TESTOSTERONE

The testes produce 95% of the Testosterone (TTT), about 5 mg/day& about 50 to 100 mcg of dihydrotestosterone (DHT) and estradiol.  TTT is 60% bonded to a plasma protein, 38% to albium, and 2% free.  TTT is derived from LH, and TTT is readily metabolized by the liver.  DHT is more potent than TTT.  TTT freely enters target cells and binds to intracellular receptors which then bind to DNA promoting gene transcription.  DHT works is more active at these sites.  DHT is necessary in early development for enlargement of the prostate, penis, and hair growth at the time of puberty.  TTT for muscle mass and sex drive

Androsol, 8 ml, $37, Biotest, Colorado Springs, biotest-online.com, 800-525-1940.  7 sprays = 1 ml contains 50 mg of 4-androstene-3,7-diol

30-35 years old the normal level of free testosterone is 700-900 ng/dl, women 50-70 (only 2% is free.  [Goodman & Gilman list plasma less of less than 20 ng/dl prior to puberty.  And the adult male has a rate of product of 2.5 to 11 mg/day.].  Androgens may be therapeutic value against Alzheimer's disease and male aging.

Journal of Neurochemistry   77(5), 1319-26.

ANDROGENS:

In circulation Androgens serve as prohormones for the formation of two classes of steroids:  5 alpha reduced androgens, which act as the intracellular mediators of most actions of the hormone, and estrogens, which enhance some androgenic effects and block others.  Androgens may be responsible in part for organizational effects in the brain during prenatal or early postnatal life (1442).  "Normal men experience only a transient positive nitrogen balance of a slight degree when exogenous androgens are administered.  A maximally effective dose of 25 mg of testosterone propionate daily causes an average retention of nitrogen of 63 mg/kg daily in hypogonadal men. 

Testosterone Replacement Therapy

Wayne J.G. Hellstrom, M.D.

Tulane University Medical Center
New Orleans, LA

    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.²⁰ More specifically, testosterone replacement therapy has been shown to improve positive mood parameters, such as feelings of wellness and friendliness, while reducing negative mood parameters, such as anger, nervousness, and irritability.²¹ Testosterone replacement is an effective treatment for some depressive symptoms in hypogonadal men and may effectively augment treatment in selective serotonin reuptake inhibitor (SSRI)-refractory major depression.²² Relative to eugonadal men, hypogonadal men in one study were impaired in their verbal fluency and showed improvement in verbal fluency following testosterone replacement therapy.²³Testosterone 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,²⁴ an increase in weight,²⁵ and increases in muscle size.²⁶ Parenteral testosterone replacement in hypogonadal men resulted in improved strength and increased hemoglobin compared to controls.²⁷ In another study by Urban and colleagues,²⁸ testosterone administration also increased skeletal muscle protein synthesis and strength in elderly men.

     Improvements in bone density have also been shown with testosterone replacement therapy. Increases in spinal bone density have been realized in hypogonadal men,³¹ with most treated men maintaining bone density above the fracture threshold.³² Testosterone replacement in hypogonadal men improves both trabecular and cortical bone mineral density of the spine, independent of age and type of hypogonadism.³³

    Lipid Abnormalities

Physiologic testosterone replacement is known to reduce total cholesterol, low density lipoprotein (LDL), and high density lipoprotein (HDL) levels,²⁴ but the extent to which these parameters are affected by treatment varies considerably between studies. While reductions in HDL did not reach significance in a study by Tenover²⁴ and testosterone replacement was not associated with unfavorable changes in lipid profiles in a separate study by Tan and colleagues,³⁸ research by Anderson and colleagues³⁹ suggests testosterone replacement therapy may result in significant reductions in HDL and elevations in blood viscosity. Some authorities recommend that lipid values be followed closely in men receiving testosterone replacement therapy.

     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.^45,46

20. Meikle, A.W., Arver, S., Dobs, A.S., Sanders, S.W. and Mazer, N.A.: Androderm: A permeation-enhanced, non-scrotal testosterone transdermal system for the treatment of male hypogonadism. In: Pharmacology, Biology, and Clinical Applications of Androgens. Edited by S. Bhasin. New York, NY: Wiley Liss, Inc., pp. 449-457, 1996.

21. Wang, C.W., Alexander, G., Berman, N., Salehian, B., Davidson, T., McDonald, V., Steiner, B., Hill, L., Callegari, C. and Swerdloff, R.S.: Testosterone replacement therapy improves mood in hypogonadal menóa clinical research center study. J Clin Endocrinol Metab, 81:3578, 1996.

22. Seidman, S.N. and Rabkin, J.G.: Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression. J Affect Disord, 48:157, 1998.

23. 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.

24. Tenover, J.S.: Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab, 75:1092, 1992.

25. Wang, C., Eyre, D.R., Clark, R., Kleinberg, D., Newman, C., Iranmanesh, A., Veldhuis, J., Dudley, R.E., Berman, N., Davidson, T., Barstow, T.J., Sinow, R., Alexander, G. and Swerdloff, R.S.: Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, increases bone formation markers in hypogonadal menóa clinical research center study. J Clin Endocrinol Metab, 81:3654, 1996.

26. 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.

27. Sih, R., Morley, J.E., Kaiser, F.E., Perry, H.M., Patrick, P. and Ross, C.: Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab, 82:1661, 1997.

28. Urban, R.J., Bodenburg, Y.H. and Gilkison, C.: Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol, 269 (Endocrinol Metab 32): E828ñE826, 1995.

31. 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.

32. 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.

33. Leifke, E., Korner, H.C., Link, T.M., Behre, H.M., Peters, P.E. and Nieschlag, E.: Effects of testosterone replacement on cortical and trabecular bone mineral density, vertebral body area and paraspinal muscle area in hypogonadal men. Eur J Endocrinol, 138:51, 1998.

34. Burstein, S., Grumbach, M.M. and Kaplan, S.L.: Early determination of androgen-responsiveness is important in the management of microphallus. Lancet, 2:983, 1979.

39. Anderson, F.H., Francis, R.M. and Faulkner, K.: Androgen supplementation in eugonadal men with osteoporosis(effects of 6 months of treatment on bone mineral density and cardiovascular risk factors). Bone, 18:171, 1996.

40. Arver, S., Meikle, A.W., Dobs, A.S., et al.: Hypogonadal men treated with the Androderm testosterone transdermal system had fewer abnormal hematocrit evaluations than those treated with testosterone enanthate injections. In: Program and Abstracts of the 77th Annual Meeting of the Endocrine Society, Washington DC, June 14-17, 1995, Abstract P1-327.

45. 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.

46. 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.

• Normal sexual function requires conversion of testosterone into other hormones!
• Early sexual dysfunction can be reversed easily with proper hormone replacement.
• Hormone replacement with estrogen alone fails to normalize sexuality without adequate testosterone.
• Most specialists feel that only 5% of impotence is due to hormonal deficiency. In my experience they are way off the mark.
• Hormonal mechanisms play a part in every major element in normal erectile function.
• When the first signs of sexual difficulty appear, they may reflect risk for major diseases.
• Most hormonal treatments have been wrong for many individuals.

AndroGel, a newly approved topical drug which is administered in 5 to 10 gms. daily (1%) to yield 50 to 100 mgs. of which an unknown fraction enters the body.  It compared quite favorable to the testosterone patch--which caused skin irritation in 66%.

from rxlist.com  ("Clinical Pharmacology") 

Geriatric

No age related effects on testosterone pharmacokinetics were observed in clinical trials of Androderm in men up to 65 years of age. In a group of 9 elderly testosterone deficient men (65-79 years of age, average baseline testosterone level 184±50 ng/dL). a single application of two Androderm 2.5 mg systems to the back resulted in an average testosterone level of 591±121 ng/dL with a Tmax of 14.2±4.2 hours. The total testosterone delivered over the 24-hour application time was 3.8±0.6 mg, approximately 20% less than the average amount delive

Table 1

Steady-state serum testosterone pharmacokinetic parameters in hypogonadal men measured during continuous Androderm (testosterone transdermal system) treatment.