[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.147.238.168. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Figure 1.
Study flow diagram showing number of patients and subject disposition through the course of study. AD indicates Alzheimer disease; MRI, magnetic resonance image.

Study flow diagram showing number of patients and subject disposition through the course of study. AD indicates Alzheimer disease; MRI, magnetic resonance image.

Figure 2.
Change in Quality of Life–Alzheimer Disease (QOL-AD) scores (caregiver) across study points in male patients with AD receiving testosterone and placebo.

Change in Quality of Life–Alzheimer Disease (QOL-AD) scores (caregiver) across study points in male patients with AD receiving testosterone and placebo.

Table 1. 
Comparison of Testosterone- and Placebo-Treated Groups on Demographic Characteristics, Outcome Measures, and Hormone Levels for Male Patients With Alzheimer Disease at Baseline
Comparison of Testosterone- and Placebo-Treated Groups on Demographic Characteristics, Outcome Measures, and Hormone Levels for Male Patients With Alzheimer Disease at Baseline
Table 2. 
Comparison of Testosterone- and Placebo-Treated Groups on Demographic Characteristics, Outcome Measures, and Hormone Levels for Male Healthy Control Subjects at Baseline*
Comparison of Testosterone- and Placebo-Treated Groups on Demographic Characteristics, Outcome Measures, and Hormone Levels for Male Healthy Control Subjects at Baseline*
Table 3. 
Within-Group and Between-Group Comparisons of Neuropsychiatric and Cognitive Outcome Measures at End of Study for Testosterone- and Placebo-Treated Men With Alzheimer Disease*
Within-Group and Between-Group Comparisons of Neuropsychiatric and Cognitive Outcome Measures at End of Study for Testosterone- and Placebo-Treated Men With Alzheimer Disease*
Table 4. 
Within-Group and Between-Group Comparisons of Neuropsychiatric and Cognitive Outcome Measures at End of Study for Testosterone- and Placebo-Treated Healthy Control Men*
Within-Group and Between-Group Comparisons of Neuropsychiatric and Cognitive Outcome Measures at End of Study for Testosterone- and Placebo-Treated Healthy Control Men*
Table 5. 
Between-Group Comparisons of Hormone Levels at End of Study for Testosterone- and Placebo-Treated Healthy Control Men*
Between-Group Comparisons of Hormone Levels at End of Study for Testosterone- and Placebo-Treated Healthy Control Men*
1.
Robinson  DFriedman  LMarcus  RTinklenberg  JYesavage  J Estrogen replacement therapy and memory in older women. J Am Geriatr Soc 1994;42919- 922
PubMed
2.
Kampen  DLSherwin  BB Estrogen use and verbal memory in healthy postmenopausal women. Obstet Gynecol 1994;83979- 983
PubMedArticle
3.
Schmidt  RFazekas  FReinhart  B  et al.  Estrogen replacement therapy in older women: a neuropsychological and brain MRI study. J Am Geriatr Soc 1996;441307- 1313
PubMed
4.
Baldereschi  MDi Carlo  ALepore  V  et al.  Estrogen-replacement therapy and Alzheimer’s disease in the Italian Longitudinal Study on Aging. Neurology 1998;50996- 1002
PubMedArticle
5.
Kawas  CResnick  SMorrison  A  et al.  A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 1997;481517- 1521
PubMedArticle
6.
Mortel  KFMeyer  JS Lack of postmenopausal estrogen replacement therapy and the risk of dementia. J Neuropsychiatry Clin Neurosci 1995;7334- 337
PubMed
7.
Paganini-Hill  AHenderson  VW Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol 1994;140256- 261
PubMed
8.
Tang  MXJacobs  DStern  Y Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996;348429- 432
PubMedArticle
9.
Yaffe  KSawaya  GLieberburg  IGrady  D Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998;279688- 695
PubMedArticle
10.
Shumaker  SALegault  CRapp  SR Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;2892651- 2662
PubMedArticle
11.
Schneider  LS Estrogen and dementia: insights from the Women’s Health Initiative Memory Study. JAMA 2004;2913005- 3007
PubMedArticle
12.
Shumaker  SALegault  CKuller  L Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004;2912947- 2958
PubMedArticle
13.
Henderson  VWPaganini-Hill  AMiller  BL Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000;54295- 301
PubMedArticle
14.
Mulnard  RACotman  CWKawas  C Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer’s Disease Cooperative Study. JAMA 2000;2831007- 1015
PubMedArticle
15.
Wang  PNLiao  SQLiu  RS Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology 2000;542061- 2066
PubMedArticle
16.
Cherrier  MMMatsumoto  AMAmory  JK The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology 2005;64290- 296
PubMedArticle
17.
Vermeulen  A Androgen replacement therapy in the aging male: a critical evaluation. J Clin Endocrinol Metab 2001;862380- 2390
PubMed
18.
Matsumoto  AM Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci 2002;57M76- M99
PubMedArticle
19.
Barrett-Connor  EGoodman-Gruen  DPatay  B Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 1999;843681- 3685
PubMed
20.
Yaffe  KLui  LYZmuda  JCauley  J Sex hormones and cognitive function in older men. J Am Geriatr Soc 2002;50707- 712
PubMedArticle
21.
Yaffe  KEdwards  ERLui  LYZmuda  JMFerrell  RECauley  JA Androgen receptor CAG repeat polymorphism is associated with cognitive function in older men. Biol Psychiatry 2003;54943- 946
PubMedArticle
22.
Cherrier  MMAsthana  SPlymate  S Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 2001;5780- 88
PubMedArticle
23.
Janowsky  JSOviatt  SKOrwoll  ES Testosterone influences spatial cognition in older men. Behav Neurosci 1994;108325- 332
PubMedArticle
24.
Moffat  SDZonderman  ABMetter  EJBlackman  MRHarman  SMResnick  SM Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab 2002;875001- 5007
PubMedArticle
25.
Janowsky  JSChavez  BOrwoll  E Sex steroids modify working memory. J Cogn Neurosci 2000;12407- 414
PubMedArticle
26.
Kenny  AMBellantonio  SGruman  CAAcosta  RDPrestwood  KM Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2002;57M321- M325
PubMedArticle
27.
Harman  SMMetter  EJTobin  JDPearson  JBlackman  MR Longitudinal effects of aging on serum total and free testosterone levels in healthy men: Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86724- 731
PubMedArticle
28.
Swerdloff  RSWang  C Androgens and aging in men. Exp Gerontol 1993;28435- 446
PubMedArticle
29.
Morley  JE Andropause, testosterone therapy, and quality of life in aging men. Cleve Clin J Med 2000;67880- 882
PubMedArticle
30.
Tenover  JS Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992;751092- 1098
PubMed
31.
Moffat  SDZonderman  ABMetter  EJ Free testosterone and risk for Alzheimer disease in older men. Neurology 2004;62188- 193
PubMedArticle
32.
Hogervorst  EWilliams  JBudge  MBarnetson  LCombrinck  MSmith  AD Serum total testosterone is lower in men with Alzheimer’s disease. Neuroendocrinol Lett 2001;22163- 168
PubMed
33.
Gouras  GKXu  HGross  RS Testosterone reduces neuronal secretion of Alzheimer’s beta-amyloid peptides. Proc Natl Acad Sci U S A 2000;971202- 1205
PubMedArticle
34.
Papasozomenos  SShanavas  A Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3 beta but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of tau: implications for Alzheimer’s disease. Proc Natl Acad Sci U S A 2002;991140- 1145
PubMedArticle
35.
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34939- 944
PubMedArticle
36.
Folstein  MFFolstein  SEMcHugh  PR “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMedArticle
37.
American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC: American Psychiatric Association; 1994
38.
Morris  JC The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;432412- 2414
PubMedArticle
39.
Rosen  WGMohs  RCDavis  KL A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;1411356- 1364
PubMed
40.
Delis  DCKramer  JHKaplan  EOber  BA The California Verbal Learning Test.  San Antonio, Tex: Harcourt Brace & Co; 1987
41.
Wechsler  D Manual for the Wechsler Adult Intelligence Scale–Revised.  New York, NY: Harcourt Brace & Co; 1987
42.
Benton  ALHamsher  KVarney  NRSpreen  O Contributions to Neuropsychological Assessment: A Clinical Manual.  New York, NY: Oxford; 1983
43.
Beery  KE The Beery-Buktenica Developmental Test of Visual-Motor Integration, 4th Edition. Parsippany, NJ: Modern Curriculum Press; 1997
44.
Cummings  JLMega  MGray  KRosenberg-Thompson  SCarusi  DAGornbein  J The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;442308- 2314
PubMedArticle
45.
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMedArticle
46.
Oremus  MPerrault  ADemers  LWolfson  C Review of outcome measurement instruments in Alzheimer’s disease drug trials: psychometric properties of global scales. J Geriatr Psychiatry Neurol 2000;13197- 205
PubMedArticle
47.
Logsdon  RGGibbons  LEMcCurry  SMTeri  L Assessing quality of life in older adults with cognitive impairment. Psychosom Med 2002;64510- 519
PubMedArticle
48.
Swerdloff  RSWang  CCunningham  G Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab 2000;854500- 4510
PubMed
49.
Sorgi  PRatey  JKnoedler  DWMarkert  RJReichman  M Rating aggression in the clinical setting. A retrospective adaptation of the Overt Aggression Scale: preliminary results. J Neuropsychiatry Clin Neurosci 1991;3S52- S56
PubMed
50.
Clayton  AHMcGarvey  ELClavet  GJ The Changes in Sexual Functioning Questionnaire (CSFQ): development, reliability, and validity. Psychopharmacol Bull 1997;33731- 745
PubMed
51.
Ly  LPJimenez  MZhuang  TNCelermajer  DSConway  AJHandelsman  DJ A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. J Clin Endocrinol Metab 2001;864078- 4088
PubMedArticle
52.
Park  NCYan  BQChung  JMLee  KM Oral testosterone undecanoate (Andriol) supplement therapy improves the quality of life for men with testosterone deficiency. Aging Male 2003;686- 93
PubMedArticle
53.
Reddy  PWhite  CMDunn  ABMoyna  NMThompson  PD The effect of testosterone on health-related quality of life in elderly males: a pilot study. J Clin Pharm Ther 2000;25421- 426
PubMedArticle
54.
Ready  REOtt  BRGrace  J Patient versus informant perspectives of quality of life in mild cognitive impairment and Alzheimer’s disease. Int J Geriatr Psychiatry 2004;19256- 265
PubMedArticle
55.
Tan  RSPu  SJ A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. Aging Male 2003;613- 17
PubMedArticle
56.
Gouchie  CKimura  D The relationship between testosterone levels and cognitive ability patterns. Psychoneuroendocrinology 1991;16323- 334
PubMedArticle
57.
Wolkowitz  OMKramer  JHReus  VI DHEA treatment of Alzheimer’s disease: a randomized, double-blind, placebo-controlled study. Neurology 2003;601071- 1076
PubMedArticle
58.
Kenny  AMFabregas  GSong  CBiskup  BBellantonio  S Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci 2004;5975- 78
PubMedArticle
59.
Gruenewald  DAMatsumoto  AM Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc 2003;51101- 115
PubMedArticle
Clinical Trials
February 2006

Effects of Testosterone on Cognition and Mood in Male Patients With Mild Alzheimer Disease and Healthy Elderly Men

Author Affiliations

Author Affiliations: Departments of Neurology (Drs Lu, Masterman, Porter, and Cummings and Ms Reback) and Psychiatry and Biobehavioral Sciences (Dr Cummings), David Geffen School of Medicine, University of California, Los Angeles; Department of Neurology, University of California, Irvine (Drs Mulnard and Cotman); Department of Neurology, University of California, San Francisco (Drs Miller and Yaffe); and Department of Endocrinology, Harbor-UCLA Medical Center, Torrance, Calif (Dr Swerdloff).

 

IRASHOULSONMD

Arch Neurol. 2006;63(2):177-185. doi:10.1001/archneur.63.2.nct50002
Abstract

Context  There is a compelling need for therapies that prevent, defer the onset, slow the progression, or improve the symptoms of Alzheimer disease (AD).

Objective  To evaluate the effects of testosterone therapy on cognition, neuropsychiatric symptoms, and quality of life in male patients with mild AD and healthy elderly men.

Design  Twenty-four–week, randomized, double-blind, placebo-controlled, parallel-group study.

Setting  Memory disorders clinics as well as general neurology and medicine clinics from University of California medical centers at Los Angeles, San Francisco, and Irvine.

Patients or Other Participants  Sixteen male patients with AD and 22 healthy male control subjects. Healthy elderly control men were recruited from the community through advertisements as well as through the university-based clinics.

Intervention  Testosterone and placebo, in the form of hydroalcoholic gel (75 mg), were applied daily to the skin of the participants.

Main Outcome Measures  Instruments assessing cognitive functioning (Alzheimer’s Disease Assessment Scale–Cognitive Subscale, California Verbal Learning Test, Block Design Subtest, Judgment of Line Orientation, Developmental Test of Visual-Motor Integration), neuropsychiatric symptoms (Neuropsychiatric Inventory), global functioning (Clinician’s Interview-Based Impression of Change), and quality of life (Quality of Life–Alzheimer Disease Scale).

Results  For the patients with AD, the testosterone-treated group had significantly greater improvements in the scores on the caregiver version of the quality-of-life scale (P = .01). No significant treatment group differences were detected in the cognitive scores at end of study, although numerically greater improvement or less decline on measures of visuospatial functions was demonstrated with testosterone treatment compared with placebo. In the healthy control group, a nonsignificant trend toward greater improvement in self-rated quality of life was observed in the testosterone-treated group (P = .09) compared with placebo treatment. No difference between the treatment groups was detected in the remaining outcome measures. Testosterone treatment was well tolerated with few adverse effects relative to placebo.

Conclusions  Results suggest that testosterone replacement therapy improved overall quality of life in patients with AD. Testosterone had minimal effects on cognition.Published online December 12, 2005 (doi:10.1001/archneur.63.2.nct50002).

There is a compelling need for therapies that prevent, defer the onset, slow the progression, or improve the symptoms of Alzheimer disease (AD). Hormonal therapies for AD have been the focus of research attention in recent years. Estrogen-replacement therapy has been shown to have cognitive benefits in healthy elderly women.13 Several epidemiological studies provide evidence that estrogen-replacement therapy, when given alone, decreases the risk and delays the onset of AD in postmenopausal women.49 Despite the apparent cognitive benefits reported in several observational trials, the Women’s Health Initiative Memory Study recently concluded that postmenopausal women receiving estrogen-replacement therapy, either a combined estrogen/progesterone preparation or estrogen alone, showed evidence of deleterious cognitive effects and were more likely to develop dementia.1012 Furthermore, 3 controlled clinical trials of estrogen therapy in women with AD uniformly found a lack of benefit in delaying disease progression.1315

In the male brain, testosterone is converted to estrogen by aromatase enzymes; therefore, testosterone can exert its effects on cognition independently or indirectly via conversion to estrogen. Several studies have reported positive associations between testosterone level and spatial cognitive function and memory for verbal and visual stimuli in older men.1621 In small, placebo-controlled clinical trials of relatively short duration (1 to 12 months), testosterone supplementation was reported to improve spatial cognition2224 and working memory.25,26

Male aging is associated with a gradual, progressive decline in serum levels of total testosterone, bioavailable testosterone, and free testosterone.27 The gradual decline in testosterone level is associated with decreased muscle mass and strength, osteoporosis, decreased libido, mood alterations, and changes in cognition,28 conditions that may be reversed with testosterone replacement.29,30 The age-related decline in testosterone is potentially relevant to AD. Moffat et al31 reported significantly lower free testosterone concentrations in middle-aged and elderly men who developed AD; Hogervorst et al32 suggested that low total serum testosterone may be a comorbid feature of AD in men. In laboratory models, testosterone reduces formation of β-amyloid from the amyloid precursor protein33 and decreases hyperphosphorylation of tau protein.34

We report the results of a randomized, double-blind, placebo-controlled trial investigating the effects of testosterone treatment on cognition and mood in male patients with mild AD and age-matched healthy control men. We hypothesized that testosterone therapy would yield benefits in cognition, mood, and quality of life.

METHODS
STUDY DESIGN AND SUBJECTS

The study had a 24-week, double-blind, placebo-controlled, randomized, parallel-group design. Male participants with AD were recruited from memory disorders clinics and general neurology and medicine clinics from University of California campuses at Los Angeles, San Francisco, and Irvine. Healthy elderly control men were recruited through advertisements and university-based clinics. Hormone measurements for all sites were performed at Harbor-UCLA Medical Center, Torrance, Calif. Written informed consent, approved by the institutional review board at each participating institution, was obtained from each subject or legally authorized representative. Complete medical and psychiatric history was taken, and subjects underwent a physical examination (including prostate examination and urinary flow study), a complete neurological examination, laboratory evaluation (complete blood count, blood chemistry, lipid profile, and prostate specific antigen and hormone levels), and cognitive screening for determination of eligibility.

All subjects with AD met the NINCDS-ADRDA criteria (National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association) for probable AD35 and had a caregiver informant who was available to monitor and administer medication and accompany the subject to clinical visits. In addition, subjects with AD scored 15 or above on the Mini-Mental State Examination,36 indicating a mild to moderate stage of disease. The healthy control subjects did not meet criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition37 for dementia and scored 0 (normal) on the Clinical Dementia Rating Scale.38 All subjects were aged 50 years or older, demonstrated sufficient English to be able to perform cognitive testing, and were stable on concomitant medications for 1 month prior to starting the study medication.

Subjects were excluded from the study if they had current or recent history of major psychiatric illness, non-AD neurological illness, or significant uncontrolled systemic illness; history of alcoholism or substance abuse within the past year; history of taking other drugs that might interfere with the results of the study (ie, antiandrogen, estrogens, p450 enzyme inducers, barbiturates); known history of prostate cancer; abnormal prostate evidenced by prostatic symptoms, prostatic masses or induration on rectal examination, elevated levels of prostate specific antigen (>4 mg/mL), a urine flow rate of less than 8 mL/s, or an International Prostate Symptom Score greater than 25; serum testosterone levels greater than 600 ng/dL; hematocrit greater than 50%; greater than 140% or less than 80% of their ideal body weight based on Metropolitan Life Insurance tables; generalized skin disease that could affect the absorption of T-gel (ie, psoriasis) or known skin intolerance to alcohol; or morning prolactin level greater than 40 mg/mL. The flow of subjects through the study and completion rate is shown in Figure 1.

PROCEDURES AND TREATMENT

Subjects who met the entry criteria were randomized to either the testosterone or placebo group. Testosterone was provided in the form of 1% hydroalcoholic dermal gel (T-gel; Laboratoires Besins-Iscovesco, Paris, France) for daily application to the skin. Subjects randomized to the testosterone treatment group were instructed to apply 75 mg of T-gel (3 packets of 25 mg) to 3 different sites each morning after showering or bathing (75 mg total dose). The placebo group performed an identical application of the placebo gel to the same 3 sites. The treatment trial was 24 weeks in duration; subjects returned on weeks 4 and 12 for monitoring of any treatment adverse effects or occurrence of any intercurrent illness, review of current medication list, and neuropsychological testing. A telephone interview was conducted at week 18 to monitor any adverse effects of treatment. The T-gel and placebo gel packets were returned at each visit; unused medication was tabulated to ensure compliance. Neuropsychiatric outcome measures were administered at baseline, prior to randomization, and repeated at weeks 4 and 12 and at end of study. Cognitive measures were administered at baseline and at end of study.

OUTCOME MEASURES
Cognition

The Alzheimer’s Disease Assessment Scale–Cognitive Subscale39 was used to quantify global cognitive functioning across study visits. In addition, the California Verbal Learning Test40 was administered to assess short-term retention of verbal information; the number of words recalled after a 20-minute delay was the variable of interest. Visuospatial functions were assessed using the Block Design Subtest of the Wechsler Adult Intelligence Scale-Revised,41 which measures visual perception and spatial construction; Judgment of Line Orientation (JOLO),42 which examines visual recognition and perception of angular relationships; and the Developmental Test of Visual-Motor Integration (VMI),43 a constructional task that integrates perceptual activity with motor response.

Neuropsychiatric Symptoms

The Neuropsychiatric Inventory (NPI)44 provides a multidimensional profile of the behavioral disturbances occurring in patients with dementia based on responses from an informed caregiver. The symptoms assessed by this scale include delusions, hallucinations, agitation/aggression, depression, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, sleep, and appetite. The Beck Depression Inventory45 is a 21-item self-administered measure of depressive symptoms that determines the presence and intensity of depression.

Global Assessment and Quality of Life

The Clinician’s Interview-Based Impression of Change46 systematically evaluates cognition and behavior to assess the severity of illness at baseline (scored on a 7-point scale with 1 being “not at all ill” and 7 being “among the most extremely ill patients”) and global change from baseline (also scored on a 7-point scale, ranging from 1 [“markedly improved”] to 7 [“markedly worse”]). The Quality of Life–Alzheimer Disease (QOL-AD)47 scale is a 13-item questionnaire covering the domains of physical health, energy, mood, living situation, memory, family, marriage, friends, chores, fun, money, self, and life as a whole. The items are scored on a 4-point Likert scale, ranging from 1 (poor) to 4 (excellent). The scale obtains separate ratings of the patient’s quality of life from the patient and the caregiver.

Hormone Assays

The serum testosterone (T) concentration used for screening was measured at each center’s clinical laboratory; all subsequent hormone assays were performed at the Endocrine Research Laboratory of the Harbor-UCLA Medical Center. The procedure has been previously described in detail48 so will only be summarized here. Serum T, dihydrotestosterone (DHT), and estradiol (E2) were measured by specific radioimmunoassays. Free T was measured by a radioimmunoassay of the dialysate after an overnight equilibrium dialysis using the same radioimmunoassay reagents as in the T assay. Serum follicle-stimulating hormone and luteinizing hormone were measured by highly sensitive and specific fluoroimmunometric assays with reagents provided by Delfia (Wallac, Inc, Gaithersburg, Md).48

ADVERSE EFFECTS

Adverse events were reported and recorded at each follow-up contact. In addition, we used the Overt Aggression Scale,49 a modified version of the Change in Sexual Functioning Questionnaire,50 and the agitation/aggression subscale from the NPI to monitor adverse effects.

DATA ANALYSES

Data analyses were performed using an analysis of covariance. Treatment groups were the independent variables, and the outcome measures were the dependent variables with baseline scores treated as covariates. Paired-sample t tests were conducted to evaluate the significance of within-group change between baseline and end of study. The analyses were performed on subjects who completed the trial. As a check for effects of excluding cases that did not complete the study, we performed intent-to-treat analyses with last observation carried forward, including all cases who were randomized and had at least 1 postbaseline assessment. These results did not differ meaningfully from the primary analyses with subjects who completed the study and are therefore not reported. Although the statistical results are based on covariance analyses adjusting for baseline, the adjusted means were very close to the raw means in all cases. Because raw means and standard deviations are easier to interpret, they are reported in result tables.

RESULTS
BASELINE COMPARISONS OF TESTOSTERONE- AND PLACEBO-TREATED GROUPS

Table 1 and Table 2 compare the treatment groups on baseline measures for AD and healthy control men, respectively. With the exception of a chance significant finding in education level, with the testosterone-AD group averaging more years of education, the 2 AD treatment groups did not differ on any of the cognitive, mood, behavioral, quality-of-life, and hormone measures at baseline. For the control group, no significant differences in demographic and outcome variables were observed between treatment groups. At baseline, 5 (28%) of 18 subjects with AD and 6 (21%) of 29 healthy control subjects were identified as hypogonadal (T levels below 298 ng/dL).48

OUTCOME COMPARISONS OF THE TESTOSTERONE- AND PLACEBO-TREATED GROUPS

Sixteen patients with AD and 22 healthy control men completed the study. Mean scores of the study variables at baseline and at end of study for the AD treatment groups are presented in Table 3. The change in scores across the study interval is also provided (as within-group t tests) along with the results of the analysis-of-covariance models (between-group comparisons) for the outcome measures at end of study (adjusted for baseline). The results for the healthy control subjects are presented in Table 4.

COGNITIVE FUNCTION

For the subjects with AD, no significant group differences were detected on any of the cognitive measures at end of study. However, within-group analysis indicated that placebo subjects displayed a significant decline on VMI score at the end of study while the testosterone-treated group performed at near baseline levels. Similar trends were observed for the JOLO score, but the findings were not statistically significant. Introducing years of education into the model as a covariate did not meaningfully alter the results.

For the healthy control subjects, the testosterone-treated group demonstrated a statistically significant improvement on the VMI score at the end of study while the mean score for the placebo-treated group remained near baseline levels. Between-subject comparisons at the end of study did not reveal significant treatment group differences on this score. Significant improvements on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale and California Verbal Learning Test were observed within the placebo group; however, both measures are subject to practice effects, particularly in a cognitively intact population. Within-group and between-group analyses at the end of study did not reveal significant results on other cognitive measures.

NEUROPSYCHIATRIC SYMPTOMS

For the AD patients, testosterone treatment produced no change in NPI or Beck Depression Inventory scores (P>.30). Closer inspection of the NPI data revealed that 4 (44%) of 9 patients in the testosterone-treated group and 7 (78%) of 9 subjects in the placebo group displayed at least 1 neuropsychiatric symptom of mild severity at baseline. In contrast, the number of testosterone-treated patients with symptoms of mild severity declined to 2 at the study end point while the 7 placebo subjects continued to manifest behavioral disturbances of at least mild severity. This difference did not reach statistical significance (χ2<2.0, P>.16). The healthy control group did not endorse any neuropsychiatric symptoms.

GLOBAL ASSESSMENT AND QUALITY OF LIFE

No significant differences between testosterone and placebo treatment for the AD patients were evidenced on the Clinician’s Interview-Based Impression of Change (mean ± SD score: testosterone, 4.7 ± 0.49; placebo, 5.0 ± 0.49; t = 1.1, P = .30). The 2 AD treatment groups differed significantly in response to treatment on the QOL-AD scale, based on the caregivers’ ratings of the patients’ quality of life. Higher mean scores were obtained by the testosterone-treated group compared with the placebo-treated group. Within-group analysis revealed that the quality-of-life score for the placebo subjects declined significantly from baseline while a nonsignificant trend toward improved scores was observed for the testosterone-treated group. The divergent trajectory of the quality-of-life outcome between week 12 and the end of study accounted for the significant between-group differences (Figure 2). Within the healthy control sample, the self-rated QOL-AD score remained at baseline levels for the testosterone group but declined for the placebo-treated group, although the mean reduction in score was not statistically significant (P = .08).

HORMONE MEASURES

As expected, subjects with AD in the testosterone-treated group, compared with those in the placebo group, showed large increases in serum T and its metabolites and significant decreases in follicle-stimulating hormone and luteinizing hormone at the end of the study (Table 5). The healthy controls showed similar changes in hormone levels following testosterone treatment, but the difference did not reach statistical significance in serum T and E2 levels (P = .10).

In the AD sample, Pearson correlation analyses revealed significant positive associations between changes (from baseline to end of study) in hormone level (serum T, free T, DHT, E2) and JOLO score (r>0.59, P<.03). A significant positive correlation was also found between changes in DHT level and QOL-AD (caregiver) score (r = 0.60, P = .04). In the healthy elderly sample, none of the associations between hormone and outcome changes reached statistical significance (P>.10).

For the participants who completed the study, 4 (25%) of 16 subjects with AD and 5 (23%) of 22 healthy controls were identified to have baseline testosterone levels below the normal range.48 For the patients with AD, significant inverse relationships were observed between change in JOLO score and baseline free T (r = −0.57, P = .03) and E2 (r = −0.64, P = .01). Baseline DHT was negatively correlated with the change in VMI score (r = −0.61, P = .02). These associations suggest that in AD, a lower hormone level at baseline is associated with a greater positive change in spatial cognition, findings that were not replicated in the healthy elderly sample (P>.09).

ADVERSE EFFECTS

Figure 1 indicates that 2 (22%) of 9 patients with AD dropped out of the testosterone-treated group; 1 subject complained of rash at the site of application and the other patient was discontinued from the study because he scored an 11 on the Mini-Mental State Examination during a follow-up visit, thus failing the inclusion/exclusion criteria. No patients with AD withdrew from the study in the placebo group. In the healthy control sample, of the 4 subjects (29%) who discontinued from the testosterone group, 2 reported adverse events (decreased sexual functioning; testicular failure/shrinkage). A similar dropout rate was observed in the placebo group (3/15 or 20%), but only 1 of the subjects reported adverse effects involving nausea and sexual dysfunction. Analysis of the differential rate of study withdrawal did not reveal significant differences in frequency of dropout for the treatment groups (χ2<2.3, P>.13).

Medication adverse effects were further assessed using the Overt Aggression Scale and the agitation/aggression subscale of the NPI. The AD-testosterone patients did not exhibit more aggression or agitation than placebo subjects (P>.11). Sexual functioning, as measured by the modified Change in Sexual Functioning Questionnaire, did not reveal significant treatment group differences for AD or healthy control subjects on the total or any of the subscale scores. Caregivers did not observe any marked changes in sexual behavior of study patients on this scale.

COMMENT

The results from this 6-month randomized, placebo-controlled trial demonstrate that testosterone-treated patients with AD, as a group, displayed significantly better quality of life (as assessed by their caregivers on the QOL-AD scale) than their placebo-treated counterparts. Specifically, testosterone treatment in patients with mild AD produced a nonsignificant trend toward improved quality of life over a 6-month period while the placebo-treated group exhibited a significant decline. A similar pattern was observed in healthy control men although the results were not statistically significant.

Controlled clinical trials of supplemental testosterone treatment in healthy elderly men have yielded equivocal results in relation to quality of life. Some studies found increased sense of well-being30,51,52 while others detected no effect of testosterone supplementation on quality of life.53 Overall quality of life has been demonstrated to be significantly associated with dementia severity, functional impairment, and neuropsychiatric symptoms in patients with AD.47,54 In the absence of direct observational methods, assessment of quality of life provides a window into the effects of intervention on the patients’ and the caregivers’ perceived well-being and helps inform the consumers and clinicians on the potential functional benefits and risks of therapy. To our knowledge, this is the first study to report on the positive effects of testosterone treatment on the quality of life of patients with AD.

With regards to cognition, the treatment groups did not differ significantly on any of the cognitive variables within the AD and healthy control populations. However, the testosterone-treated AD group exhibited either numerically greater improvement or less decline in scores on all 3 measures of visual-spatial functioning when compared with the placebo group.The present results generally support the existing literature reporting improved spatial cognition with testosterone treatment in men with AD55 and healthy elderly2123,56 men, although other studies have failed to detect discernible changes in cognitive functioning with treatment with dehydroepiandrosterone57 and intramuscular testosterone administration.58 The absence of any treatment effect on visual-spatial skills in the healthy control group may reflect the observation that the subjects are performing at near maximal levels on these measures. The results on the effects of testosterone treatment on mood and psychiatric symptoms of patients with AD paralleled that of cognitive functioning but were not statistically significant.

In the AD sample, significant positive relationships were observed between changes in hormone level and a measure of visual-spatial recognition. Additionally, inverse relationships were observed between baseline levels of free T, DHT, and E2 and improved performance on measures of visuospatial functions (JOLO and VMI). These findings are consistent with previous reports indicating that benefits of testosterone administration may be greater in more severely androgen-deficient men rather than men with less marked testosterone deficiency.59 Therefore, selection of only hypogonadal men or individuals with low normal testosterone levels may result in greater response to treatment.

Hormone levels of 8 (47%) of 17 subjects assigned to the testosterone group did not display a discernible increase in serum T level at the end of study. Neither patients nor their caregivers reported poor adherence to protocol or improper application of the gel during the follow-up visits, but suboptimal compliance to treatment remains a possibility. Poor absorption of the testosterone gel is another potential cause for the minimal increase in testosterone level. It is also possible that the blood sampling occurred more than 24 hours since the last application, when testosterone level was at its nadir. Future studies should establish a dose that achieves a desired hormone level for each patient prior to follow-up assessment.

The major limitation of this study is the small sample sizes. Subject recruitment was more difficult than anticipated due to the strict inclusion and exclusion criteria and the caregivers’ fear of adverse events associated with testosterone. However, testosterone treatment was actually well tolerated with few adverse effects reported or documented on objective measures. It should also be noted that the P values reported were not adjusted for multiple comparisons. The small sample sizes and large number of outcome variables limit conclusive interpretation of the study findings and require replication in larger-scale studies with more focused primary outcome variables.

Additional study limitations must be acknowledged. Testosterone treatment in hypogonadal men has shown improvement in mood, muscle mass, strength, bone density, libido, and certain focused cognitive functions28; many of these changes are related to the degree of improvement in testosterone levels and inversely related to baseline testosterone concentration. The present study also found baseline free T and E2 levels to be inversely correlated with visuospatial functions; thus, it is possible that the cognitive findings would be more robust if low T level were an inclusion criterion. In addition, the ethnicity of the sample was predominantly white, limiting the generalizability of the results to other ethnic groups; the chosen instruments may lack sensitivity to detect small changes or are vulnerable to ceiling effects in cognitively intact subjects; longer duration of study may have yielded greater effects; and proxy reports of quality of life should be interpreted with caution.

In conclusion, the present results should be considered preliminary and do not warrant routine treatment of AD and healthy control men with testosterone. Future studies with larger sample sizes are needed before clinical decisions regarding testosterone therapy can be rationally based. For men with compromised quality of life, as reflected on the type of measure employed in this study, and who suffer from low serum T levels, testosterone therapy may be a reasonable consideration.

Back to top
Article Information

Correspondence: Po H. Lu, PsyD, UCLA Alzheimer’s Disease Center, 710 Westwood Plaza, Room 2-238, Los Angeles, CA 90095-1769 (plu@mednet.ucla.edu).

Accepted for Publication: October 5, 2005.

Author Contributions:Study concept and design: Masterman, Mulnard, Cotman, Yaffe, Swerdloff, and Cummings. Acquisition of data: Lu, Masterman, Mulnard, Cotman, Miller, Yaffe, Reback, Porter, and Swerdloff. Analysis and interpretation of data: Lu, Mulnard, Cotman, and Cummings. Drafting of the manuscript: Lu, Mulnard, Cotman, Swerdloff, and Cummings. Critical revision of the manuscript for important intellectual content: Masterman, Miller, Yaffe, Reback, Porter, and Cummings. Statistical analysis: Lu. Obtained funding: Masterman, Mulnard, Cotman, Miller, Swerdloff, and Cummings. Administrative, technical, and material support: Masterman, Mulnard, Cotman, Miller, Yaffe, Reback, Swerdloff, and Cummings. Study supervision: Masterman, Mulnard, Cotman, Yaffe, and Porter.

Previous Presentation: This work was presented in part at the 56th Annual Meeting of the American Academy of Neurology; April 27, 2004; San Francisco, Calif.

Acknowledgment: This work was supported by the John Douglas French Alzheimer’s Foundation, Los Angeles, Calif; grant P50 AG16570 from the National Institute on Aging, Bethesda, Md, to the University of California, Los Angeles (UCLA), Alzheimer’s Disease Research Center; the UCLA Alzheimer’s Disease Research Center of California; the Sidell-Kagan Foundation, Los Angeles; grant P50 AG16573 from the National Institute of Aging to the University of California, Irvine (UCI), Alzheimer’s Disease Research Center; the UCI Institute for Brain Aging and Dementia, Irvine; the UCI Alzheimer’s Disease Research Center of California; and the University of California, San Francisco, Memory and Aging Center. Testosterone and placebo gel was supplied by Unimed Pharmaceuticals, Inc, Marietta, Ga.

References
1.
Robinson  DFriedman  LMarcus  RTinklenberg  JYesavage  J Estrogen replacement therapy and memory in older women. J Am Geriatr Soc 1994;42919- 922
PubMed
2.
Kampen  DLSherwin  BB Estrogen use and verbal memory in healthy postmenopausal women. Obstet Gynecol 1994;83979- 983
PubMedArticle
3.
Schmidt  RFazekas  FReinhart  B  et al.  Estrogen replacement therapy in older women: a neuropsychological and brain MRI study. J Am Geriatr Soc 1996;441307- 1313
PubMed
4.
Baldereschi  MDi Carlo  ALepore  V  et al.  Estrogen-replacement therapy and Alzheimer’s disease in the Italian Longitudinal Study on Aging. Neurology 1998;50996- 1002
PubMedArticle
5.
Kawas  CResnick  SMorrison  A  et al.  A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 1997;481517- 1521
PubMedArticle
6.
Mortel  KFMeyer  JS Lack of postmenopausal estrogen replacement therapy and the risk of dementia. J Neuropsychiatry Clin Neurosci 1995;7334- 337
PubMed
7.
Paganini-Hill  AHenderson  VW Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol 1994;140256- 261
PubMed
8.
Tang  MXJacobs  DStern  Y Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996;348429- 432
PubMedArticle
9.
Yaffe  KSawaya  GLieberburg  IGrady  D Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998;279688- 695
PubMedArticle
10.
Shumaker  SALegault  CRapp  SR Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;2892651- 2662
PubMedArticle
11.
Schneider  LS Estrogen and dementia: insights from the Women’s Health Initiative Memory Study. JAMA 2004;2913005- 3007
PubMedArticle
12.
Shumaker  SALegault  CKuller  L Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004;2912947- 2958
PubMedArticle
13.
Henderson  VWPaganini-Hill  AMiller  BL Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000;54295- 301
PubMedArticle
14.
Mulnard  RACotman  CWKawas  C Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer’s Disease Cooperative Study. JAMA 2000;2831007- 1015
PubMedArticle
15.
Wang  PNLiao  SQLiu  RS Effects of estrogen on cognition, mood, and cerebral blood flow in AD: a controlled study. Neurology 2000;542061- 2066
PubMedArticle
16.
Cherrier  MMMatsumoto  AMAmory  JK The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology 2005;64290- 296
PubMedArticle
17.
Vermeulen  A Androgen replacement therapy in the aging male: a critical evaluation. J Clin Endocrinol Metab 2001;862380- 2390
PubMed
18.
Matsumoto  AM Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci 2002;57M76- M99
PubMedArticle
19.
Barrett-Connor  EGoodman-Gruen  DPatay  B Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 1999;843681- 3685
PubMed
20.
Yaffe  KLui  LYZmuda  JCauley  J Sex hormones and cognitive function in older men. J Am Geriatr Soc 2002;50707- 712
PubMedArticle
21.
Yaffe  KEdwards  ERLui  LYZmuda  JMFerrell  RECauley  JA Androgen receptor CAG repeat polymorphism is associated with cognitive function in older men. Biol Psychiatry 2003;54943- 946
PubMedArticle
22.
Cherrier  MMAsthana  SPlymate  S Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 2001;5780- 88
PubMedArticle
23.
Janowsky  JSOviatt  SKOrwoll  ES Testosterone influences spatial cognition in older men. Behav Neurosci 1994;108325- 332
PubMedArticle
24.
Moffat  SDZonderman  ABMetter  EJBlackman  MRHarman  SMResnick  SM Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab 2002;875001- 5007
PubMedArticle
25.
Janowsky  JSChavez  BOrwoll  E Sex steroids modify working memory. J Cogn Neurosci 2000;12407- 414
PubMedArticle
26.
Kenny  AMBellantonio  SGruman  CAAcosta  RDPrestwood  KM Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2002;57M321- M325
PubMedArticle
27.
Harman  SMMetter  EJTobin  JDPearson  JBlackman  MR Longitudinal effects of aging on serum total and free testosterone levels in healthy men: Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86724- 731
PubMedArticle
28.
Swerdloff  RSWang  C Androgens and aging in men. Exp Gerontol 1993;28435- 446
PubMedArticle
29.
Morley  JE Andropause, testosterone therapy, and quality of life in aging men. Cleve Clin J Med 2000;67880- 882
PubMedArticle
30.
Tenover  JS Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992;751092- 1098
PubMed
31.
Moffat  SDZonderman  ABMetter  EJ Free testosterone and risk for Alzheimer disease in older men. Neurology 2004;62188- 193
PubMedArticle
32.
Hogervorst  EWilliams  JBudge  MBarnetson  LCombrinck  MSmith  AD Serum total testosterone is lower in men with Alzheimer’s disease. Neuroendocrinol Lett 2001;22163- 168
PubMed
33.
Gouras  GKXu  HGross  RS Testosterone reduces neuronal secretion of Alzheimer’s beta-amyloid peptides. Proc Natl Acad Sci U S A 2000;971202- 1205
PubMedArticle
34.
Papasozomenos  SShanavas  A Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3 beta but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of tau: implications for Alzheimer’s disease. Proc Natl Acad Sci U S A 2002;991140- 1145
PubMedArticle
35.
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34939- 944
PubMedArticle
36.
Folstein  MFFolstein  SEMcHugh  PR “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMedArticle
37.
American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC: American Psychiatric Association; 1994
38.
Morris  JC The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993;432412- 2414
PubMedArticle
39.
Rosen  WGMohs  RCDavis  KL A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;1411356- 1364
PubMed
40.
Delis  DCKramer  JHKaplan  EOber  BA The California Verbal Learning Test.  San Antonio, Tex: Harcourt Brace & Co; 1987
41.
Wechsler  D Manual for the Wechsler Adult Intelligence Scale–Revised.  New York, NY: Harcourt Brace & Co; 1987
42.
Benton  ALHamsher  KVarney  NRSpreen  O Contributions to Neuropsychological Assessment: A Clinical Manual.  New York, NY: Oxford; 1983
43.
Beery  KE The Beery-Buktenica Developmental Test of Visual-Motor Integration, 4th Edition. Parsippany, NJ: Modern Curriculum Press; 1997
44.
Cummings  JLMega  MGray  KRosenberg-Thompson  SCarusi  DAGornbein  J The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;442308- 2314
PubMedArticle
45.
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMedArticle
46.
Oremus  MPerrault  ADemers  LWolfson  C Review of outcome measurement instruments in Alzheimer’s disease drug trials: psychometric properties of global scales. J Geriatr Psychiatry Neurol 2000;13197- 205
PubMedArticle
47.
Logsdon  RGGibbons  LEMcCurry  SMTeri  L Assessing quality of life in older adults with cognitive impairment. Psychosom Med 2002;64510- 519
PubMedArticle
48.
Swerdloff  RSWang  CCunningham  G Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab 2000;854500- 4510
PubMed
49.
Sorgi  PRatey  JKnoedler  DWMarkert  RJReichman  M Rating aggression in the clinical setting. A retrospective adaptation of the Overt Aggression Scale: preliminary results. J Neuropsychiatry Clin Neurosci 1991;3S52- S56
PubMed
50.
Clayton  AHMcGarvey  ELClavet  GJ The Changes in Sexual Functioning Questionnaire (CSFQ): development, reliability, and validity. Psychopharmacol Bull 1997;33731- 745
PubMed
51.
Ly  LPJimenez  MZhuang  TNCelermajer  DSConway  AJHandelsman  DJ A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. J Clin Endocrinol Metab 2001;864078- 4088
PubMedArticle
52.
Park  NCYan  BQChung  JMLee  KM Oral testosterone undecanoate (Andriol) supplement therapy improves the quality of life for men with testosterone deficiency. Aging Male 2003;686- 93
PubMedArticle
53.
Reddy  PWhite  CMDunn  ABMoyna  NMThompson  PD The effect of testosterone on health-related quality of life in elderly males: a pilot study. J Clin Pharm Ther 2000;25421- 426
PubMedArticle
54.
Ready  REOtt  BRGrace  J Patient versus informant perspectives of quality of life in mild cognitive impairment and Alzheimer’s disease. Int J Geriatr Psychiatry 2004;19256- 265
PubMedArticle
55.
Tan  RSPu  SJ A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. Aging Male 2003;613- 17
PubMedArticle
56.
Gouchie  CKimura  D The relationship between testosterone levels and cognitive ability patterns. Psychoneuroendocrinology 1991;16323- 334
PubMedArticle
57.
Wolkowitz  OMKramer  JHReus  VI DHEA treatment of Alzheimer’s disease: a randomized, double-blind, placebo-controlled study. Neurology 2003;601071- 1076
PubMedArticle
58.
Kenny  AMFabregas  GSong  CBiskup  BBellantonio  S Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci 2004;5975- 78
PubMedArticle
59.
Gruenewald  DAMatsumoto  AM Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc 2003;51101- 115
PubMedArticle
×