate and
enanthate are frequently used parenteral preparations that provide a
safe means of hormone replacement in hypogonadal men. In men 20-50 years
of age, an intramuscular injection of 200 to 300 mg testosterone
enanthate is generally sufficient to produce serum testosterone levels
that are supranormal initially and fall into the normal ranges over the
next 14 days. Fluctuations in testosterone levels may yield variations
in libido, sexual function, energy, and mood. Some patients may be
inconvenienced by the need for frequent testosterone injections.1Increasing
the dose to 300 to 400 mg may allow for maintenance of eugonadal levels
of serum testosterone for up to three weeks, but higher doses will not
lengthen the eugonadal period.2
Sublingual testosterone is
placed under the tongue and is usally in the form of a square or circle,
depending on strength of troche. A sublingual dose is given twice a
day, same as the transdermal therapy below. It by-passes the liver and
takes about 2 to 3 minutes to melt. The taste is generally bitter but
the compounding pharmacies will flavor it to mask the bitterness
somewhat. Testosterone levels will peak and drop on this therapy, this
is why it would be best to take it two or three times a day in smaller
Clinical studies of
transdermal systems demonstrate their efficacy in providing adequate
testosterone replacement therapy.3,4 Transdermal therapy can
be made in a cream or gel by a compounding pharmacy. Different strengths
are used, ranging from 10mg to 200mg per ml. A daily dose is given in
the early morning hours. For best results of maintaining physiologic
testosterone levels you would want to take testosterone twice a day
early am (5am to 7am) and again around (1 to 4pm).
Monitoring Patients on
Patients on testosterone
replacement therapy should be monitored to ensure that testosterone
levels are within normal levels. The physician prescribing testosterone
replacement should evaluate any changes in the clinical symptoms and
signs of testosterone deficiency and should assess for other concerns,
such as acne and increase in breast size and tenderness. Serum
testosterone levels should be checked between 5 to 7 hours after
application of a transdermal or sublingual delivery systems.
A prostate specific
antigen (PSA) checked in all men before initiating treatment. These
should be repeated at approximately three to six months, and then
annually in men >40 years of age. A confirmed increase in PSA >2 ng/mL,
or a total PSA >4.0 ng/mL requires urologic evaluation. The hematocrit
level should also be checked at baseline, at three to six months, and
then annually. A hematocrit >55% warrants evaluation for hypoxia and
sleep apnea and/or a reduction in the dose of testosterone therapy.
Measurement of bone mineral density of the lumbar spine and/or the
femoral necks at one year may be considered in hypogonadal men with
Benefits of Testosterone Replacement Therapy
A number of benefits of
testosterone replacement therapy have been recorded, including better
stability with moods, energy levels, and libido. Testosterone
replacement has also been shown to enhance libido and the frequency of
sexual acts and sleep-related erections.5 Transdermal
testosterone replacement therapy, in particular, has been linked to
positive effects on fatigue, mood, and sexual function, as well as
significant increases in sexual activity.6 More specifically,
testosterone replacement therapy has been shown to improve positive mood
parameters, such as feeling of friendliness, reducing negative mood
parameters, such as anger and irritability.7
therapy is also associated with potentially positive changes in body
composition. In hypogonadal men, testosterone replacement therapy has
demonstrated a number of effects, including an increase in lean body
mass and decrease in body fat,8 and increases in muscle size.9
with transdermal testosterone delivery systems in HIV-infected men with
low testosterone levels has been associated with statistically
significant gains in lean body mass (p=0.02), increased red cell counts,
and improvements in emotional distress.10 Transdermal
testosterone has also been administered to HIV-positive women, yielding
positive trends in weight gain and quality of life.11
Improvements in bone
density have also been shown with testosterone replacement therapy.
Increases in spinal bone density have been realized in hypogonadal men,12
with most treated men maintaining bone density above the fracture
Testosterone Replacement Therapy
is contraindicated in men with carcinoma of the breast or known or
suspected carcinoma of the prostate, as it may cause rapid growth of
these tumors. Hormone therapy is also inappropriate in men with severe
benign prostatic hypertrophy (BPH)-related bladder outlet obstruction.
Use of testosterone to improve athletic performance or correct short
stature is potentially dangerous and inappropriate.
replacement is known to reduce total cholesterol, low density
lipoprotein (LDL), and high density lipoprotein (HDL) levels. Some
authorities recommend that lipid values be followed closely in men
receiving testosterone replacement therapy.
Although PSA is not
specific for prostate cancer, it is a good surrogate for judging the
effects of androgens on the prostate. In one study of
testosterone-treated men, PSA rose to normal levels but no higher than
in the controls, leading the authors to conclude that
testosterone-induced prostate growth should not preclude hypogonadal men
from testosterone replacement therapy. Indeed, another study indicates
that even men who achieved supraphysiologic levels of serum testosterone
had no significant changes in PSA levels.14
The effects of transdermal
testosterone replacement on prostate size and PSA levels in hypogonadal
men have also been evaluated.15 Prostate size during therapy
with transdermal testosterone was comparable to that reported in normal
men, and PSA levels were within the normal range.
There appears to be little
association between testosterone replacement therapy and the development
of prostate cancer. The etiology of prostate cancer is apparently
multifactorial, and dietary, geographic, genetic, and other influences
are all thought to play a role in the development of the disease. Recent
studies indicate that testosterone levels have no apparent systematic
relationship to the incidence of prostate cancer.16,17
1. McClure, R.D., Oses, R. and Ernest, M.L.: Hypogonadal impotence
treated by transdermal testosterone. Urology, 37(3):224, 1991.
2. Snyder, P.J. and Lawrence, D.A.: Treatment of male hypogonadism with
testosterone enanthate. J Clin Endocrinol Metab, 51:1335, 1980.
3. Cofrancesco, J. and
Dobs, A.S.: Transdermal testosterone delivery systems. The
Endocrinologist, 6:207, 1996.
4. Yu, Z., Gupta, S.K., Hwang, S.S., Kipnes, M.S., Mooradian, A.D.,
Snyder, P.J. and Atkinson, L.E.: Testosterone pharmacokinetics after
application of an investigational transdermal system in hypogonadal men.
J Clin Pharmacol, 37:1139, 1997.
5. Shabsigh, R.: The effects of testosterone on the cavernous tissue and
erectile function. World J Urol, 15:21, 1997.
6. Meikle, A.W., Arver, S., Dobs, A.S., Sanders, S.W. and Mazer, N.A.:
Androderm: A permeation-enhanced, non-scrotal testosterone transdermal
7. Alexander, G.M.,
Swerdloff, R.S., Wang, C., Davidson, T., McDonald, V., Steiner, B. and
Hines, M.: Androgen-behavior correlations in hypogonadal men II.
Cognitive abilities. Horm Behav, 33:85, 1998.
8. Tenover, J.S.: Effects of testosterone supplementation in the aging
male. J Clin Endocrinol Metab, 75:1092, 1992.
9. Bhasin, S., Storer, T.W., Berman, N., Yarasheski, K.E., Clevenger,
B., Phillips, J., Lee, W.P., Bunnell, T.J. and Casaburi, R.:
Testosterone replacement increases fat-free mass and muscle size in
hypogonadal men. J Clin Endocrinol Metab, 82:407, 1997.
10. Bhasin, S., Storer, T.W., Asbel-Sethi, N., Hays, R., Sinha-Hikim,
I., Shen, R., Arver, S. and Beall, G.: Effects of testosterone
replacement with a nongenital, transdermal system, Androderm, in human
immunodeficiency virus-infected men with low testosterone levels. J Clin
Endocrinol Metab, 83:3155, 1998.
11. Miller, K., Corcoran, C., Armstrong, C., Caramelli, K., Anderson,
E., Cotton, D., Basgoz, N., Hirschhorn, L., Tuomala, R., Schoenfeld,
Daugherty, C., Mazer, N. and Grinspoon, S.: Transdermal testosterone
administration in women with acquired immunodeficiency syndrome wasting:
a pilot study. J Clin Endocrinol Metab, 83:2717, 1998.
12. Finkelstein, J.S., Klibanski, A., Neer, R.M., Dopplet, S.H.,
Rosenthal, D.I., Segre, G.V. and Crowley, W.F.: Increases in bone
density during treatment of men with idiopathic hypogonadotropic
hypogonadism. J Clin Endocrinol Metab, 69:776, 1989.
13. Behre, H.M., Kliesch, S., Leifke, E., Link, T.M. and Nieschlag, E.:
Long-term effect of testosterone therapy on bone mineral density in
hypogonadal men. J Clin Endocrinol Metab, 82:2386, 1997.
14. Cooper, C.S., MacIndoe, J.H., Perry, P.J., Yates, W.R. and Williams,
R.D.: The effect of exogenous testosterone on total and free prostate
specific antigen levels in healthy young men. J Urol, 156:438, 1996.
15. Meikle, A.W., Arver, S., Dobs, A.S., Adolfsson, J., Sanders, S.W.,
Middleton, R.G., Stephenson, R.A., Hoover, D.R., Rajaram, L. and Mazer,
NA. Prostate size in hypogonadal men treated with a nonscotal
permeation-enhanced testosterone transdermal system. Urology 1997;
16. Ebling DW, Ruffer J, Whittington R, Vanarsdalen K, Broderick GA,
Malkowicz SB, Wein AJ. Development of prostate cancer after pituitary
dysfunction: A report of 8 patients. Urology 1997;49:564-568.
17. Gustafsson O, Norming U, Gustafsson S, Eneroth P, Astrom G, Nyman
CR. Dihydrotestosterone and testosterone levels in men screened for
prostate cancer: a study of a randomized population. Br J Urol