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.
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
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-
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-
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).
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
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.
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
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).
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).
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-
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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