Introduction To Male Testosterone
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 Estrone.


The Clinical rational for Testosterone Replacement Therapy

Testosterone replacement 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 adipose
-improving energy and mood
-improving libido and erectile function

Types of Testosterone Replacement Therapy

Ideal testosterone 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

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.

Intramuscular injection

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

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 doses.

Transdermal Vehicle

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 Testosterone Replacement

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 osteopenia.

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

Testosterone replacement 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

Testosterone replacement 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 threshold.13

Contraindications to Testosterone Replacement Therapy

Testosterone replacement 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.

Lipid Abnormalities

Physiologic testosterone 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.

Prostate Changes

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.

Prostate Cancer

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


References


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; 49:191-6.

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 1996;77:433-440.