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Testosterone and Aging: Clinical Research Directions (2004)

Chapter: Appendix C: Additional Studies of Testosterone Therapy

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Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

C
Additional Studies of Testosterone Therapy

As described in Chapter 2 and Appendix B, the committee focused its attention on placebo-controlled randomized trials in older men. However, the committee recognized that there is a larger literature on testosterone therapy in men, including clinical trials conducted in young adult male populations and studies involving older male populations that did not include a placebo-controlled comparison population. This appendix is not meant to be an exhaustive literature review, but rather to provide context and acknowledgement of a large body of work on the administration of exogenous testosterone to adult men. Studies of the administration of exogenous testosterone to women or children are not included.

BONE

A number of studies of testosterone therapy primarily in young to middle-aged hypogonadal males have shown increases in bone mass with increases in testosterone to normal levels (Arisaka et al., 1995; Katznelson et al., 1996; Leifke et al., 1998; Rabijewski et al., 1998; Behre et al., 1999; Snyder et al., 2000). For example, a study of 72 patients diagnosed with primary and secondary hypogonadism (who received testosterone through transscrotal patches for up to 16 years) found the greatest increase in bone mineral density (BMD) in the first year of therapy; normal age-related ranges of BMD were reached and maintained after several years of testosterone therapy (Behre et al., 1997). In a three-year study by Snyder and colleagues (2000), peak effects on BMD of the spine and hip

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

were reached after 24 months of transdermal testosterone therapy and then decreased or leveled off (testosterone levels reached the normal range within 3 months and then leveled off). Two studies found that osteopenia persisted in hypogonadal men undergoing long-term testosterone supplementation (Medras et al., 2001; Ishizaka et al., 2002).

Studies of biochemical markers of bone turnover have widely variable results. Wang and colleagues (2001) found that osteoblastic activity markers increased significantly during 90-day treatment of hypogonadal men with either a 50 or 100 mg dose of testosterone gel daily; the study also found an increase in BMD of the hip and spine in those receiving the 100 mg/day dose. Serum osteocalcin, a bone formation marker, increased in studies of elderly men undergoing testosterone therapy (Morley et al., 1993; Brill et al., 2002), and levels were maintained in a study of elderly men that suppressed endogenous testosterone production and then examined testosterone and estrogen replacement (Falahati-Nini et al., 2000). Anderson and colleagues (1997) found decreases in bone markers with testosterone therapy in eugonadal men with osteoporotic vertebral crush fractures, indicating to the investigators that testosterone suppressed bone resorption.

BODY COMPOSITION AND STRENGTH

Positive effects on body composition and muscle strength were reported in testosterone therapy studies of males diagnosed or identified as hypogonadal, including increases in lean body mass (also termed fat-free mass in the journal articles), muscle volume and area, and muscle strength (Brodsky et al., 1996; Katznelson et al., 1996; Wang et al., 1996b; Bhasin et al., 1997; Leifke et al., 1998; Snyder et al., 2000). Many of the studies included older hypogonadal males but were not placebo-controlled studies. A study of strength measures by Wang and colleagues (2000) of 227 hypogonadal men receiving 180 days of transdermal treatment found increases in several measures of strength compared to baseline. Improvements were seen in the leg press exercise during the first 90 days, but further improvement after this period was not significant.

Studies in eugonadal male populations with normal levels of testosterone also generally found increases in lean body mass, muscle volume, and/or muscle strength with testosterone administration (Friedl et al., 1991; Forbes et al., 1992; Young et al., 1993; Urban et al., 1995; Bhasin et al., 1996, 2001b; Giorgi et al., 1999; Sinha-Hikim et al., 2002; Woodhouse et al., 2003). Most of these studies were in populations of young adults who received supraphysiologic doses for 3 to 6 months. Bhasin and colleagues (1996) assessed the effect of testosterone and exercise and found that the group undergoing testosterone therapy with exercise had greater in-

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

creases in fat-free mass and muscle size than either of the no-exercise groups (testosterone or placebo). A study that followed young adult male volunteers found that body composition changes that occurred during testosterone therapy, reverted slowly back to normal during the five to six months of follow-up after cessation of supplementation (Forbes et al., 1992). A study of 10 healthy older men administered growth hormone, testosterone, or a combination found no significant changes in strength, or percentage body fat with testosterone supplementation; however, increases in some performance measures were noted (Brill et al., 2002). In a study of healthy young men, testosterone administration did not preserve muscle strength during prolonged bed rest (Zachwieja et al., 1999).

A number of studies have examined testosterone as a potential therapy for weight loss in HIV-infected male patients. Several of these studies have found that testosterone supplementation increased lean body mass, muscle mass, and muscle strength (Grinspoon et al., 1998, 1999, 2000; Fairfield et al., 2001) The duration of treatment was generally three to six months.

Testosterone therapy has been evaluated for potential effects on body composition and muscle strength in patients with muscular dystrophy (Welle et al., 1992) and myotonic dystrophy (Griggs et al., 1989a), and in patients receiving long-term glucocorticoid treatment for asthma (Reid et al., 1996). The studies reported increases in lean body mass; however, muscle strength did not increase in the patients with myotonic dystrophy who received testosterone therapy for 12 months (Griggs et al., 1989b).

COGNITIVE FUNCTION, MOOD, AND DEPRESSION

There have been few additional studies of cognitive function and administration of testosterone. Alexander and colleagues (1998) found that verbal fluency was enhanced in their study of 33 hypogonadal men receiving testosterone therapy as compared with baseline measures. Verbal fluency measures were also improved in a study of 30 healthy eugonadal men with testosterone levels raised into supraphysiological ranges after 8 weeks of intramuscular injections of 200 mg testosterone enanthate (O’Connor et al., 2001). The authors of a study of 19 men with hypogonadrotrophic hypogonadism speculated that prepubertal effects of androgen deficits may explain why six of the patients did not improve their spatial ability after androgen replacement therapy (Hier and Crowley, 1982). A randomized placebo-controlled trial in healthy young men (average age of 33) did not find a significant difference between the testosterone- and placebo-treated groups on cognitive measures after 8 weeks of testosterone therapy (Cherrier et al., 2002).

Studies of hypogonadal males have reported improvements in mea-

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

sures of mood and depression. In a study by Burris and colleagues (1992), hypogonadal men undergoing testosterone therapy had improvements over their baseline in measures of depression, anger, fatigue, and confusion, although these levels remained higher than those for nonhypogonadal men. Mood parameters (anger, irritability, sadness, tiredness, nervousness) were also improved in a study of 51 hypogonadal men who received intramuscular or sublingual testosterone for 60 days (Wang et al., 1996a). O’Connor and colleagues (2002) found reductions in negative mood parameters (tension, anger, fatigue) in hypogonadal men treated with testosterone enanthate for eight weeks.

Similarly, several studies of men with HIV and low testosterone levels found significant improvement with testosterone supplementation in mood as measured by depression inventory scores or self-reports (Rabkin et al., 1995; Grinspoon et al., 2000). A study by Okun and colleagues (2002) of 10 patients with Parkinson’s disease found trends in improvements with testosterone therapy on measures of cognition and mood and on scales of nonmotor symptoms of Parkinson’s disease.

Studies in which testosterone was administered to normal eugonadal males (in some cases using supraphysiologic doses) to assess mood and aggressive responses found mixed results. Several studies found no or minimal changes in aggression or mood levels in the treated groups (Anderson et al., 1992; Tricker et al., 1996; Yates et al., 1999; O’Connor et al., 2002), while others found increases in aggressive responses (Kouri et al., 1995; Giorgi et al., 1999; Pope et al., 2000).

SEXUAL FUNCTION

Many of the studies that assessed sexual function were conducted to examine the safety and effectiveness of testosterone as a contraceptive measure and involved young eugonadal males who were administered supraphysiological levels of testosterone. These studies and others of men with normal levels of testosterone generally found increases in sexual awareness and measures of arousal, but no change in overt sexual behavior (Anderson et al., 1992; Bagatell et al., 1994b; Yates et al., 1999). A study examining dose-response relationships in testosterone administered to 61 eugonadal men (ages 18 to 35) found that sexual function did not change significantly with dose (25, 50, 125, 300, or 600 mg of testosterone enanthate weekly for 20 weeks) (Bhasin et al., 2001a).

In hypogonadal males, studies of sexual dysfunction have generally found no change or slight improvements with testosterone therapy. Improvements in erectile dysfunction measures were rarely statistically significant but modest improvements in sexual desire have been observed (O’Carroll and Bancroft, 1984; Aydin et al., 1996; Morales et al., 1997; Rakic

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

et al., 1997; Schultheiss et al., 2000; Gomaa et al., 2001; Monga et al., 2002). A number of studies of hypogonadal males found increases in measures of sexual interest and arousal with testosterone therapy (Luisi and Franchi, 1980; Salmimies et al., 1982; Bancroft and Wu, 1983; Kwan et al., 1983; O’Carroll et al., 1985; Carani et al., 1990; Cunningham et al., 1990; Burris et al., 1992; Arver et al., 1996; Hajjar et al., 1997; Dobs et al., 1998; 1999b; Snyder et al., 2000; Wang et al., 2000; Cutter, 2001; Hong and Ahn, 2002). Most studies have focused on young and middle-aged hypogonadal men. The study by Hajjar and colleagues (1997) retrospectively examined 31 hypogonadal older males (mean age 71.8 +/– 1.7 years) receiving testosterone supplementation for at least 1 year compared with 27 older hypogonadal males who did not receive treatment, and found a much greater improvement in self-assessment of changes in libido in the testosterone-treated group.

HEALTH-RELATED QUALITY OF LIFE AND PHYSICAL FUNCTION/FRAILTY

Several studies in hypogonadal males using comparison with baseline measures found improvements in quality of life indicators (Wang et al., 1996a; Snyder et al., 2000; Cutter, 2001). For example, improvements in mood, energy level, and sense of well-being were seen in a study of hypogonadal men who responded to a questionnaire at baseline and several times during the six months of treatment (Wang et al., 1996a). O’Connor and colleagues (2002) found significant reductions in fatigue (as well as several negative mood parameters) for hypogonadal males, but no changes in mood or aggression levels in eugonadal males after both groups received 200 mg testosterone enanthate biweekly for eight weeks. Arver and colleagues (1997) also found improvement in symptoms of hypogonadism including fatigue. A study of short-term (1 month) administration of growth hormone or testosterone or both found improvements in 30-meter walk time and stair-climb time with testosterone therapy in 10 men (mean age 68) (Brill et al., 2002).

Several randomized placebo-controlled studies of HIV-infected patients found the sense of well-being or quality of life improved with testosterone treatment (Coodley and Coodley, 1997; Grinspoon et al., 1998). A study of 133 HIV-infected patients by Dobs and colleagues (1999a) did not find changes in quality of life in either the placebo or testosterone treatment group after 12 weeks. Wagner and colleagues (1998) found improved energy levels and declining fatigue in a study of HIV-positive hypogonadal males.

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

CARDIOVASCULAR AND HEMATOLOGIC OUTCOMES

Studies on Lipid Profiles

Studies in hypogonadal males that have looked at lipid profiles have found mixed results, with several longer-term studies generally finding no change in lipid profiles as compared with baseline measures. A number of these studies included hypogonadal males over age 65 years. Several studies found no significant change in lipid profiles (or specific measures) with administration of testosterone undecanoate (Hong and Ahn, 2002; Li et al., 2002; von Eckardstein and Nieschlag, 2002), transdermal testosterone (Snyder et al., 2000), or when transdermal and intramuscular routes were compared (Dobs et al., 1999b). On the other hand, a study by Jockenhovel and colleagues (1999) of 55 hypogonadal men that met the study entry criteria of total cholesterol and triglyceride levels less than 200 mg/dL found that after approximately 6 months of testosterone therapy, there was a significant increase in total cholesterol and a decrease in high density lipoprotein (HDL). Salehian and colleagues (1995) also found a decrease in HDL. Other studies found decreased total cholesterol (Conway et al., 1988; Morley et al., 1993), decreases in total cholesterol and low density lipoprotein (LDL) (Zgliczynski et al., 1996; Rabijewski et al., 1998; Tripathy et al., 1998), decreases in all cholesterol fractions (Dobs et al., 2001; Cutter, 2001), or no significant changes in HDL (Morley et al., 1993; Zgliczynski et al., 1996; Tripathy et al., 1998). The majority of the studies involved 6 months or less of testosterone treatment with small numbers of hypogonadal patients (generally less than 50 men). In 2 studies in which men received testosterone for 3 years or more, there were no changes seen in the lipid profiles as compared with baseline, but again, with small numbers of participants (Snyder et al., 2000; von Eckardstein and Nieschlag, 2002). A small study of older men (70.6 +/– 6.2 years of age) found that physiologic or supraphysiologic intravenous administrations of testosterone did not significantly affect blood pressure or electrocardiogram variables (White et al., 1999).

Studies in eugonadal males have generally seen decreases in HDL with testosterone administration, but again, there were mixed results. Several studies found significant decreases in HDL with supraphysiologic doses of intramuscular testosterone injections (Bagatell et al., 1994a; Anderson et al., 1995a; Meriggiola et al., 1995; Kouri et al., 1996). Singh and colleagues (2002) found a significant HDL decline only in the treatment group receiving the highest dose (600 mg testosterone enanthate monthly for 20 weeks) in the regimens they were testing (25, 50, 125, 300, 600 mg). The results for other lipoproteins were somewhat mixed, with most of the studies finding no effects on one or more lipoproteins (total

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

cholesterol, LDL, or serum triglycerides) (Friedl et al., 1990; Bagatell et al., 1992, 1994a; Meriggiola et al., 1995; Kouri et al., 1996; Wu et al., 1996), while one study found favorable decreases (Anderson et al., 1996). One study that followed participants after testosterone administration found that the lipid levels returned to the baseline range for one or more months (Bagatell et al., 1994a). Zmuda and colleagues (1996) found decreases in levels of lipoprotein(a) with exogenous testosterone. A study of male weightlifters administered testosterone did not find significant changes in total homocysteine levels (Zmuda et al., 1997).

Insulin Sensitivity Measures

No changes in insulin or measures of insulin sensitivity were seen in studies of healthy eugonadal males receiving testosterone supplementation (Friedl et al., 1990; Singh et al., 2002). Tripathy and colleagues (1998) found in a study of 10 hypogonadal males that testosterone supplementation did not decrease insulin sensitivity. A study of 30 normal males given pharmacological doses of testosterone for 6 weeks did not find glucose tolerance or insulin secretion impaired (Friedl et al., 1989). When supraphysiologic doses (300 mg/week testosterone enanthate) were administered for 6 weeks to 11 healthy men, no adverse effects on glucose metabolism were seen (Hobbs et al., 1996).

Studies Reporting Hematocrit, Hemostasis

Several studies of hypogonadal males (many of the studies included older men) found significant increases in hematocrit with testosterone supplementation (Morley et al., 1993; Hajjar et al., 1997; Jockenhovel et al., 1997; Rabijewski et al., 1998; Snyder et al., 2000). However, there were also studies that found no significant change in hemoglobin or hematocrit levels or red blood cell count in hypogonadal males after testosterone administration (Bhasin et al., 1997; Hong and Ahn, 2002; von Eckardstein and Nieschlag, 2002).

In a retrospective study of 45 older hypogonadal males receiving 200 mg testosterone enanthate or cypionate every 2 weeks for 1 year or more, the hematocrit was significantly increased as compared with 27 controls (Hajjar et al., 1997). Eleven men in the treatment group developed polycythemia sufficient to require temporary withdrawal from testosterone or phlebotomy. A study of transdermal testosterone supplementation in 18 hypogonadal males found that hematocrit increased significantly within 3 months of treatment (from mildly anemic to mid-normal ranges) and stayed in the normal range for the duration of treatment (1 to 3 years) (Snyder et al., 2000).

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Studies of eugonadal males reported the expected rises in hematocrit (Anderson et al., 1995b; Wu et al., 1996). Platelet aggregation responses to testosterone administration were examined by Ajayi and colleagues (1995), who found an increase during 4 weeks of treatment with testosterone cypionate (200 mg at 2 and 4 weeks) and a return to baseline after 4 weeks of no treatment. A study examining contraceptive measures found that in the group of healthy men aged 28 to 38 years receiving testosterone undecanoate plus the placebo (as opposed to an additional contraceptive compound), there was significant down-regulation of fibrinolysis (Zitzmann et al., 2002). Hemoglobin levels also increased in HIV-infected patients receiving testosterone supplementation (Bhasin et al., 2000).

PROSTATE OUTCOMES

Studies assessing prostate volume and changes in prostate-specific antigen (PSA) levels found mixed results, with treatment and follow-up periods that were generally of short duration. Several studies in hypogonadal men found increases in PSA level or prostate volume in response to various delivery methods of testosterone therapy (Sasagawa et al., 1990; Meikle et al., 1997; Svetec et al., 1997; Nieschlag et al., 1999; Guay et al., 2000). However, other studies found no changes or no significant increases in prostate volume or PSA level between the treated and untreated groups or when compared with baseline measures (Morley et al., 1993; Behre et al., 1994, 1999; Kamischke et al., 2000; Jin et al., 2001; Li et al., 2002). Often the men in these studies had received one year or less of testosterone therapy. In a 2-year follow-up study of 45 elderly hypogonadal men and 27 hypogonadal men taking testosterone, the increase in PSA level from baseline level was not statistically significant (Hajjar et al., 1997). Studies of healthy volunteers (generally less than 40 years old) found no significant changes in prostate volume or serum PSA levels, generally with short durations of testosterone therapy (Wallace et al., 1993; Cooper et al., 1998).

OTHER HEALTH OUTCOMES

Several additional studies of hypogonadal men have looked at sleep apnea and respiratory outcomes. Matsumoto and colleagues (1985) examined five hypogonadal men receiving testosterone enanthate. Three of the men did not have significant sleep apnea during or after the therapy. One man developed obstructive sleep apnea during testosterone administration, and the sleep apnea in the fifth man significantly worsened during therapy. The study also measured ventilatory drive and found that hypoxic ventilatory drive decreased significantly during testosterone therapy, while there were not significant changes in hypercapnoeic venti-

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

latory drive. A study by Schneider and colleagues (1986), compared respiratory rhythm during sleep in 11 hypogonadal males during and after testosterone administration and found a significant increase in disordered breathing events (apnea and hypopnea [shallow or slower breathing]) during testosterone therapy with wide variability in the extent of sleep disturbances between individuals. White and colleagues (1985) found changes in ventilatory responses (increased O2 consumption and CO2 production) after testosterone administration in 12 hypogonadal males.

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Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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Griggs RC, Kingston W, Jozefowicz RF, Herr BE, Forbes G, Halliday D. 1989a. Effect of testosterone on muscle mass and muscle protein synthesis. Journal of Applied Physiology 66(1):498–503.

Griggs RC, Pandya S, Florence JM, Brooke MH, Kingston W, Miller JP, Chutkow J, Herr BE, Moxley RT 3rd. 1989b. Randomized controlled trial of testosterone in myotonic dystrophy. Neurology 39(2 Pt 1):219–222.

Grinspoon S, Corcoran C, Askari H, Schoenfeld D, Wolf L, Burrows B, Walsh M, Hayden D, Parlman K, Anderson E, Basgoz N, Klibanski A. 1998. Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine 129(1):18–26.

Grinspoon S, Corcoran C, Anderson E, Hubbard J, Stanley T, Basgoz N, Klibanski A. 1999. Sustained anabolic effects of long-term androgen administration in men with AIDS wasting. Clinical Infectious Diseases 28(3):634–636.

Grinspoon S, Corcoran C, Stanley T, Baaj A, Basgoz N, Klibanski A. 2000. Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. Journal of Clinical Endocrinology and Metabolism 85(1):60–65.

Guay AT, Perez JB, Fitaihi WA, Vereb M. 2000. Testosterone treatment in hypogonadal men: prostate-specific antigen level and risk of prostate cancer. Endocrine Practice 6(2):132–138.


Hajjar RR, Kaiser FE, Morley JE. 1997. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. Journal of Clinical Endocrinology and Metabolism 82(11):3793–3796.

Hier DB, Crowley WF Jr. 1982. Spatial ability in androgen-deficient men. New England Journal of Medicine 306(20):1202–1205.

Hobbs CJ, Jones RE, Plymate SR. 1996. Nandrolone, a 19-nortestosterone, enhances insulin-independent glucose uptake in normal men. Journal of Clinical Endocrinology and Metabolism 81(4):1582–1585.

Hong JH, Ahn TY. 2002. Oral testosterone replacement in Korean patients with PADAM. Aging Male 5(1):52–56.


Ishizaka K, Suzuki M, Kageyama Y, Kihara K, Yoshida K. 2002. Bone mineral density in hypogonadal men remains low after long-term testosterone replacement. Asian Journal of Andrology 4(2):117–121.


Jin B, Conway AJ, Handelsman DJ. 2001. Effects of androgen deficiency and replacement on prostate zonal volumes. Clinical Endocrinology 54(4):437–445.

Jockenhovel F, Vogel E, Reinhardt W, Reinwein D. 1997. Effects of various modes of androgen substitution therapy on erythropoiesis. European Journal of Medical Research 2(7):293–298.

Jockenhovel F, Bullmann C, Schubert M, Vogel E, Reinhardt W, Reinwein D, Muller-Wieland D, Krone W. 1999. Influence of various modes of androgen substitution on serum lipids and lipoproteins in hypogonadal men. Metabolism: Clinical and Experimental 48(5):590–596.


Kamischke A, Ploger D, Venherm S, von Eckardstein S, von Eckardstein A, Nieschlag E. 2000. Intramuscular testosterone undecanoate with or without oral levonorgestrel: a randomized placebo-controlled feasibility study for male contraception. Clinical Endocrinology 53(1):43–52.

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. 1996. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. Journal of Clinical Endocrinology and Metabolism 81(12):4358–4365.

Kouri EM, Lukas SE, Pope HG Jr, Oliva PS. 1995. Increased aggressive responding in male volunteers following the administration of gradually increasing doses of testosterone cypionate. Drug and Alcohol Dependence 40(1):73–79.

Kouri EM, Pope HG Jr, Oliva PS. 1996. Changes in lipoprotein-lipid levels in normal men following administration of increasing doses of testosterone cypionate. Clinical Journal of Sport Medicine 6(3):152–157.

Kwan M, Greenleaf WJ, Mann J, Crapo L, Davidson JM. 1983. The nature of androgen action on male sexuality: a combined laboratory-self-report study on hypogonadal men. Journal of Clinical Endocrinology and Metabolism 57(3):557–562.


Leifke E, Korner HC, Link TM, Behre HM, Peters PE, Nieschlag E. 1998. Effects of testosterone replacement therapy on cortical and trabecular bone mineral density, vertebral body area, and paraspinal muscle area in hypogonadal men. European Journal of Endocrinology 138(1):51–58.

Li JY, Zhu JC, Dou JT, Bai WJ, Deng SM, Li M, Huang W, Jin H. 2002. Effects of androgen supplementation therapy on partial androgen deficiency in the aging male: a preliminary study. Aging Male 5(1):47–51.

Luisi M, Franchi F. 1980. Double-blind group comparative study of testosterone undecanoate and mesterolone in hypogonadal male patients. Journal of Endocrinological Investigation 3:305–308.


Matsumoto AM, Sandblom RE, Schoene RB, Lee KA, Giblin EC, Pierson DJ, Bremner WJ. 1985. Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep. Clinical Endocrinology 22(6):713–721.

Medras M, Jankowska EA, Rogucka E. 2001. Effects of long-term testosterone substitutive therapy on bone mineral content in men with hypergonadotrophic hypogonadism. Andrologia 33(1):47–52.

Meikle AW, Arver S, Dobs AS, Adolfsson J, Sanders SW, Middleton RG, Stephenson RA, Hoover DR, Rajaram L, Mazer NA. 1997. Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology 49(2):191–196.

Meriggiola MC, Marcovina S, Paulsen CA, Bremner WJ. 1995. Testosterone enanthate at a dose of 200 mg/week decreases HDL-cholesterol levels in healthy men. International Journal of Andrology 18(5):237–242.

Monga M, Kostelec M, Kamarei M. 2002. Patient satisfaction with testosterone supplementation for the treatment of erectile dysfunction. Archives of Andrology 48(6):433–442.

Morales A, Johnston B, Heaton JP, Lundie M. 1997. Testosterone supplementation for hypogonadal impotence: assessment of biochemical measures and therapeutic outcomes. Journal of Urology 157(3):849–854.

Morley JE, Perry HM 3rd, Kaiser FE, Kraenzle D, Jensen J, Houston K, Mattammal M, Perry HM Jr. 1993. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. Journal of the American Geriatrics Society 41(2):149–152.


Nieschlag E, Buchter D, Von Eckardstein S, Abshagen K, Simoni M, Behre HM. 1999. Repeated intramuscular injections of testosterone undecanoate for substitution therapy in hypogonadal men. Clinical Endocrinology 51(6):757–763.


O’Carroll R, Bancroft J. 1984. Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. British Journal of Psychiatry 145:146–151.

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

O’Carroll R, Shapiro C, Bancroft J. 1985. Androgens, behaviour, and nocturnal erection in hypogonadal men: the effects of varying the replacement dose. Clinical Endocrinology 23(5):527–538.

O’Connor DB, Archer J, Hair WM, Wu FC. 2001. Activational effects of testosterone on cognitive function in men. Neuropsychologia 39(13):1385–1394.

O’Connor DB, Archer J, Hair WM, Wu FC. 2002. Exogenous testosterone, aggression, and mood in eugonadal and hypogonadal men. Physiology and Behavior 75(4):557–566.

Okun MS, Walter BL, McDonald WM, Tenover JL, Green J, Juncos JL, DeLong MR. 2002. Beneficial effects of testosterone replacement for the nonmotor symptoms of Parkinson disease. Archives of Neurology 59(11):1750–1753.


Pope HG Jr, Kouri EM, Hudson JI. 2000. Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial. Archives of General Psychiatry 57(2):133–140.


Rabijewski M, Adamkiewicz M, Zgliczynski S. 1998. [The influence of testosterone replacement therapy on well-being, bone mineral density, and lipids in elderly men]. [Polish]. [Abstract]. Polskie Archiwum Medycyny Wewnetrznej 100(3):212–221.

Rabkin JG, Rabkin R, Wagner G. 1995. Testosterone replacement therapy in HIV illness. General Hospital Psychiatry 17(1):37–42.

Rakic Z, Starcevic V, Starcevic VP, Marinkovic J. 1997. Testosterone treatment in men with erectile disorder and low levels of total testosterone in serum. Archives of Sexual Behavior 26(5):495–504.

Reid IR, Wattie DJ, Evans MC, Stapleton JP. 1996. Testosterone therapy in glucocorticoid-treated men. Archives of Internal Medicine 156(11):1173–1177.


Salehian B, Wang C, Alexander G, Davidson T, McDonald V, Berman N, Dudley RE, Ziel F, Swerdloff RS. 1995. Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate—a clinical research center study. Journal of Clinical Endocrinology and Metabolism 80(12):3567–3575.

Salmimies P, Kockott G, Pirke KM, Vogt HJ, Schill WB. 1982. Effects of testosterone replacement on sexual behavior in hypogonadal men. Archives of Sexual Behavior 11(4):345–353.

Sasagawa I, Nakada T, Kazama T, Satomi S, Terada T, Katayama T. 1990. Volume change of the prostate and seminal vesicles in male hypogonadism after androgen replacement therapy. International Urology and Nephrology 22(3):279–284.

Schneider BK, Pickett CK, Zwillich CW, Weil JV, McDermott MT, Santen RJ, Varano LA, White DP. 1986. Influence of testosterone on breathing during sleep. Journal of Applied Physiology 61(2):618–623.

Schultheiss D, Hiltl DM, Meschi MR, Machtens SA, Truss MC, Stief CG, Jonas U. 2000. Pilot study of the transdermal application of testosterone gel to the penile skin for the treatment of hypogonadotropic men with erectile dysfunction. World Journal of Urology 18(6):431–435.

Singh AB, Hsia S, Alaupovic P, Sinha-Hikim I, Woodhouse L, Buchanan TA, Shen R, Bross R, Berman N, Bhasin S. 2002. The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. Journal of Clinical Endocrinology and Metabolism 87(1):136–143.

Sinha-Hikim I, Artaza J, Woodhouse L, Gonzalez-Cadavid N, Singh AB, Lee MI, Storer TW, Casaburi R, Shen R, Bhasin S. 2002. Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. American Journal of Physiology, Endocrinology & Metabolism 283(1):E154–E164.

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL. 2000. Effects of testosterone replacement in hypogonadal men. Journal of Clinical Endocrinology and Metabolism 85(8):2670–2677.

Svetec DA, Canby ED, Thompson IM, Sabanegh ES Jr. 1997. The effect of parenteral testosterone replacement on prostate specific antigen in hypogonadal men with erectile dysfunction. Journal of Urology 158(5):1775–1777.


Tricker R, Casaburi R, Storer TW, Clevenger B, Berman N, Shirazi A, Bhasin S. 1996. The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men—a clinical research center study. Journal of Clinical Endocrinology and Metabolism 81(10):3754–3758.

Tripathy D, Shah P, Lakshmy R, Reddy KS. 1998. Effect of testosterone replacement on whole body glucose utilisation and other cardiovascular risk factors in males with idiopathic hypogonadotrophic hypogonadism. Hormone and Metabolic Research 30(10):642–645.


Urban RJ, Bodenburg YH, Gilkison C, Foxworth J, Coggan AR, Wolfe RR, Ferrando A. 1995. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. American Journal of Physiology 269(5 Pt 1):E820–E826.


von Eckardstein S, Nieschlag E. 2002. Treatment of male hypogonadism with testosterone undecanoate injected at extended intervals of 12 weeks: a phase II study. Journal of Andrology 23(3):419–425.


Wagner GJ, Rabkin JG, Rabkin R. 1998. Testosterone as a treatment for fatigue in HIV+ men. General Hospital Psychiatry 20(4):209–213.

Wallace EM, Pye SD, Wild SR, Wu FC. 1993. Prostate-specific antigen and prostate gland size in men receiving exogenous testosterone for male contraception. International Journal of Andrology 16(1):35–40.

Wang C, Alexander G, Berman N, Salehian B, Davidson T, McDonald V, Steiner B, Hull L, Callegari C, Swerdloff RS. 1996a. Testosterone replacement therapy improves mood in hypogonadal men—a clinical research center study. Journal of Clinical Endocrinology and Metabolism 81(10):3578–3583.

Wang C, Eyre DR, Clark R, Kleinberg D, Newman C, Iranmanesh A, Veldhuis J, Dudley RE, Berman N, Davidson T, Barstow TJ, Sinow R, Alexander G, Swerdloff RS. 1996b. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men—a clinical research center study. Journal of Clinical Endocrinology and Metabolism 81(10):3654–3662.

Wang C, Swedloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N. 2000. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone Gel Study Group. Journal of Clinical Endocrinology and Metabolism 85(8):2839–2853.

Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N. 2001. Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men. Clinical Endocrinology 54(6):739–750.

Welle S, Jozefowicz R, Forbes G, Griggs RC. 1992. Effect of testosterone on metabolic rate and body composition in normal men and men with muscular dystrophy. Journal of Clinical Endocrinology and Metabolism 74(2):332–335.

White CM, Ferraro-Borgida MJ, Moyna NM, McGill CC, Ahlberg AW, Thompson PD, Heller GV. 1999. The effect of pharmacokinetically guided acute intravenous testosterone administration on electrocardiographic and blood pressure variables. Journal of Clinical Pharmacology 39(10):1038–1043.

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
×

White DP, Schneider BK, Santen RJ, McDermott M, Pickett CK, Zwillich CW, Weil JV. 1985. Influence of testosterone on ventilation and chemosensitivity in male subjects. Journal of Applied Physiology 59(5):1452–1457.

Woodhouse LJ, Reisz-Porszasz S, Javanbakht M, Storer TW, Lee M, Zerounian H, Bhasin S. 2003. Development of models to predict anabolic response to testosterone administration in healthy young men. American Journal of Physiology, Endocrinology, and Metabolism 284(5):E1009–E1017.

Wu FC, Farley TM, Peregoudov A, Waites GM. 1996. Effects of testosterone enanthate in normal men: experience from a multicenter contraceptive efficacy study: World Health Organization Task Force on Methods for the Regulation of Male Fertility. Fertility & Sterility 65(3):626–636.


Yates WR, Perry PJ, MacIndoe J, Holman T, Ellingrod V. 1999. Psychosexual effects of three doses of testosterone cycling in normal men. Biological Psychiatry 45(3):254–260.

Young NR, Baker HW, Liu G, Seeman E. 1993. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. Journal of Clinical Endocrinology and Metabolism 77(4):1028–1032.


Zachwieja JJ, Smith SR, Lovejoy JC, Rood JC, Windhauser MM, Bray GA. 1999. Testosterone administration preserves protein balance but not muscle strength during 28 days of bed rest. Journal of Clinical Endocrinology and Metabolism 84(1):207–212.

Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, Brzezinska A, Zgliczynski W, Soszynski P, Chotkowska E, Srzednicki M, Sadowski Z. 1996. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis 121(1):35–43.

Zitzmann M, Junker R, Kamischke A, Nieschlag E. 2002. Contraceptive steroids influence the hemostatic activation state in healthy men. Journal of Andrology 23(4):503–511.

Zmuda JM, Thompson PD, Dickenson R, Bausserman LL. 1996. Testosterone decreases lipoprotein(a) in men. American Journal of Cardiology 77(14):1244–1247.

Zmuda JM, Bausserman LL, Maceroni D, Thompson PD. 1997. The effect of supraphysiologic doses of testosterone on fasting total homocysteine levels in normal men. Atherosclerosis 130(1–2):199–202.

Suggested Citation:"Appendix C: Additional Studies of Testosterone Therapy." Institute of Medicine. 2004. Testosterone and Aging: Clinical Research Directions. Washington, DC: The National Academies Press. doi: 10.17226/10852.
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Popular culture often equates testosterone with virility, strength, and the macho male physique. Viewed by some as an “antiaging tonic,” testosterone’s reputation and increased use by men of all ages in the United States have outpaced the scientific evidence about its potential benefits and risks. In particular there has been growing concern about an increase in the number of middle-aged and older men using testosterone and the lack of scientific data on the effect it may have on aging males. Studies of testosterone replacement therapy in older men have generally been of short duration, involving small numbers of participants and often lacking adequate controls. Testosterone and Aging weighs the options of future research directions, examines the risks and benefits of testosterone replacement therapy, assesses the potential public health impact of such therapy in the United States, and considers ethical issues related to the conduct of clinical trials. Testosterone therapy remains an attractive option to many men even as speculation abounds regarding its potential.

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