The present study was undertaken to determine whether the addition of an androgen to estrogen therapy in postmenopausal women would alter the skeletal response as determined by measurements of markers of bone formation and resorption. Postmenopausal women were treated for 9 weeks with either a combination of 1.25 mg esterified estrogen and 2.5 mg methyltestosterone (E+A) or 1.25 mg conjugated equine estrogen (CEE). Both groups showed a similar decrease in urinary excretion of the bone resorption markers, deoxypyridinoline, pyridinoline, and hydroxyproline. Patients treated with CEE showed decreases in the serum markers of bone formation, bone-specific alkaline phosphatase, osteocalcin, and C-terminal procollagen peptide. In contrast, subjects treated with E+A showed increases in these markers of bone formation. CEE increased, and E+A decreased serum levels of sex hormone-binding globulin as well as triglycerides and high density lipoprotein levels. Only CEE significantly reduced low density lipoproteins. Both regimens were effective in reducing postmenopausal somatic symptoms, but only E+A had a significant effect on psychological symptoms. We conclude that short term administration of androgen with estrogen may reverse the inhibitory effects of estrogen on bone formation. Long term studies are needed to determine the relative benefits and risks of the combination of estrogen and androgen and whether this results in greater increases in bone mass and strength.

See editorial comments by Dr. Sanjay Asthana on pp 316-318. OBJECTIVES:To determine the effect of estrogen (E) alone (without the influence of testosterone (T)) on cognitive function in older men, using 17-b micronized estradiol versus placebo in older men rendered hypogonadal (low T and E) by treatment for prostate cancer. DESIGN: Short-term double-blind, randomized, controlled trial. SETTING: An outpatient General Clinical Research Center. PARTICIPANTS: Twenty-seven community-dwelling men aged 65 and older receiving neoadjuvant or established therapy with luteinizing-hormone releasing-hormone agonists for treatment of prostate cancer enrolled in a shortterm randomized, controlled trial of 17-b micronized estradiol versus placebo on the effect on biochemical markers of bone turnover. MEASUREMENTS: Hormone levels, including E, T, and sex hormone-binding globulin; standardized neurocognitive tests, including measures of sustained attention, executive function, and memory; and questionnaires to assess subjects' perception of cognitive deficits and symptoms of depression. RESULTS: There were no significant differences between patients receiving E or placebo on 15 of 17 neurocognitive measures and no significant differences in self-reported cognitive deficits or number of depressive symptoms. CONCLUSION: Although studies have suggested that E replacement therapy may improve cognitive function, most notably memory performance in postmenopausal woman, there was no evidence in the present study that the addition of short-term E therapy was more beneficial than placebo in tests of cognitive performance in hypogonadal men. J Am Geriatr Soc 52:269-273, 2004. Key words: estrogen; cognitive function; older men; estradiol A number of studies have investigated the role of sex steroids and cognitive function in older men and women. The role of estrogen (E) in women has been looked at more closely, because animal models have indicated that E can increase acetylcholine activity, improve neuronal survival and dendritic sprouting, and protect neurons from cerebral ischemia.1 Studies in postmenopausal women have examined the effect of E on cognition and memory and its potential for protection from dementia, but a recent metaanalysis 2 found inconsistent results. Ten studies in the same meta-analysis addressed the risk of the effect of E on development of dementia. Results ranged from the suggestion of a beneficial effect (a 29% lower risk of developing dementia in E users) to an increased risk of developing Alzheimer's disease. In sum, studies of E in women show an effect on cognition, but the specific benefits, risks, and longterm consequences are not yet understood.Studies of the effect of endogenous gonadal steroids on cognition in older men are fairly limited in number. Most have focused on the role of the major male gonadal steroid, testosterone (T), and have suggested some correlations with specific tasks of cognitive function in younger [3][4][5] and older men;6-10 studies of the role of E on cognitive function in men are ev...

The development of new biochemical markers has made it possible to assess the effects of therapeutic agents on bone turnover more rapidly and precisely. In this early phase II study, we analyzed the effects of short-term, high-dose treatment with risedronate, a potent pyridinyl bisphosphonate, on markers of bone resorption and formation. Resorption markers included urinary free deoxypyridinoline (D-Pyr) crosslinks, N-terminal telopeptide (NTx) and C-terminal telopeptide (CTx) type I collagen crosslinks. Bone formation markers included osteocalcin (OC), bone-specific alkaline phosphatase (BSAP) and the C-terminal peptide of type I procollagen (PICP). All three resorption markers showed rapid, significant (p<0.05) decreases from baseline following daily administration of 30 mg risedronate for 2 weeks. The mean decreases at 2 weeks were 28% for D-Pyr, 61% for NTx and 73% for CTx, respectively. Over the next 10 weeks after treatment, D-Pyr approached baseline while NTx and CTx remained well below baseline values. The markers of bone formation showed little change during therapy but decreased significantly at 4-10 weeks after therapy - an expected outcome of bisphosphonate therapy. Moreover, there was a significant correlation between the early effects on bone resorption markers and the delayed effects on formation markers. This study demonstrates that the approved dose of risedonate (30 mg/day) for Paget's disease is effective at decreasing bone turnover after 2 weeks of treatment, as observed by the sensitive response of bone turnover markers.

To examine the effect of estradiol (E(2)) without the confounding effect of hypothalamic-pituitary feedback, we studied men with prostate cancer in whom gonadotropin secretion was suppressed by LH-releasing hormone agonists (LHRH-A). Fourteen men over 65 yr of age and receiving established LHRH-A treatment (EST group) without bony metastases and 12 men who received LHRH-A as neoadjuvant therapy for locally advanced prostate cancer (NEO group) were randomized (double blind) to receive either 1 mg/d micronized E(2) (n = 12) or placebo (PL; n = 13) for 9 wk. E(2), estrone, testosterone, SHBG, PTH, and 25-hydroxy- and 1,25-dihydroxyvitamin D levels as well as markers of bone resorption [N- and C-telopeptide cross-links (NTX and CTX) and deoxypyridinoline] and bone formation (bone-specific alkaline phosphatase, osteocalcin, and N-terminal type I collagen) were measured before LHRH-A in the NEO group, before [baseline (BL)] and after 9 wk of E(2) or PL in all patients, and 6 wk after E(2) treatment in the EST group. In the NEO group, hormone levels fell 3 wk after the initial LHRH-A injection, and deoxypyridinoline increased significantly (P = 0.006). At BL, the EST group had higher bone turnover due to the longer duration of LHRH-A treatment. With E(2) treatment, E(2) levels rose into the normal male range, and two resorption markers decreased significantly from BL by 33% for NTX (P < 0.001) and 28% for CTX (P = 0.009). Bone formation markers did not change. PTH increased by 43% from BL (P < 0.01) in the E(2) group and decreased 16% from BL in the PL group (P < 0.01). Ionized calcium did not change in the E(2) group, but increased in the PL group by 2.3% (P < 0.01). NTX and CTX increased 6 wk after E(2) withdrawal in the EST group. We conclude that E(2) inhibits bone resorption in hypogonadal men through a direct skeletal effect that is independent of PTH. Low dose estrogen may be an option for the prevention and/or treatment of bone loss in this population.