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May 5, 1989, Vol 261, No. 17 >
ARTICLE | May 5, 1989

Testosterone Replacement With Transdermal Therapeutic Systems: Title and subTitle BreakPhysiological Serum Testosterone and Elevated Dihydrotestosterone Levels FREE

Glenn R. Cunningham, MD; Emilia Cordero, RN; Jack I. Thornby, PhD
[+] Author Affiliations

Reprint requests to Endocrinology Section (111E), Veterans Administration Medical Center, 2002 Holcombe Blvd, Houston, TX 77030 (Dr Cunningham).


JAMA. 1989;261(17):2525-2530. doi:10.1001/jama.1989.03420170069032
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References

Testosterone was administered transdermally to hypogonadal men under three protocols. In the first protocol, it was shown that peak levels of testosterone were achieved three to eight hours after scrotal application of a transdermal therapeutic system containing 5, 10, or 15 mg of testosterone, and values at 22 hours were greater than 60% of peak values. In the second protocol, patients were treated with 10-mg systems for four weeks followed by 15-mg systems for eight weeks. Serum samples were obtained three to five hours after application of the transdermal therapeutic system. Testosterone increased from a pretreatment level (mean ± SE) of 1.5 ± 0.4 nmol/L to 15.2 ±3.4 nmol/L at four weeks, 18.6 ± 3.3 nmol/L at eight weeks, and 17.3 ± 2.8 nmol/L at 12 weeks. The serum testosterone/dihydrotestosterone (DHT) ratio fell from 4.53 to 2.47 at four weeks and was similar at eight and 12 weeks, reflecting a greater rise in DHT with this route of treatment (normal testosterone/DHT ratio, 9/1 to 12/1). Eight patients were treated with the 15-mg systems for an additional year. Seven of the eight were compliant and maintained serum testosterone levels (at six time points from two to 12 months [mean ± SE]) ranging from 11.5 ±1.2 to 44.9 ±2.4 nmol/L. It was possible to achieve physiological serum levels of testosterone by transdermal administration of testosterone in two thirds of our hypogonadal men.

(JAMA. 1989;261:2525-2530)

REFERENCES

1 +
Shinohara Y, Baba S, Kasuya Y:  Absorption, metabolism, and excretion of oral testosterone in humans by mass fragmentography . J Clin Endocrinol Metab 1980;;51:1459-1462.
2 +
Johnsen SG, Bennett EP, Jensen VG:  Therapeutic effectiveness of oral testosterone . Lancet 1974;;2:1473-1475.
3 +
Southren AL, Gordon GG, Tochimoto S, et al:  Mean plasma concentration, metabolic clearance and basal plasma production rates of testosterone in normal young men and women using a constant infusion procedure: Effect of time of day and plasma concentration on the metabolic clearance rate of testosterone . J Clin Endocrinol 1967;;27:686-694.
4 +
Cantrill JA, Dewis P, Large DM, et al:  Which testosterone replacement therapy? Clin Endocrinol 1984;;21:97-107.
5 +
Aakvaag A, Vogt JH:  Plasma testosterone values in different forms of testosterone treatment . Acta Endocrinol 1969;;60:537-542.
6 +
Burris AS, Ewing LL, Sherins RJ:  Initial trial of slow-release testosterone microspheres in hypogonadal men . Fertil Steril 1988;;50:493-497.
7 +
Werner SC, Hanger FM, Kritzler RA:  Jaundice due to methyl testosterone therapy . Am J Med 1950;;8:325.
8 +
Gordon RD, Thomas MJ, Poynting JM, et al:  Effect of mesterolone on plasma L.H., F.S.H. and testosterone . Andrologia 1975;;7:287-296.
9 +
Maisey NM, Bingham J, Marks V, et al:  Clinical efficacy of testosterone undecanoate in male hypogonadism . Clin Endocrinol 1981;;14:625-629.
10 +
Franchi F, Luisi M, Kicovic PM:  Long-term study of oral testosterone undecanoate in hypogenadal males . Int JAndrol 1978;;1:270-278.
11 +
Luisi F, Franchi F:  Double-blind group comparative study of testosterone undecanoate and mesterolone in hypogonadal male patients . J Endocrinol Invest 1980;;3:305-308.
12 +
Fujioka M, Shinohara Y, Baba S, et al:  Pharmacokinetic properties of testosterone propionate in normal men . J Clin Endocrinol Metab 1986;;63:1361-1364.
13 +
Cunningham GR, Silverman V, Kohler PO:  Gonadotropin suppression in normal males and males with 1° hypogonadism: Evaluation of four androgens . Int J Androl 1978;;( (suppl 2) , pt 2):720-730.
14 +
Schulte-Beerbuhl M, NieschlagE:  Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle-stimulating hormone in serum after injection of testosterone enanthate or testosterone cypionate . Fertil Steril 1980;;33:201-203.
15 +
Snyder PJ, Lawrence DA:  Treatment of male hypogonadism with testosterone enanthate . J Clin Endocrinol Metab 1980;;51:1335-1339.
16 +
Sokol RZ, Palacios A, Campfield LA, et al:  Comparison of the kinetics of injectable testosterone in eugonadal and hypogonadal men . Fertil Steril 1982;;37:425-430.
17 +
Powers MS, Schnenkel L, Darley PE, et al:  Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17β-estradiol: Comparison with conventional oral estrogens used for hormone replacement . Am J Obstet Gynecol 1985;;152:1099.
18 +
Korenman SG, Viosca S, Garza D, et al:  Androgen therapy of hypogonadal men with transscrotal testosterone systems . Am J Med 1987;;83:471-478.
19 +
Furuyama S, Mayes DM, Nugent CA:  A radio-immunoassay for plasma testosterone . Steroids 1970;;16:415-428.
20 +
Wu C-H, Lundy LE:  Radioimmunoassay of plasma estrogens . Steroids 1971;;18:91-111.
21 +
Rosner W:  A simplified method for the quantitative determination of testosterone-estradiol— binding globulin activity in human plasma . J Clin Endocrinol Metab 1972;;34:983-988.
22 +
Bremner WJ, Vitiello MV, Prinz PN:  Loss of circadian rhythmicity in blood testosterone levels with aging in normal men . J Clin Endocrinol Metab 1983;;56:1278-1281.
23 +
Findlay JC, Place VA, Snyder PJ:  Transdermal delivery of testosterone . J Clin Endocrinol Metab 1987;;64:266-268.
24 +
Bals-Pratsch M, Knuth UA, Yoon YD, et al:  Transdermal testosterone substitution therapy for male hypogonadism . Lancet 1986;;2:943-946.
25 +
Ahmed SR, Boucher AE, Manni A, et al:  Transdermal testosterone therapy in the treatment of male hypogonadism . J Clin Endocrinol Metab 1988;;66:546-551.
26 +
Findlay JC, Place V, Snyder PJ:  Treatment of primary hypogonadism in men by the transdermal administration of testosterone . J Clin Endocrinol Metab 1989;;68:369-373.
27 +
Kirkland RT, Keenan BS, Probstfield JL, et al:  Decrease in plasma high-density lipoprotein cholesterol levels at puberty in boys with delayed adolescence . JAMA 1987;;257:502-507.
28 +
Sorva R, Kuusi T, Taskinen M-R, et al:  Testosterone substitution increases the activity of lipoprotein lipase and hepatic lipase in hypogonadal males . Atherosclerosis 1988;;69:191-197.
29 +
Wilson JD, Walker JD:  The conversion of testosterone to 5α-androstan-17β-ol-3-one (dihydrotestosterone) by skin slices of man . J Clin Invest 1969;;48:371-379.
30 +
Cunningham GR, Tindall DJ, Lobl TJ, et al:  Steroid structural requirements for high affinity binding to human sex steroid binding protein (SBP) . Steroids 1981;;38:243-262.
31 +
Moghissi E, Ablan F, Horton R:  Origin of plasma androstanediol glucuronide in men . J Clin Endocrinol Metab 1984;;59:417-421.
32 +
Walsh PC, Hutchins GM, Ewing LL:  Tissue content of dihydrotestosterone in human prostatic hyperplasia is not supra-normal . J Clin Invest 1983;;72:1772-1777.
33 +
Imperato-McGinley J, Guerrero L, Gautier T, et al:  Steroid 5α-reductase deficiency in man: An inherited form of male pseudohermaphroditism . Science 1974;;186:1213-1215.
34 +
Imperato-McGinley J, Peterson RE, Leshin M, et al:  Steroid 5α-reductase deficiency in a 65-year-old male pseudohermaphrodite: The natural history, ultrastructure of the testes, and evidence for inherited enzyme heterogeneity . J Clin Endocrinol Metab 1980;;50:15-22.
35 +
Price P, Wass JAH, Griffin JE, et al:  High dose androgen therapy in male pseudohermaphroditism due to 5α-reductase deficiency and disorders of the androgen receptor . J Clin Invest 1984;;74:1496-1508.
36 +
Brooks JR, Baptista EM, Berman C, et al:  Response of rat ventral prostate to a new and novel 5a-reductase inhibitor . Endocrinology 1981;;109: 830-836.
37 +
Brooks JR, Berman C, Games D, et al:  Prostatic effects induced in dogs by chronic or acute oral administration of 5α-reductase inhibitors . Prostate 1986;;9:65-75.
38 +
Skakkenbaek NE, Bancroft J, Davidson DW, et al:  Androgen replacement with oral testosterone undecanoate in hypogonadal men: A double blind controlled study . Clin Endocrinol 1981;;14:49-61.
39 +
Gooren LJG:  Long-term safety of the oral androgen testosterone undecanoate . Int J Androl 1986;;9:21-26.
40 +
Nankin HR:  Hormone kinetics after intramuscular testosterone cypionate . Fertil Steril 1987;; 47:1004-1009.

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1 +
Shinohara Y, Baba S, Kasuya Y:  Absorption, metabolism, and excretion of oral testosterone in humans by mass fragmentography . J Clin Endocrinol Metab 1980;;51:1459-1462.
2 +
Johnsen SG, Bennett EP, Jensen VG:  Therapeutic effectiveness of oral testosterone . Lancet 1974;;2:1473-1475.
3 +
Southren AL, Gordon GG, Tochimoto S, et al:  Mean plasma concentration, metabolic clearance and basal plasma production rates of testosterone in normal young men and women using a constant infusion procedure: Effect of time of day and plasma concentration on the metabolic clearance rate of testosterone . J Clin Endocrinol 1967;;27:686-694.
4 +
Cantrill JA, Dewis P, Large DM, et al:  Which testosterone replacement therapy? Clin Endocrinol 1984;;21:97-107.
5 +
Aakvaag A, Vogt JH:  Plasma testosterone values in different forms of testosterone treatment . Acta Endocrinol 1969;;60:537-542.
6 +
Burris AS, Ewing LL, Sherins RJ:  Initial trial of slow-release testosterone microspheres in hypogonadal men . Fertil Steril 1988;;50:493-497.
7 +
Werner SC, Hanger FM, Kritzler RA:  Jaundice due to methyl testosterone therapy . Am J Med 1950;;8:325.
8 +
Gordon RD, Thomas MJ, Poynting JM, et al:  Effect of mesterolone on plasma L.H., F.S.H. and testosterone . Andrologia 1975;;7:287-296.
9 +
Maisey NM, Bingham J, Marks V, et al:  Clinical efficacy of testosterone undecanoate in male hypogonadism . Clin Endocrinol 1981;;14:625-629.
10 +
Franchi F, Luisi M, Kicovic PM:  Long-term study of oral testosterone undecanoate in hypogenadal males . Int JAndrol 1978;;1:270-278.
11 +
Luisi F, Franchi F:  Double-blind group comparative study of testosterone undecanoate and mesterolone in hypogonadal male patients . J Endocrinol Invest 1980;;3:305-308.
12 +
Fujioka M, Shinohara Y, Baba S, et al:  Pharmacokinetic properties of testosterone propionate in normal men . J Clin Endocrinol Metab 1986;;63:1361-1364.
13 +
Cunningham GR, Silverman V, Kohler PO:  Gonadotropin suppression in normal males and males with 1° hypogonadism: Evaluation of four androgens . Int J Androl 1978;;( (suppl 2) , pt 2):720-730.
14 +
Schulte-Beerbuhl M, NieschlagE:  Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle-stimulating hormone in serum after injection of testosterone enanthate or testosterone cypionate . Fertil Steril 1980;;33:201-203.
15 +
Snyder PJ, Lawrence DA:  Treatment of male hypogonadism with testosterone enanthate . J Clin Endocrinol Metab 1980;;51:1335-1339.
16 +
Sokol RZ, Palacios A, Campfield LA, et al:  Comparison of the kinetics of injectable testosterone in eugonadal and hypogonadal men . Fertil Steril 1982;;37:425-430.
17 +
Powers MS, Schnenkel L, Darley PE, et al:  Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17β-estradiol: Comparison with conventional oral estrogens used for hormone replacement . Am J Obstet Gynecol 1985;;152:1099.
18 +
Korenman SG, Viosca S, Garza D, et al:  Androgen therapy of hypogonadal men with transscrotal testosterone systems . Am J Med 1987;;83:471-478.
19 +
Furuyama S, Mayes DM, Nugent CA:  A radio-immunoassay for plasma testosterone . Steroids 1970;;16:415-428.
20 +
Wu C-H, Lundy LE:  Radioimmunoassay of plasma estrogens . Steroids 1971;;18:91-111.
21 +
Rosner W:  A simplified method for the quantitative determination of testosterone-estradiol— binding globulin activity in human plasma . J Clin Endocrinol Metab 1972;;34:983-988.
22 +
Bremner WJ, Vitiello MV, Prinz PN:  Loss of circadian rhythmicity in blood testosterone levels with aging in normal men . J Clin Endocrinol Metab 1983;;56:1278-1281.
23 +
Findlay JC, Place VA, Snyder PJ:  Transdermal delivery of testosterone . J Clin Endocrinol Metab 1987;;64:266-268.
24 +
Bals-Pratsch M, Knuth UA, Yoon YD, et al:  Transdermal testosterone substitution therapy for male hypogonadism . Lancet 1986;;2:943-946.
25 +
Ahmed SR, Boucher AE, Manni A, et al:  Transdermal testosterone therapy in the treatment of male hypogonadism . J Clin Endocrinol Metab 1988;;66:546-551.
26 +
Findlay JC, Place V, Snyder PJ:  Treatment of primary hypogonadism in men by the transdermal administration of testosterone . J Clin Endocrinol Metab 1989;;68:369-373.
27 +
Kirkland RT, Keenan BS, Probstfield JL, et al:  Decrease in plasma high-density lipoprotein cholesterol levels at puberty in boys with delayed adolescence . JAMA 1987;;257:502-507.
28 +
Sorva R, Kuusi T, Taskinen M-R, et al:  Testosterone substitution increases the activity of lipoprotein lipase and hepatic lipase in hypogonadal males . Atherosclerosis 1988;;69:191-197.
29 +
Wilson JD, Walker JD:  The conversion of testosterone to 5α-androstan-17β-ol-3-one (dihydrotestosterone) by skin slices of man . J Clin Invest 1969;;48:371-379.
30 +
Cunningham GR, Tindall DJ, Lobl TJ, et al:  Steroid structural requirements for high affinity binding to human sex steroid binding protein (SBP) . Steroids 1981;;38:243-262.
31 +
Moghissi E, Ablan F, Horton R:  Origin of plasma androstanediol glucuronide in men . J Clin Endocrinol Metab 1984;;59:417-421.
32 +
Walsh PC, Hutchins GM, Ewing LL:  Tissue content of dihydrotestosterone in human prostatic hyperplasia is not supra-normal . J Clin Invest 1983;;72:1772-1777.
33 +
Imperato-McGinley J, Guerrero L, Gautier T, et al:  Steroid 5α-reductase deficiency in man: An inherited form of male pseudohermaphroditism . Science 1974;;186:1213-1215.
34 +
Imperato-McGinley J, Peterson RE, Leshin M, et al:  Steroid 5α-reductase deficiency in a 65-year-old male pseudohermaphrodite: The natural history, ultrastructure of the testes, and evidence for inherited enzyme heterogeneity . J Clin Endocrinol Metab 1980;;50:15-22.
35 +
Price P, Wass JAH, Griffin JE, et al:  High dose androgen therapy in male pseudohermaphroditism due to 5α-reductase deficiency and disorders of the androgen receptor . J Clin Invest 1984;;74:1496-1508.
36 +
Brooks JR, Baptista EM, Berman C, et al:  Response of rat ventral prostate to a new and novel 5a-reductase inhibitor . Endocrinology 1981;;109: 830-836.
37 +
Brooks JR, Berman C, Games D, et al:  Prostatic effects induced in dogs by chronic or acute oral administration of 5α-reductase inhibitors . Prostate 1986;;9:65-75.
38 +
Skakkenbaek NE, Bancroft J, Davidson DW, et al:  Androgen replacement with oral testosterone undecanoate in hypogonadal men: A double blind controlled study . Clin Endocrinol 1981;;14:49-61.
39 +
Gooren LJG:  Long-term safety of the oral androgen testosterone undecanoate . Int J Androl 1986;;9:21-26.
40 +
Nankin HR:  Hormone kinetics after intramuscular testosterone cypionate . Fertil Steril 1987;; 47:1004-1009.

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