Many studies have shown cross-sectional (and two small studies, longitudinal) declines in total and/or free testosterone (T) levels, with age, in men. The extent to which decline in T is the result of the aging process per se, as opposed to chronic illness, medication use, and other age-related factors, remains controversial. The frequency with which aging leads to T levels consistent with hypogonadism has also not been defined. These issues bear on the potential use of T replacement in aging men, because aging and hypogonadism have, in common, reduced bone and lean body mass and muscle strength and increased total and abdominal fat. We measured T and sex hormone-binding globulin (SHBG), by RIA, in stored samples from 890 men in the Baltimore Longitudinal Study on Aging. Using a mixed-effects model, we found independent effects of age and date of sampling to reduce T levels. After compensating for date effects, which investigation suggested was artifactual, we observed significant, independent, age-invariant, longitudinal effects of age on both T and free T index (free T index = T/SHBG), with an average change of -0.124 nmol/L.yr and -0.0049 nmol T/nmol SHBG.yr. T, but not free T index, also decreased with increasing body mass index. Use of beta-blocking drugs was associated with higher T and higher free T index levels. Using total T criteria, incidence of hypogonadal T levels increased to about 20% of men over 60, 30% over 70 and 50% over 80 yr of age, and even greater percentages when free T index criteria were employed. Our observations of health factor independent, age-related longitudinal decreases in T and free T, resulting in a high frequency of hypogonadal values, suggest that further investigation of T replacement in aged men, perhaps targeted to those with the lowest serum T concentrations, are justified.

Many studies have shown cross-sectional (and two small studies, longitudinal) declines in total and/or free testosterone (T) levels, with age, in men. The extent to which decline in T is the result of the aging process per se, as opposed to chronic illness, medication use, and other age-related factors, remains controversial. The frequency with which aging leads to T levels consistent with hypogonadism has also not been defined. These issues bear on the potential use of T replacement in aging men, because aging and hypogonadism have, in common, reduced bone and lean body mass and muscle strength and increased total and abdominal fat. We measured T and sex hormone-binding globulin (SHBG), by RIA, in stored samples from 890 men in the Baltimore Longitudinal Study on Aging. Using a mixed-effects model, we found independent effects of age and date of sampling to reduce T levels. After compensating for date effects, which investigation suggested was artifactual, we observed significant, independent, age-invariant, longitudinal effects of age on both T and free T index (free T index = T/SHBG), with an average change of -0.124 nmol/L.yr and -0.0049 nmol T/nmol SHBG.yr. T, but not free T index, also decreased with increasing body mass index. Use of beta-blocking drugs was associated with higher T and higher free T index levels. Using total T criteria, incidence of hypogonadal T levels increased to about 20% of men over 60, 30% over 70 and 50% over 80 yr of age, and even greater percentages when free T index criteria were employed. Our observations of health factor independent, age-related longitudinal decreases in T and free T, resulting in a high frequency of hypogonadal values, suggest that further investigation of T replacement in aged men, perhaps targeted to those with the lowest serum T concentrations, are justified.

In humans, both aging and GH deficiency are associated with reduced protein synthesis, decreased lean body and bone mass, and increased percent body fat. In healthy individuals, spontaneous and stimulated GH secretion, as well as circulating IGF-I and IGFBP-3 levels, are significantly decreased with advancing age. The extent to which these age-related changes in GH and IGF-I contribute to alterations in body composition and function remains to be elucidated. GH treatment of GH-deficient adults or old men with reduced IGF-I levels with exogenous GH increases plasma IGF-I, nitrogen retention, and lean body mass, decreases percent body fat, and exerts little effect on bone mineral density. Short-term adverse effects of GH therapy have been minimized by using low-dose regimens, but it is still uncertain whether long-term GH supplementation in adult life increases the risk of metabolic abnormalities or malignancy. Administration of GHRH, which has been shown to maintain the pattern of pulsatile GH secretion in old men, may represent another possible physiological approach to therapy. It may be justifiable initially to limit use of GH to certain elderly patients such as those suffering from catabolic illnesses, malnourishment, burns, cachexia, etc. A great deal more research will be necessary to determine whether normalization of GH and IGF-I levels in healthy older persons will lead to improvements in their physical and psychological functional capacity and quality of life.

Circulating testosterone (T) levels have behavioral and neurological effects in both human and nonhuman species. Both T concentrations and neuropsychological function decrease substantially with age in men. The purpose of this prospective, longitudinal study was to investigate the relationships between age-associated decreases in endogenous serum T and free T concentrations and declines in neuropsychological performance. Participants were volunteers from the Baltimore Longitudinal Study of Aging, aged 50-91 yr at baseline T assessment. Four hundred seven men were followed for an average of 10 yr, with assessments of multiple cognitive domains and contemporaneous determination of serum total T, SHBG, and a free T index (FTI). We administered neuropsychological tests of verbal and visual memory, mental status, visuomotor scanning and attention, verbal knowledge/language, visuospatial ability, and depressive symptomatology. Higher FTI was associated with better scores on visual and verbal memory, visuospatial functioning, and visuomotor scanning and a reduced rate of longitudinal decline in visual memory. Men classified as hypogonadal had significantly lower scores on measures of memory and visuospatial performance and a faster rate of decline in visual memory. No relations between total T or the FTI and measures of verbal knowledge, mental status, or depressive symptoms were observed. These results suggest a possible beneficial relationship between circulating free T concentrations and specific domains of cognitive performance in older men.

Observational studies have indicated that hormone therapy given at or after menopause is linked to substantial reduction in cardiovascular disease and its risk factors. Recent findings from the Women's Health Initiative (WHI) clinical trial, however, indicate that combined estrogen plus progestin hormone therapy, as well as estrogen-alone hormone therapy (given to women without a uterus), is ineffective in preventing the new onset of cardiac events in previously healthy late menopausal women. Further, the secondary prevention trial, the Heart and Estrogen/progestin Replacement Study (HERS), also failed to demonstrate any benefit of initiation of hormone therapy in women with established coronary heart disease. In light of these results, a hypothesis has arisen that early initiation of hormone therapy, in women who are at the inception of their menopause, will delay the onset of subclinical cardiovascular disease in women. The rationale that earlier intervention than that performed in the WHI and HERS trials will provide cardiovascular benefit to women is the driving force behind the Kronos Early Estrogen Prevention Study, or KEEPS. KEEPS is a multicenter, 5-year clinical trial that will evaluate the effectiveness of 0.45 mg of conjugated equine estrogens, 50 microg weekly transdermal estradiol (both in combination with cyclic oral, micronized progesterone, 200 mg for 12 days each month), and placebo in preventing progression of carotid intimal medial thickness and the accrual of coronary calcium in women aged 42-58 years who are within 36 months of their final menstrual period. A total of 720 women are planned to be enrolled in 2005, with an anticipated close-out of the trial in 2010. This overview summarizes the recruitment and methodology of the KEEPS trial.

BackgroundMenopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women.Methods and FindingsKEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes.On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was −5.36 × 10−2 (95% CI, −8.27 × 10−2 to −2.44 × 10−2; ES = 0.49, p < 0.001) and for the anxiety subscale was −3.01 × 10−2 (95% CI, −5.09 × 10−2 to −9.34 × 10−3; ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importa...

Calculated free testosterone concentrations were lower in men who developed Alzheimer disease, and this difference occurred before diagnosis. Future research may determine whether higher endogenous free testosterone levels offer protection against a diagnosis of Alzheimer disease in older men.

Aurora Foundation.