Age in men does not determine gonadotropin-releasing hormone's dose-dependent stimulation of luteinizing hormone secretion under an exogenous testosterone clamp.

BACKGROUND: Aging is associated with a decline in incremental LH pulse amplitude, which could be due to decreased GnRH secretion or impaired GnRH action. HYPOTHESIS: Inconsistent published studies of GnRH action in older men may be due to disparate sex-steroid milieus. FACILITY: This study was conducted at a clinical translational-research unit. SUBJECTS: We studied 16 healthy men (8 young men and 8 older men). METHODS: An overnight transdermal testosterone (T) clamp was implemented before randomly ordered injections of 0, 2.5, 10, 25, 250, and 750 ng GnRH on separate days (96 study sessions). OUTCOMES: LH responses were quantified by variable-waveform deconvolution analysis. RESULTS: The T clamp maintained age-invariant mean concentrations of total, bioavailable, and free T, SHBG, LH, FSH, and prolactin. By two-way analysis of covariance, GnRH dose (P < 0.001) but not age (0.15 < or = P < or = 0.83) determined mean, peak, incremental, and pulsatile LH responses. Statistical power (median) was 95, 98, 90, and 99% to detect a 30% or greater age contrast at P < or = 0.05 in mean, peak, incremental, and pulsatile LH responses, and greater than 99% to detect a 30% or greater age contrast in bioavailable or total T concentrations. Higher GnRH doses (P < 0.001) abbreviated LH secretory bursts in both age groups. CONCLUSION: In the face of eugonadal concentrations of total, bioavailable, and free T, young and older men exhibit remarkably similar LH responses to a 300-fold dose range of exogenous GnRH. Accordingly, previously reported disparate effects of age on GnRH action may reflect in part age-discrepant sex-steroid milieus.

Religiosity and self-rated health among Latin American and Caribbean elders.

OBJECTIVE: To describe religious affiliation, importance of religion, and the relationship between religion and self-rated health in persons aged 60 or older living in Latin America or the Caribbean. METHOD: We used data from seven cities (n = 10,587). Multivariate models were used to analyze the associations between religious affiliation and importance of religion with sociodemographic or health factors and self-rated health. RESULTS: Overall, 92% of the total study population had a religious affiliation; among those who are religious, 80% considered religion to be important in their lives. Half of the population (51%) reported fair or poor health. In multivariate models, older age increased odds of having a religious affiliation and religion being important. Women were about four times more likely to have a religious affiliation and over twice as likely as men to indicate that religion was important. Although religious affiliation was associated with poor health, this association was no longer significant after controlling for functional status. Older adults who considered religion as very important were less likely to report fair or poor health compared to those who were less religious (somewhat important, not very important). CONCLUSIONS: These older adults have a high prevalence of religious affiliation and most of them consider religion to be important. Better self-rated health was associated with higher self-rated religiosity.

Testosterone replacement therapy for older men.

Despite intensive research on testosterone therapy for older men, important questions remain unanswered. The evidence clearly indicates that many older men display a partial androgen deficiency. In older men, low circulating testosterone is correlated with low muscle strength, with high adiposity, with insulin resistance and with poor cognitive performance. Testosterone replacement in older men has produced benefits, but not consistently so. The inconsistency may arise from differences in the dose and duration of testosterone treatment, as well as selection of the target population. Generally, studies reporting anabolic responses to testosterone have employed higher doses of testosterone for longer treatment periods and have targeted older men whose baseline circulating bioavailable testosterone levels were low. Most studies of testosterone replacement have reported anabolic that are modest compared to what can be achieved with resistance exercise training. However, several strategies currently under evaluation have the potential to produce greater anabolic effects and to do so in a safe manner. At this time, testosterone therapy can not be recommended for the general population of older men. Older men who are hypogonadal are at greater risk for the catabolic effects associated with a number of acute and chronic medical conditions. Future research is likely to reveal benefits of testosterone therapy for some of these special populations. Testosterone therapy produces a number of adverse effects, including worsening of sleep apnea, gynecomastia, polycythemia and elevation of PSA. Efficacy and adverse effects should be assessed frequently throughout the course of therapy.

Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study.

BACKGROUND: Testosterone deficiency has been reported in patients with Parkinson disease (PD), Alzheimer disease, and Huntington disease. It is not known whether testosterone therapy (TT) in men with borderline hypogonadism and neurodegenerative diseases will be of substantial benefit. Previously, we reported that testosterone deficiency is more common in patients with PD compared with age-matched control subjects, and we also reported in 2 small open-label studies that some nonmotor symptoms responded favorably to TT. OBJECTIVE: To define the effects of TT on nonmotor and motor symptoms in men with PD and probable testosterone deficiency. DESIGN: Double-masked, placebo-controlled, parallel-group, single-center trial. PATIENTS: Two experimental groups: patients with PD who were receiving either TT or placebo. INTERVENTIONS: Participants received either the study drug by intramuscular injection (200 mg/mL of testosterone enanthate every 2 weeks for 8 weeks) or placebo (isotonic sodium chloride solution injections). In patients in each group, the testosterone serum concentration was obtained at each study visit. During 2 study visits, testosterone levels were blindly evaluated and the intramuscular testosterone dose was increased by 200 mg/mL if the free testosterone value failed to double from the baseline value. MAIN OUTCOME MEASURES: The primary outcome variable was the St Louis Testosterone Deficiency Questionnaire, and secondary outcome measures included measures of mood, cognition, fatigue, motor function, and frequency of adverse events. At the end of the double-blind phase, all patients were offered open-label TT and were followed up after 3 and 6 months. RESULTS: Fifteen patients in the placebo group (mean age, 69.9 years), receiving a mean total levodopa equivalent dose of 924 mg/d, had a baseline free testosterone level of 47.91 pg/mL, compared with 15 patients in the TT group (mean age, 66.7 years), receiving an average total levodopa equivalent dose of 734 mg/d, who had a baseline free testosterone level of 63.49 pg/mL. Testosterone was generally well tolerated. More subjects in the TT group experienced lower extremity edema (40% vs 20%). In 2 patients, 1 in each group, prostate-specific antigen levels were elevated from baseline. The improvement in the TT group compared with the placebo group (1.7 vs 1.1) on the St Louis Testosterone Deficiency Scale was not statistically significant. In addition, there were no significant differences in motor and nonmotor features of PD between the 2 groups, although a few subscales showed improvements (Hopkins Verbal Learning Test, P<.04; and Backward Visual Span subtrial, P<.03). However, long-term open-label TT resulted in delayed but sustained improvement in subjects in the TT group who continued to receive treatment (n = 6) compared with subjects in the placebo group who elected not to receive TT (n = 3). CONCLUSIONS: Testosterone therapy was generally well tolerated in elderly men with PD and probable testosterone deficiency. While there was no significant difference in the motor and nonmotor scales between the TT and placebo groups at the end of 8 weeks compared with baseline, this may be due to several study limitations, including small sample size, a strong placebo effect with intramuscular therapy, and short follow-up that did not allow measurement of delayed effects of TT in some subjects. Until more definitive studies are reported, practitioners should be particularly cautious in treatment of low testosterone concentrations in men with PD and borderline testosterone deficiency, and careful consideration should be given to the risks vs the benefits of TT.

Religion and health: does religious activity improve health outcomes?

A majority of Americans believe in God and say that religion plays a major role in their lives. Several studies have found a potential link between religious activity and longevity, overall health status, and the ability to recover from an adverse health event. The high level of interest among patients and health care providers for incorporating religion into health care suggests the need for further investigation into the role of religion in health outcomes.

Does religious activity improve health outcomes? A critical review of the recent literature.

OBJECTIVE: Many Americans use religious activity to cope with stressful life events. Our goal was to review systematically the recent medical literature to assess the role of religion in health outcomes. DATA SOURCES: We conducted a comprehensive literature search using MEDLINE to identify studies published in the English language between January 1999 and June 2003 describing the effect of religion on health outcomes. The search strategy used the medical subject headings (MeSH) of religion; religion AND medicine; religion OR intercessory prayer; prayer; prayer therapy; religious rites; faith; medicine, traditional; religiosity; religion AND psychology; and religion AND health. STUDY SELECTION: Religious, but not spiritual, interventions were selected for inclusion. Thus, papers describing interventions such as yoga, meditation, acupuncture, and qigong were excluded. Manuscripts describing randomized controlled trials, clinical trials, and partnerships with faith-based organizations were included. DATA EXTRACTION: We found five randomized controlled trials, four clinical trials, and seven faith-based partnerships that describe the impact of religious intervention on health outcomes. Papers were analyzed by four reviewers using a modified Delphi technique to reach consensus. DATA SYNTHESIS: Religious intervention such as intercessory prayer may improve success rates of in vitro fertilization, decrease length of hospital stay and duration of fever in septic patients, increase immune function, improve rheumatoid arthritis, and reduce anxiety. Frequent attendance at religious services likely improves health behaviors. Moreover, prayer may decrease adverse outcomes in patients with cardiac disease. CONCLUSIONS: Religious activity may improve health outcomes.

Age and testosterone feedback jointly control the dose-dependent actions of gonadotropin-releasing hormone in healthy men.

Healthy older men manifest combined declines in testosterone concentrations, LH secretory burst mass (amount of LH released per pulse), and feedback-sensitive regularity of unknown cause. To test a unifying hypothesis of simultaneous reductions in GnRH outflow, gonadotrope responsiveness to GnRH, and androgenic negative feedback, we monitored LH secretion 1) after bolus iv injection of a 1000-fold range of randomly ordered individual doses of GnRH on separate mornings, 2) during unmodified (eugonadal) or testosterone-withdrawn (hypoandrogenemic) negative feedback, and 3) in 16 young (age, 18-35 yr) and 15 older (age, 60-85 yr) healthy men. LH secretory burst mass and pattern regularity were quantitated by intensive blood sampling, high specificity LH beta-subunit-directed immunoradiometric assay, deconvolution analysis, and approximate entropy. GnRH dose responsiveness was assessed by four-parameter nonlinear regression analysis. We demonstrated that older men exhibit 1) delayed attainment of GnRH-evoked maximal LH secretion; 2) enhanced potency of GnRH stimulation in both the feedback-intact and feedback-withdrawn states; 3) elevated gonadotrope sensitivity to GnRH, unmasked by experimental testosterone depletion; 4) comparable young adult-like GnRH efficacy, independent of testosterone feedback milieu; and 5) diminished regularity of GnRH-induced LH release evident only during unmodified androgenic feedback. We conclude that a 3-fold interaction among GnRH dose, testosterone concentration, and age governs GnRH action, and age determines both testosterone-modulated and testosterone-independent actions of GnRH.

Disorders of male sexual function.

Sexuality remains an important issue in the older population. In spite of a decreased ability to achieve an erection, there is continued sexual desire. Many studies suggest that erectile dysfunction in the aged is primarily caused by age-associated chronic disease rather than normal, healthy aging. Therefore, preventive measures that are aimed at the underlying diseases should be sought. Nevertheless, effective treatment options are now available to successfully regain sexual function and thereby, improve quality of life.

A trial study: the effect of low dose human chorionic gonadotropin on the symptoms of benign prostatic hyperplasia.

PURPOSE: Human chorionic gonadotropin (HCG) is a glycoprotein hormone with multiple physiological functions. It interferes with mammary tumorigenesis and modulates growth and tumorigenesis in prostate cancer cells. In addition, HCG receptor transcripts and protein have been demonstrated in normal and hyperplastic prostate glands. Functionally HCG has a growth modulating effect on androgen independent prostate cell lines. We investigated the possible clinical effects of HCG on the symptoms associated with benign prostatic hyperplasia (BPH) in this trial study. MATERIALS AND METHODS: We performed a multicenter, double-blind, placebo controlled, randomized pilot study evaluating the effects of low dose HCG vs placebo in 101 men (50 to 79 years old) with BPH. The primary efficacy measure was the American Urological Association total symptom index score. Secondary efficacy parameters included peak urinary flow and sexual self-efficacy questionnaire changes. RESULTS: Low dose HCG appeared to positively effect moderate to severe BPH symptoms according to American Urological Association scores and sexual function but not peak urinary flow. No HCG induced changes were noted in prostate specific antigen or prostate volume. CONCLUSIONS: These findings suggest that HCG may provide a well tolerated and beneficial therapy for BPH that will be investigated in subsequent studies.

Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers.

To investigate the effect of orlistat on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin), the authors performed double-blind, placebo-controlled, randomized two-period crossover (for fluoxetine and simvastatin) or parallel (for amiodarone) studies in healthy volunteers ages 18 to 65 years of a body mass index between 18 and 30 kg/m2. During treatment with orlistat or matching placebo for 5 to 13 1/3 days, a single oral dose of highly lipophilic drug was administered, followed by obtaining serial blood samples for measuring plasma (for fluoxetine and simvastatin) or serum (for amiodarone) concentrations of the lipophilic drug and its active metabolite. Treatments were compared for the pharmacokinetic parameters AUC0-infinity, Cmax, tmax, and t 1/2 of highly lipophilic drugs and active metabolites. Analysis of variance was performed to assess the significance of the sequence effect and provide the variance estimate for the 90% confidence intervals. Subjects were also evaluated for adverse events, vital signs, and clinical and laboratory safety. The absorption of amiodarone (and active metabolite) was significantly reduced by approximately one-quarter using parameters of Cmax and AUC, while no inhibition of absorption was observed for fluoxetine and simvastatin as well as their active metabolites. There were no clinically significant differences in t 1/2 and tmax for all three drugs tested. Due to expected gastrointestinal adverse events known to occur with orlistat, there was a higher incidence of adverse events under regimen B (highly lipophilic drugs and orlistat) than under regimen A (highly lipophilic drugs and placebo). Other adverse events were sporadic and unremarkable. There were no clinically relevant changes in vital signs or laboratory values. In conclusion, except for amiodarone, there was no effect of orlistat on the pharmacokinetics of highly lipophilic drugs when these drugs were taken concomitantly with orlistat.

Understanding wire/bracket relationships.

All orthodontists encounter wire/bracket relationships during orthodontic treatment. A knowledge of the forces and moments involved in the different wire/bracket angles that can purposely be introduced by the orthodontist, as well as recognition of those produced by the malocclusion or prescription brackets, affords the opportunity for the orthodontist to recognize or create force systems most helpful in treating various malocclusions. Visual determination of force systems can be very misleading, but an understanding of wire/bracket angles provides the opportunity to purposely create those force systems that will more directly lead to the intended tooth movement.

Pharmacokinetic evaluation of the possible interaction between selected concomitant medications and orlistat at steady state in healthy subjects.

To investigate the influence of orlistat on the pharmacokinetics of selected concomitant medications (amitriptyline, atorvastatin, cyclosporine, losartan, metformin, phentermine, and sibutramine) at or within two-fold of therapeutic doses, open-label, multiple-dose (for 6 or 7 days), randomized, two-period (except for cyclosporine, for which a three-way crossover design was used) crossover studies were performed in healthy volunteers ages 18 to 65 years, with a body mass index between 18 and 30 kg/m2. At steady state, blood samples were taken for measuring plasma concentrations of interacting drugs and/or active metabolites. Subjects were also evaluated for adverse events, vital signs, and clinical and laboratory safety. Treatments were compared for AUC0-24, Cmax, tmax, and t1/2 of selected concomitant medications (parent drugs and/or active metabolites). ANOVA was performed to assess the significance of the carry-over effect and provide the variance estimate for the 90% confidence intervals (CIs). With the exception of cyclosporine, whose absorption was reduced by approximately one-third, the results of the statistical analysis demonstrated equivalencefor the two primary parameters for all drugs studied: ratios of the log-transformed means for both AUC and Cmax were close to 1.00, with 90% CIs contained entirely within the bioequivalence region of 0.80 to 1.25; there were no clinically significant differences in t1/2 and tmax. There was a higher incidence of adverse events under treatment B (selective concomitant medications and orlistat) than under treatment A (selective concomitant medications alone); most of this difference was due to expected gastrointestinal adverse events known to occur with orlistat. Other adverse events were sporadic and unremarkable. All adverse events were either mild or moderate in intensity. There were no clinically relevant changes in vital signs or laboratory values. In conclusion, except for cyclosporine, there was no effect of orlistat on the pharmacokinetics of selective concomitant medications when these drugs were taken concomitantly with orlistat.