Index
A
AACE. See American Association of Clinical Endocrinologists
Absorptiometry, dual-energy X-ray, 48
Acetylcholine, 58
Activities of daily living (ADL), 55
Acute urinary retention (AUR), 139
ADL. See Activities of daily living
Adrenopause, 13
Age, in selected studies of endogenous testosterone levels, 35
Age-related changes
in hormones, 12–14
in testosterone levels, 6, 9, 118
Albumin-bound testosterone, 16–17
Alcohol abuse, exclusion criteria, monitoring, and follow-up of research participants for, 145
Alzheimer’s disease, 132–133
American Association of Clinical Endocrinologists (AACE), 22
American College of Pathologists, 123
American Urological Association (AUA), 141–142
Androgen concentrations, 67, 86, 135
potency of, 15
Androgen-metabolizing enzymes, 87
Androgen receptors (ARs), 58, 86
polymorphisms in, 87–88
ARs. See Androgen receptors
AUA. See American Urological Association
AUR. See Acute urinary retention
B
Baltimore Longitudinal Study of Aging (BLSA), 33–34, 76, 142–143, 165
BDI. See Beck Depression Inventory
Beck Depression Inventory (BDI), 62, 66
Benefits, communicating to study participants, 6, 9, 118
Benign prostatic hyperplasia (BPH), 5, 81, 86, 118, 138, 142–143
Bioavailable testosterone (BT), 16, 18
BLSA. See Baltimore Longitudinal Study of Aging
BMD. See Bone mineral density
BMI. See Body mass index
Body composition, measures of, 135
Body composition and strength, 47–54
additional studies of testosterone therapy and, 183–184
clinical trials of testosterone therapy and, 49, 50, 52–54
and endogenous testosterone levels, 48–49
Body mass index (BMI), 39
Bone metabolism and density, 41–47, 136–137
additional studies of testosterone therapy and, 182–183
clinical trials of testosterone therapy and, 43, 45, 46, 47
and endogenous testosterone levels, 43–44
Bone mineral density (BMD), 43, 45, 182–183
BOP. See N-nitrosobis(2-oxypropyl)amine
BPH. See Benign prostatic hyperplasia
Breast Cancer Prevention Trial, 146
Brown-Séquard, Charles, 19
BT. See Bioavailable testosterone
Butenandt, Adolf, 19
C
CAD. See Coronary artery disease
Calcium signaling, 58
Cancer risk factors, as a function of serum prostate specific antigen level and digital rectal examination findings, 140
Carbohydrate metabolism, and cardiovascular risk, 135
Cardiovascular and hematologic outcomes, 73–81
additional studies of testosterone therapy and, 187–189
clinical trials of testosterone therapy and, 79–82
endogenous testosterone levels and, 76, 79
exclusion criteria, monitoring, and follow-up of research participants for, 144–145
Cardiovascular risk factors
and lipid and carbohydrate metabolism, 135
and selected studies of endogenous testosterone levels, 77
Central nervous system function, 67–68
CGI. See Clinical Global Impression score
Changes
in the digital rectal examination, monitoring participants for, 5, 9, 118
in prostate specific antigen levels, monitoring participants for, 5, 9, 118
in testosterone levels, age-related, 6, 9, 118
Cirrhosis, treating with testosterone therapy, 23
Clinical Global Impression score (CGI), 66
Clinical trials of testosterone therapy
and body composition and strength, 49, 52–54
and bone-related outcomes, 43, 45, 47
and cardiovascular and hematologic outcomes, 79–81
and cognitive function, 59–61
coordination of, 8
and health-related quality of life, 73
insulin sensitivity measures, 188
and mood and depression, 63, 66
and physical function, 56–58
and prostate outcomes, 92–93
red blood cell measures, 80
Clinical trials of testosterone therapy in middle-aged men, 7, 161–162
Clinical trials of testosterone therapy in older men, 2–4, 8, 27–28, 117
if short-term efficacy is established, 4, 9, 117
Cognitive function, 3, 58–61, 113, 131–133
additional studies of testosterone therapy and, 184–185
clinical trials of testosterone therapy and, 59–61
endogenous testosterone levels and, 58–59
Concentrations, of estrogen and androgens, 135
Coordination
of clinical trials, 8
of initial efficacy trials, 119–120
Coronary artery disease (CAD), 73, 76, 79
CYP17 polymorphisms, 87
Cytokines, 42
D
Data sources and methods, 165–172
committee meetings and workshop, 167–172
literature review, 165–167
Dehydroepiandrosterone (DHEA), 13
additional studies of testosterone therapy and, 184–185
clinical trials of testosterone therapy and, 63, 64, 66
endogenous testosterone levels and, 62–63
Design issues, 120–125
inclusion criteria, 120–122
measuring testosterone levels, 122–123
sample size, 124–125
testosterone formulation and dose, 123–124
DHEA. See Dehydroepiandrosterone
DHEAS. See Dehydroepiandrosterone-sulfate
DHT. See Dihydrotestosterone
Diabetes
exclusion criteria, monitoring, and follow-up of research participants for, 145
and selected studies of endogenous testosterone levels, 77
See also Insulin sensitivity measures
Digital rectal examination (DRE), 140
monitoring participants for changes in, 5, 9, 118
Dihydrotestosterone (DHT), 15, 20–21, 86–87, 143
Disability outcomes
continuum of diminished, 126
See also Strength, frailty, and disability outcomes
Dose, testosterone, 123–124
DRE. See Digital rectal examination
Drug abuse, exclusion criteria, monitoring, and follow-up of research participants for, 145
Dual-energy X-ray absorptiometry, 48
Dysthmia, measures of, 137
E
E2. See Estradiol
ED. See Erectile dysfunction
Efficacy, defined, 114n
Efficacy and Safety of Testosterone in Elderly Men Trial (ESTEEM), 28, 167
Emphysema, treating with testosterone therapy, 23
Endocrinology, 19
Endogenous testosterone levels, 32
and age, 35
and body composition and strength, 48–49
and cardiovascular and hematologic outcomes, 76, 79
and cardiovascular risk factors and diabetes, 77
and cognitive function, 58–59
and mood and depression, 62–63
physiologic regulation of, 6, 9, 118
and prostate outcomes, 89–91
and sexual function, 68–69
Equilibrium dialysis, 18
Erectile dysfunction (ED), 67
ESTEEM. See Efficacy and Safety of Testosterone in Elderly Men Trial
Estradiol (E2) concentrations, 14–15, 76, 91
Estrogen concentrations, 121, 135
Ethical issues, 138–145
Exclusion criteria for research participants, 138–145
for men at high risk for developing prostate cancer, 5, 9, 118
for men at high risk for requiring intervention to treat benign prostatic hyperplasia, 5, 9, 118
for prostate outcomes, 139–142
F
Family history of prostate cancer, effect on lifetime risk of clinical prostate cancer, 139
Fat distribution, 17
FDA. See Food and Drug Administration
Federal Policy for Protection of Human Subjects, 137n
Female Sexual Function Index (FSFI), 130
FICSIT. See Frailty and Injuries:
Cooperative Studies of Intervention Techniques
FIM. See Functional Independence Measure
Finasteride, 89
Follicle stimulating hormone (FSH), 15, 21
Follow-up of research participants, 138–145
for prostate outcomes, 143
Food and Drug Administration (FDA), 19, 160
Formulation, of testosterone, 123–124
Frailty. See Strength, frailty, and disability outcomes
Frailty and Injuries:
Cooperative Studies of Intervention Techniques (FICSIT), 120
Free testosterone (FT), 33, 62
Free testosterone index (FTI), 33
FSFI. See Female Sexual Function Index
FSH. See Follicle stimulating hormone
FT. See Free testosterone
FTI. See Free testosterone index
Functional Independence Measure (FIM), 57
Future research directions, 112–158
additional areas of research, 152
initial efficacy trials in older men, 119–137
protection of research participants, 137–149
strategy for future clinical trials in older men, 113–118
G
GH. See Growth hormone
Ginkgo biloba, 133
Globulin, sex hormone binding, 135
Glucocorticoid therapy, treating pronounced muscle wasting associated with, 22
Gonadotropin-releasing hormone (GnRH), 15, 23, 68
Gonadotropins, 21
Growth, in use of testosterone therapy, 24–27
Growth factor levels, 135
Growth hormone (GH), 13
Gynecomastia, 21
H
Hamilton Depression Rating Scale (Ham-D), 66
HDL. See High-density lipoprotein
Health outcomes, 32–111, 125–137
body composition and strength, 47–54
bone metabolism and density, 41–47, 136–137
cardiovascular outcomes, 73–81, 135
changes in endogenous testosterone levels with aging, 33–39
cognitive function, 58–61, 131–133
concentration of estrogen and androgens, 135
effects on sex hormone binding globulin, 135
genetic determinants of sex steroid action, 136
growth factor levels, 135
health-related quality of life, 72–73
hematologic outcomes, 73–81, 135
inflammation measures, 135
lipid and carbohydrate metabolism and cardiovascular risk, 135
literature review, 39–41
measures of body composition, 135
measures of dysthmia, 137
mood and depression, 61–66, 137
multiple outcomes, 93–99
physical function, 54–58
potentially adverse, exclusion criteria, monitoring, and follow-up of research participants for, 144–145
prostate outcomes, 81–93
sexual function, 66–72, 128–131
strength, frailty, and disability outcomes, 3, 125–128
well-being, quality of life, and vitality, 3, 133–134
Health-related quality of life (HRQoL), 72–73
additional studies of testosterone therapy and, 186
clinical trials of testosterone therapy and, 73, 74
See also Well-being, quality of life, and vitality
Hematocrit, additional studies reporting, 188–189
Hematologic outcomes
indices of, 135
and randomized placebo-controlled trials of testosterone therapy in older men, 82
Hemochromatosis, 21
Hemostasis, additional studies reporting, 189
Hepatotoxicity, 19
High-density lipoprotein (HDL), 76, 80, 187
HIV. See Human immunodeficiency virus
HRQoL. See Health-related quality of life
Human immunodeficiency virus (HIV), 73, 184, 186
Hypercapnoeic ventilatory drive, 189–190
Hypogonadism, treating with testosterone therapy, 1, 6, 21–22
I
IADL. See Instrumental activities of daily living
IIEF. See International Index of Erectile Functioning
Implementation issues, 120–125
inclusion criteria, 120–122
measuring testosterone levels, 122–123
sample size, 124–125
testosterone formulation and dose, 123–124
Inclusion criteria, 120–122
Inflammation measures, 135
Initial efficacy trials in older men, 119–137
coordination of initial efficacy trials, 119–120
design and implementation issues, 120–125
primary health outcomes, 125–134
secondary health outcomes, 134–137
Institute of Medicine (IOM), 1, 11, 28, 137–138, 147, 165
Instrumental activities of daily living (IADL), 55
Insulin sensitivity measures, in clinical trials of testosterone therapy, 188
Interim monitoring of trial results and stopping rules, 145–146
incorporation into the trial design, 5, 9, 118
International Index of Erectile Functioning (IIEF), 129–130
IOM. See Institute of Medicine
K
Klinefelter’s syndrome, 21
L
LDL. See Low-density lipoprotein
Leydig cell number, 121
LH. See Luteinizing hormone
LHRH. See Luteinizing hormone-releasing hormone
Lipid metabolism, and cardiovascular risk, 135
Lipid profiles, in clinical trials of testosterone therapy, 80, 187–188
Literature review, 165–167
LNCaP prostate cancer cells, 88
Longitudinal effects of aging, on date-adjusted testosterone and free testosterone index, 37
Low-density lipoprotein (LDL), 187
Luteinizing hormone (LH), 14–15, 21–23, 68, 121
Luteinizing hormone-releasing hormone (LHRH), 128
M
Male breast cancer, exclusion criteria, monitoring, and follow-up of research participants for, 145
Male hypogonadism, treating with testosterone therapy, 1, 6, 21–22
Male infertility, 27
Massachusetts Male Aging Study (MMAS), 34, 36, 49, 62, 68, 165
Mechanism of action, of testosterone, 6, 9, 118
Medical conditions treated, 21–23
cirrhosis, 23
emphysema, 23
hypogonadism, 21–22
pronounced muscle wasting associated with glucocorticoid therapy, 22
wasting syndrome of advanced AIDS, 22
Middle-aged men
clinical trials of testosterone therapy in, 161–162
randomized placebo-controlled studies of testosterone therapy in, 174
Mini-Mental State Examination, 132, 134
MMAS. See Massachusetts Male Aging Study
MNU. See N-methyl-N-nitrosourea
Monitoring of research participants for adverse effects, 5, 9, 118, 138–145
changes in prostate specific antigen levels, 5, 9, 118
changes in the digital rectal examination, 5, 9, 118
prostate outcomes, 142–143
Mood, 61–66
additional studies of testosterone therapy and, 184–185
clinical trials of testosterone therapy and, 63, 64, 66
endogenous testosterone levels and, 62–63
measures of, 137
MRFIT. See Multiple Risk Factor Intervention Trial
Multiple Risk Factor Intervention Trial (MRFIT), 34, 38–39, 79
Muscle mass, maintaining, 17
Muscle wasting associated with glucocorticoid therapy, pronounced, treating with testosterone therapy, 22
Muscle weakness, 113
N
N-methyl-N-nitrosourea (MNU), 86
N-nitrosobis(2-oxypropyl)amine (BOP), 86
National Cancer Institute (NCI), 1, 11, 28, 167
National Heart, Lung, and Blood Institute, 27
National Institute for Nursing Research, 120
National Institute on Aging (NIA), 1, 8, 11, 28, 120, 150, 167
National Institutes of Health (NIH), 1, 11, 27, 120, 167
National Research Council, 148, 165
Public Access Records Office, 168
NCI. See National Cancer Institute
Needle biopsies, 54
NIA. See National Institute on Aging
NIH. See National Institutes of Health
O
Obesity, exclusion criteria, monitoring, and follow-up of research participants for, 145
Occult prostate carcinoma, 139
Older men
need for efficacy studies in, 159–161
randomized placebo-controlled trials of testosterone therapy in, 173–181
recommendations regarding clinical trials of testosterone therapy in, 4, 8–9
P
Partner Encounter Profile, 130
Partner Questionnaire, 130
PCPT. See Prostate Cancer Prevention Trial
Physical function, 54–58
additional studies of testosterone therapy and, 186
clinical trials of testosterone therapy and, 56–58
in community-dwelling American men, 70 years and older, 55
continuum of diminished, 126
See also Strength, frailty, and disability outcomes
Physician’s Health Study, 34, 91
Physiologic regulation, of endogenous testosterone levels, 6, 9, 118
PIN. See Prostate intraepithelial neoplasia
Plasma testosterone. See Testosterone
PLESS. See Proscar Long-term Efficacy and Safety Study
Polycythemia, exclusion criteria, monitoring, and follow-up of research participants for, 144
Potency, 17
Primary health outcomes, 8, 125–134
Proscar Long-term Efficacy and Safety Study (PLESS), 141, 143
Prostate cancer, 86–88, 121, 138
family history of, 139
follow-up, 143
monitoring, 142-–143
occult, 139
Prostate Cancer Prevention Trial (PCPT), 89, 143
Prostate intraepithelial neoplasia (PIN), 86
Prostate outcomes, 81–93
additional studies of testosterone therapy and, 189
clinical trials of testosterone therapy and, 92–94
endogenous testosterone levels and, 89–91
exclusion criteria, monitoring, and follow-up of research participants for, 138–143
Prostate-specific antigen (PSA) levels, 5–6, 9, 92, 140–143, 147, 151
monitoring participants for changes in, 5, 9, 118
thresholds based on age and race, 141
Protection of research participants, 5–6, 9, 137–149
exclusion criteria, monitoring, and follow-up, 138–145
interim monitoring of trial results and stopping rules, 145–146
risk/benefit communication and consent, 146–149
safety and ethical issues, 138–145
PSA. See Prostate-specific antigen levels
Psychiatric illness and aggression, exclusion criteria, monitoring, and follow-up of research participants for serious, 145
Q
Quality of life. See Health-related quality of life
R
Radioimmunoassay, 18
Rancho Bernardo study, 34, 39–40, 43, 58, 79
Randomized placebo-controlled studies of testosterone therapy in middle-aged men, 174
Randomized placebo-controlled trials of testosterone therapy in older men, 1, 173–181
and body composition and strength, 50
and bone outcomes, 46
and cardiovascular or hematologic outcomes, 82
and cognitive function, 60
and mood and depression, 64
and multiple outcome measures, 98
and physical function, 56
and prostate outcomes, 94
and quality of life in, 74
and sexual function, 70
Recommendations for further research, 6, 9, 118
age-related changes in testosterone levels, 6, 9, 118
mechanism of action of testosterone, 6, 9, 118
physiologic regulation of endogenous testosterone levels, 6, 9, 118
Recommendations for protection of research participants, 5–6, 118
communicating risks and benefits to study participants, 6, 9, 118
excluding men at high risk for developing prostate cancer, 5, 9, 118
excluding men at high risk for requiring intervention to treat benign prostatic hyperplasia, 5, 9, 118
incorporating interim monitoring findings into the trial design, 5, 9, 118
monitoring participants for any adverse effects, 5, 9, 118
planning carefully to address prostate risk issues, 6, 9, 118
Recommendations regarding clinical trials of testosterone therapy in older men, 4, 8–9, 116–118, 150
beginning with short-term efficacy trials to determine benefit, 4, 8, 117
conducting longer-term studies if short-term efficacy is established, 4, 9, 117
Red blood cell measures, 80
additional studies reporting hematocrit, 188–189
additional studies reporting hemostasis, 189
in clinical trials of testosterone therapy, 80
Regulation
physiologic, of endogenous testosterone levels, 6, 9, 118
of testosterone and sperm production by LH and FSH, 16
age-related changes in testosterone levels, 6, 9, 118
mechanism of action of testosterone, 6, 9, 118
physiologic regulation of endogenous testosterone levels, 6, 9, 118
Research participants, exclusion criteria, monitoring, and follow-up of, 138–145
Research Triangle Institute (RTI), 166–167
Risks
communicating to study participants, 6, 9, 118, 146–149
See also Cancer risk factors; Cardiovascular risk factors
Rochester Epidemiology Project, 34
RTI. See Research Triangle Institute
Ruzicka, Leopold, 19
S
Safety issues, 138–145
Sample size, 124–125
SARMs. See Selective androgen receptor modulators
Secondary health outcomes, 134–137
Selective androgen receptor modulators (SARMs), 7, 20–21, 162
Serotonin, 58
Sertoli cells, 15
Sex hormone-binding globulin (SHBG), 18, 22, 33, 91, 122–123, 135
Sex steroid action, genetic determinants of, 136
Sexual Experience Profile, 130
Sexual function, 3, 66–72, 113, 128–131
additional studies of testosterone therapy and, 185–186
clinical trials of testosterone therapy and, 69, 70, 72
endogenous testosterone levels and, 68–69
SF-36. See Short Form 36 item questionnaire
SHBG. See Sex hormone-binding globulin
Short Form 36 item questionnaire (SF-36), 58, 73, 134
Short-term efficacy trials to determine benefit, 4, 8, 117
coordination of clinical trials, 8
primary outcomes, 8
study population for initial trials, 8
testosterone preparation and dosages, 8
exclusion criteria, monitoring, and follow-up of research participants for uncontrolled, 189–190
Somatopause, 13
Starling, Ernest Henry, 19
Strength, frailty, and disability outcomes, 3, 21, 113, 125–128
Study population, for initial trials, 8
T
TC. See Testosterone cypionate
TE. See Testosterone enanthate
Testosterone, 17
albumin-bound, 16–17
formulation and dose, 123–124
and human development, and health, 14–17
mechanism of action of, 6, 9, 118
partitions in the serum, 17
preparation and dosages, 8, 150
synthesis pathways in human testis, 15
using as a therapeutic intervention, not a preventive measure, 115
Testosterone and health outcomes, 32–111
body composition and strength, 47–54
bone, 41–47
cardiovascular and hematologic outcomes, 73–81
changes in endogenous testosterone levels with aging, 33–39
cognitive function, 58–61
health-related quality of life, 72–73
literature review, 39–41
mood and depression, 61–66
multiple outcomes, 93–99
other health outcomes, 93
physical function, 54–58
prostate outcomes, 81–93
sexual function, 66–72
Testosterone cypionate (TC), 19
Testosterone enanthate (TE), 19
Testosterone levels
age-related changes in, 6, 9, 17, 118
in clinical studies, 198–201
endogenous, physiologic regulation of, 6, 9, 118
measuring, 122–123
Testosterone therapy, 18–24
additional studies of, 182–197
administering, 19
and body composition and strength, 183–184
and bone, 182–183
and cardiovascular and hematologic outcomes, 187–189
categorization of studies on, 166
and cognitive function, 184–185
and health-related quality of life, 186
and mood and depression, 184–185
and physical function, 186
prescription trend, 25
and prostate outcomes, 189
and sexual function, 185–186
treating medical conditions with, 21–23
use in aging men, 23–24
TF. See Total testosterone
Thromboembolic disease, exclusion criteria, monitoring, and follow-up of research participants for, 144–145
Total testosterone (TF), 121
True andropause, 13
U
Uncontrolled sleep apnea, exclusion criteria, monitoring, and follow-up of research participants for, 189–190
V
Ventilatory drive, hypercapnoeic, 189–190
Vitality. See Well-being, quality of life, and vitality
Vitamin D deficiency, 14
W
Wasting syndrome of advanced AIDS, treating with testosterone therapy, 22
Weakness. See Strength, frailty, and disability outcomes
Well-being, quality of life, and vitality, 3, 113, 133–134
WHI. See Women’s Health Initiative
Women’s Health Initiative (WHI), 11, 13, 27, 146, 160
X
X-ray absorptiometry, dual-energy, 48