Prevalence of hypogonadism in males aged at least 45 years: the HIM study.

The Hypogonadism in Males study estimated the prevalence of hypogonadism [total testosterone (TT) < 300 ng/dl] in men aged > or = 45 years visiting primary care practices in the United States. A blood sample was obtained between 8 am and noon and assayed for TT, free testosterone (FT) and bioavailable testosterone (BAT). Common symptoms of hypogonadism, comorbid conditions, demographics and reason for visit were recorded. Of 2162 patients, 836 were hypogonadal, with 80 receiving testosterone. Crude prevalence rate of hypogonadism was 38.7%. Similar trends were observed for FT and BAT. Among men not receiving testosterone, 756 (36.3%) were hypogonadal; odds ratios for having hypogonadism were significantly higher in men with hypertension (1.84), hyperlipidaemia (1.47), diabetes (2.09), obesity (2.38), prostate disease (1.29) and asthma or chronic obstructive pulmonary disease (1.40) than in men without these conditions. The prevalence of hypogonadism was 38.7% in men aged > or = 45 years presenting to primary care offices.

Higher church attendance predicts lower fear of falling in older Mexican-Americans.

Several studies have shown that involvement in religious activity appears to benefit health. To estimate the association between church attendance and fear of falling, we used a sample of 1341 non-institutionalized Mexican-Americans aged 70 and over from the third wave (1998-1999) of the Hispanic Established Population for the Epidemiological Study of the Elderly, followed until 2000-2001. Baseline potential predictors of fear of falling were church attendance, socio-demographics, history of falls, summary measure of lower body performance (tandem balance, eight-foot walk, and repeated chair stands), functional status, depressive symptoms, cognitive status, and medical conditions. Fear of falling at the two-year follow-up was measured as no fear, somewhat afraid, fairly afraid, and very afraid. Chi-square statistic and multiple logistic regression analysis were used to estimate associations between the outcome and the potential predictors. Multiple logistic regression analysis showed that frequent church attendance was an independent predictor of lower fear of falling (odds ratio = 0.73, 95% confidence interval 0.58-0.92, P = 0.008) two years later. Other independent predictors of fear of falling were female gender, poorer objective lower body performance, history of falls, arthritis, hypertension, and urinary incontinence. Frequent church attendance is associated with decreased fear of falling in older Mexican-Americans.

Mechanisms of conjoint failure of the somatotropic and gonadal axes in ageing men.

Endogenous growth hormone (GH) production falls by 50% every 7 years and bioavailable testosterone concentrations decline concomitantly by 12-15% every decade in ageing men. Despite this temporal parallelism, the neuroendocrine bases of the somatopause and gonadopause are not known. This knowledge deficit contrasts with the recent unfolding of new insights into the nature of oestrogen-dependent control of the GH-insulin-like growth factor (IGF)1 axis in pre- and postmenopausal women. The present overview examines the postulate that the pathophysiology of somatopause and gonadopause in ageing men is bidirectionally linked. According to this broader thesis, hyposomatotropism accentuates Leydig cell steroidogenic failure and, conversely, progressive androgen deficiency exacerbates the decline in GH-IGF1 output in ageing.

Unequal impact of short-term testosterone repletion on the somatotropic axis of young and older men.

The present clinical study compares the impact of low- and high-dose parenteral testosterone (T) supplementation on daily GH secretory patterns and serum IGF-I, IGFBP-1, and IGFBP-3 concentrations in healthy older (60-82 yr) and young (20-40 yr) men. To this end, we administered three consecutive weekly injections of randomly ordered saline and either a low (100 mg) or a high (200 mg) dose of testosterone enanthate im; namely, saline (n = 17, young and n = 16, older), a low dose (n = 8 young, n = 8 older) and a high dose (n = 9 young, and n = 8 older) of androgen. To monitor somatotropic-axis responses, blood was sampled every 10 min for 24 h for later chemiluminescence-based assay of serum GH, RIA of serum IGF-I, and immunoradiometric assay of serum IGFBP-1 and IGFBP-3 concentrations. Data were analyzed via a nested analysis of covariance statistical design. At baseline (saline injection), older, compared with young, men maintained: 1) similar serum total T, IGFBP-1, and IGFBP-3 but reduced IGF-I concentrations, namely, mean (+/- SEM) IGF-I 160 plus or minus 15 vs. 280 plus or minus 18 microg/liter, (P < 0.001); 2) reduced GH secretory burst mass (0.68 +/- 0.09 vs. 1.2 +/- 0.20 microg/liter, P = 0.031); 3) more disorderly GH release patterns (approximate entropy 0.501 +/- 0.058 vs. 0.288 +/- 0.021, P < 0.001); and 4) blunted 24-h rhythmic GH output (nyctohemeral amplitude 0.25 +/- 0.05 vs. 0.47 +/- 0.08 microg/liter, P = 0.025). Serum T concentrations (ng/dl) did not differ in the two age groups supplemented with either a low dose [550 +/- 50 (young) and 544 +/- 128 (older)] and high [1320 +/- 92 (young) and 1570 +/- 140 (older)] dose of T. The 100-mg dose of androgen exerted no detectable effect on GH secretion in either age cohort but increased the serum IGF-I concentration in young men by 20% (P = 0.00098). The 200-mg dose of T failed to alter daily GH production in young volunteers but in older men stimulated: 1) a 2.03-fold rise in the mean (24-h) serum GH concentration (P = 0.0053, compared with the response to saline); 2) a 1.20-fold increase in basal (nonpulsatile) GH production (P = 0.039); 3) a 2.15-fold amplification of GH secretory burst mass (P = 0.0020); 4) a 2.17-fold elevation of the Mesor of nyctohemeral GH output (P = 0.025); 5) a 1.79-fold enhancement in GH approximate entropy (P = 0.0003); and 6) a 40% increase in the fasting serum IGF-I concentration (P = 0.000005). Multivariate statistical analysis indicated that following high-dose T administration, the E2 increment significantly predicted the IGF-I increment in both age groups combined (P = 0.003); T dose positively forecast the serum total IGF-I concentration (P = 0.0031); and age and T dose jointly determined serum LH concentrations (P = 0.031). In summary, neither a physiological nor a pharmacological dose of T administered parenterally for 3 wk augments daily GH secretion in eugonadal young men. In contrast, a high dose of aromatizable androgen significantly amplifies 24-h basal, pulsatile, entropic, and nyctohemerally rhythmic GH production and elevates the serum IGF-I concentration in older men. The mechanistic basis for the foregoing age-related distinction in GH/IGF-I axis responsivity to T is not known.

Pulsatile iv infusion of recombinant human LH in leuprolide-suppressed men unmasks impoverished Leydig-cell secretory responsiveness to midphysiological LH drive in the aging male.

The present investigation tests the clinical hypothesis that Leydig-cell responsiveness to pulsatile and midphysiological LH drive is impaired in older men. To this end, we implemented a novel clinical investigative paradigm consisting of preadministration of an LH-down-regulating dose (3.75 mg) of leuprolide acetate followed, 3-4 wk later, by controlled challenge of the testis, with pulsatile iv infusions of saline vs. recombinant human (rh) LH. Based on a preliminary dose-finding experiment, we evaluated LH action in 8 young (ages, 18-25 yr) and 7 older (ages, 60-85 yr) volunteers by infusing eight consecutive 6-min squarewave pulses of saline or 50 IU rhLH iv every 2 h. Analyses were carried out 48 or 72 h apart in a prospective, randomly assigned, double-blind, within-subject cross-over design. Serum concentrations of T (RIA) and LH (immunoradiometric assay) were measured in blood sampled every 10 min concurrently. Leuprolide injection suppressed pre-LH-infusion (0800 h baseline) serum T concentrations (pooled mean +/- SEM) markedly in both age groups (P < 10(-3)); namely, to 40 +/- 20 ng/dl (young) and 12 +/- 3.1 ng/dl (older; P < 0.05 vs. young) (to convert to nM, multiply by 0.0347). Successive iv pulses of rhLH stimulated T output, over time, to an asymptotic maximum of 166 +/- 42 ng/dl in young men (P = 0.0008 vs. saline) and 57 +/- 9.8 ng/dl in older subjects (P = NS vs. saline, and P < 0.05 vs. young). Further regression analyses identified significant reductions of both the initial rate and maximum of the time-dependent incremental rise in LH-driven serum T concentrations in older men. In contrast, infused serum LH concentrations, distribution volumes, and calculated LH half-lives were comparable in the two age cohorts. We conclude that older men manifest both a delayed initial and reduced maximal serum T concentration rise compared with young men exposed to identical controlled midphysiological pulsatile LH drive.

Neurophysiological regulation and target-tissue impact of the pulsatile mode of growth hormone secretion in the human.

Neuroendocrine axes function as an ensemble of regulatory loci which communicate and maintain homeostasis via time-delayed blood-borne signals. The growth hormone (GH)-insulin-like growth factor I (IGF-I) feedback axis sustains a vividly pulsatile mode of interglandular signalling. Pulsatility is driven jointly by hypothalamic GH-releasing hormone (GHRH) and GH-releasing peptide (GHRP), and modulated by somatostatinergic restraint. Paradoxically, intermittent somatostatin inputs also facilitate somatotrope-cell responses to recurrent secretagogue stimuli, thereby amplifying pulsatile GH secretion. A concurrent low basal (8-12% of normal total) rate of GH release is controlled positively by GHRH and GHRP and negatively by somatostatin. Sex-steroid hormones (such as oestradiol and aromatizable androgen) and normal female and male puberty augment GH secretory-burst mass 1.8- to 3.5-fold, whereas ageing, relative obesity, physical inactivity, hypogonadism, and hypopituitarism mute the amplitude/mass of pulsatile GH output. An abrupt rise in circulating GH concentration stimulates rapid internalization of the GH receptor in peripheral target tissues, and evokes second-messenger nuclear signalling via the STAT 5b pathway. Discrete GH peaks stimulate linear (skeletal) growth and drive muscle IGF-I gene expression more effectually than basal (time-invariant) GH exposure. A brief pulse of GH can saturate the plasma GH-binding protein system and achieve prolonged plasma GH concentrations by convolution with peripheral distribution and clearance mechanisms. A single burst of GH secretion also feeds back after a short latency on central nervous system (CNS) regulatory centres via specific brain GH receptors to activate somatostatinergic and reciprocally subdue GHRH outflow. This autoregulatory loop probably contributes to the time-dependent physiologically pulsatile dynamics of the GH axis. More slowly varying systemic IGF-I concentrations may also damp GH secretory pulse amplitude by delayed negative-feedback actions. According to this simplified construct, GH pulsatility emerges due to time-ordered multivalent interfaces among GHRH/GHRP feedforward and somatostatin, GH and IGF-I feedback signals. Resultant GH pulses trigger tissue-specific gene expression, thereby promoting skeletal and muscular growth, metabolic and body compositional adaptations, and CNS reactions that jointly maintain health and homeostasis.

Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans.

The present experiments examine the neuroregulatory hypothesis that the degree of sample-by-sample regularity of hormone output by an interlinked hypothalamopituitary target-organ system monitors the strength of feedback and/or feedforward signaling. To test this postulate and assess its generality, we implemented a total of nine thematically complementary perturbation experiments. In particular, we altered feedback or feedforward signaling selectively in two distinct neuroendocrine systems; namely, the growth hormone (GH) insulin-like growth factor type I (IGF-I) and the luteinizing hormone-testosterone axes. Four experimental paradigms comprised preferential reduction vs. enhancement of IGF-I or testosterone feedback signal strength; and, conversely, five others entailed selective attenuation vs. augmentation of GH-releasing hormone and gonadotropin-releasing hormone feedforward signal intensity. In these independent interventions, quantitation of subordinate (nonpulsatile) secretory pattern reproducibility via the approximate entropy statistic unmasked salient changes (P values typically <10(-3)) in the conditional regularity of serial hormone output with high consistency (96-100%). In particular, approximate entropy quantified degradation of secretory subpattern orderliness under either muted feedback restraint or heightened feedforward drive. Assuming valid interpretation of the biological constraints imposed, these experimental observations coincide with earlier reductionist mathematical predictions, wherein increased irregularity of coupled parameter output mirrors attenuated feedback and/or augmented feedforward coupling within an integrative system.

Muting of androgen negative feedback unveils impoverished gonadotropin-releasing hormone/luteinizing hormone secretory reactivity in healthy older men.

Plasma bioavailable testosterone concentrations decline in healthy older men without a uniformly commensurate rise in serum LH concentrations, which disparity is consistent with a hypothesis of relative hypogonadotropism. Likewise, preserved gonadotrope responsiveness to exogenous GnRH stimulation, despite an attenuated amplitude of endogenous LH pulses, points to reduced hypothalamic GnRH feedforward signaling in aging males. To appraise GnRH/LH secretory reserve more directly in older men, we have compared daily LH secretion, driven by profound short-term blockade of androgen biosynthesis by oral ketoconazole administration, in nine young (ages, 18-32 yr) and seven older (ages, 60-73 yr) volunteers. The ability to unleash endogenous GnRH-driven LH secretion in response to acute testosterone withdrawal was quantitated by sampling blood every 10 min, for 24 h, followed by high-precision immunoradiometric assay. The resultant serum LH concentration profiles were analyzed by: 1) model-free discrete peak detection (Cluster) analysis; 2) the approximate entropy statistic to quantitate pattern regularity; and 3) 24-h rhythmic (cosinor) analysis. At baseline, mean and integrated (24-h) serum LH concentrations were similar in both age cohorts. However, Cluster analysis established an elevated LH peak frequency [18 +/- 0.86 (older) vs. 13 +/- 1.3 pulses/24 h (young), P = 0.0028] and a reduced incremental LH pulse area [37 +/- 6.9 (older) vs. 106 +/- 20 (young) IU/L x min, P = 0.016] in older men. Approximate entropy calculations also revealed more irregular LH release patterns in older men before intervention (P = 0.00089). Feedback stress, achieved by ketoconazole-induced androgen deprivation, unmasked further neuroregulatory defects in older volunteers, who failed to equivalently increase the: 1) mean (24-h) serum LH concentration [i.e. to 5.0 +/- 0.99 (older men) vs. 9.0 +/- 1.1 (young) IU/L, P = 0.000071]; 2) maximal LH peak height (to 6.1 +/- 1.1 vs. 10.4 +/- 1.2 IU/L, P = 0.00043); 3) incremental LH pulse area (to 41 +/- 8.8 vs. 87 +/- 20 IU/L x min, P = 0.016); 4) interpeak nadir serum LH concentration (to 4.0 +/- 0.77 vs. 7.9 +/- 1.0 IU/L, P < 10(-6)); 5) the quantitable irregularity of LH release (P = 0.00089); and 6) the mesor of 24-h rhythmic LH secretion (P = 0.000062). In summary, experimental imposition of a novel hypoandrogenemic open-loop feedback stressor, for 48 h, to heighten hypothalamic GnRH feedforward drive, unveils impoverished augmentation of LH pulse mass, impaired orderliness of LH release, and diminished 24-h rhythmic LH secretion in older men. The foregoing trilogy of neuroregulatory defects identifies unequivocally attenuated hypothalamo-pituitary reactivity to muting of androgen negative feedback in the aging male.

Impact of age on cortisol secretory dynamics basally and as driven by nutrient-withdrawal stress.

The present study tests the clinical hypothesis that aging impairs homeostatic adaptations of cortisol secretion to stress. To this end, we implemented a short-term 3.5-day fast as an ethically acceptable metabolic stressor in eight young (ages 18-35 yr) and eight older (ages 60-72 yr) healthy men. Volunteers were studied in randomly ordered fed vs. fasting sessions. To capture the more complex dynamics of cortisol's feedback control, blood was sampled every 10 min for 24 h for later RIA of serum cortisol concentrations and quantitation of the pulsatile, entropic, and 24-h rhythmic modes of cortisol release using deconvolution analysis, the approximate entropy statistic, and cosine regression, respectively. The stress of fasting elevated the mean (24-h) serum cortisol concentration equivalently in the two age cohorts [i.e. from 7.2 +/- 0.35 to 11.6 +/- 0.71 microg/dL in young men and from 7.7 +/- 0.39 to 12.6 +/- 0.59 microg/dL in older individuals (P < 10(-7))]. The rise in integrated cortisol output was driven mechanistically by selective augmentation of cortisol secretory burst mass (P = 0.002). The resultant daily (pulsatile) cortisol secretion rate increased significantly but equally in young (from 94 +/- 6.3 to 151 +/- 15 microg/dL x day) and older (from 85 +/- 5.4 to 145 +/- 7.3 microg/dL x day) volunteers (P < 10(-4)). Nutrient restriction also prompted a marked reduction in the quantifiable regularity of (univariate) cortisol release patterns in both cohorts (P < 10(-4)). However, older men showed loss of joint synchrony of cortisol and LH secretion even in the fed state, which failed to change with metabolic stress (P < 10(-6)). In addition, older individuals maintained a premature (early-day) cortisol elevation in the fed state and unexpectedly evolved an anomalous further cortisol phase advance of 99 +/- 16 min during fasting (P < 10(-5)). Caloric deprivation in aging men also disproportionately elevated the mesor of 24-h rhythmic cortisol release (P = 10(-7)) and elicited a greater increment in the mean day-night variation in cortisol secretory-burst mass (P < 0.01 vs. young controls). Lastly, short-term caloric depletion in older subjects paradoxically normalized their age-associated suppression of the 24-h rhythm in cortisol interburst intervals. In summary, acute metabolic stress in healthy aging men (compared with young individuals) unmasks distinct, albeit complex, disruption of cortisol homeostasis. These dynamic anomalies impact the feedback-dependent and time-sensitive coupling of pulsatile and 24-h rhythmic cortisol secretion. Nutrient-withdrawal stress in the older male heightens the cortisol phase disparity already evident in fed elderly individuals. Conversely, the stress of fasting in young men paradoxically reproduces selected features of the aging unstressed (fed) cortisol axis; viz., abrogation of joint cortisol-LH synchrony and suppression of the normal diurnal variation in cortisol burst frequency. Whether fasting would unveil analogous disruption of feedback-dependent control of the corticotropic axis in healthy aging women is not yet known.

Testosterone improves rehabilitation outcomes in ill older men.

OBJECTIVES: To determine whether testosterone supplementation improves rehabilitation outcomes in ill older men. DESIGN: A randomized, placebo-controlled, double-blind study. SETTING: A Geriatric Evaluation and Management (GEM) unit based at a university- affiliated Veterans Affairs Medical Center. PARTICIPANTS: Fifteen men aged 65 to 90 years admitted to the GEM for rehabilitation. INTERVENTION: Subjects were randomized to receive weekly intramuscular injections with testosterone enanthate 100 mg or placebo. MEASUREMENTS: Task-specific performance using the Functional Independence Measure (FIM) and grip strength was measured at the onset of the study and at the time of discharge from the GEM. RESULTS: At baseline, FIM scores were similar between the placebo and the testosterone group (73.7 vs 70.7, P = .637), as was grip strength (49.7 vs 55.3 pounds, P = .555). At discharge from the GEM, testosterone-treated patients had improved FIM scores compared with baseline (93.6 vs 70.7; P = .012) and grip strength (68.7 vs 55.3 pounds; P = .033). In the placebo group there was no significant improvement of FIM scores compared with baseline (78.0 versus 73.7; P = .686) or of grip strength (48.9 vs 49.7 pounds; P = .686). CONCLUSIONS: Testosterone supplementation may improve rehabilitation outcomes in ill older men.

Older men manifest multifold synchrony disruption of reproductive neurohormone outflow.

Under a working clinical hypothesis that aging putatively disrupts neuroendocrine control mechanisms, here we test a specific corollary notion that transitions in sleep stage, oscillations in nocturnal penile tumescence (NPT; a neurogenically organized signal), and the rates of instantaneous secretion of LH and/or testosterone are jointly synchronous in healthy young, but not older, men. To this end, we evaluated 10 young (aged 21-31 yr) and 8 older (aged 65-74 yr) men by intensive overnight multisite monitoring, viz. simultaneous electro-encephalogram and NPT recordings (every 30 s) and remote blood sampling (every 2.5 min) to quantitate LH and testosterone release. Waveform-independent deconvolution and cross-correlation analyses of these neurohormone outflow measures revealed that healthy young men sustain four salient physiological linkages overnight: 1) a strong inverse (confirmatory) relationship between sleep stage and NPT activity, such that deeper sleep is accompanied by suppression of NPT; 2) consistent coupling between NPT and testosterone secretion, wherein heightened NPT activity respectively precedes and follows increased testosterone secretion by 12.5-32.5 and 50-60 min; 3) evident synchrony between sleep stage and testosterone secretion, in which testosterone secretion increases over a 30-min window (-2.5 to 25 min) while sleep deepens; and 4) a close temporal linkage between instantaneous LH release and NPT oscillations, whereby LH secretion increases 55-62.5 min before and again 5-30 min after NPT declines. In contrast, older men manifested global loss of expected young adult synchrony; namely, 1) abolition of the inverse relationship between sleep stage and NPT, 2) decorrelation of NPT oscillations and testosterone secretion, 3) decoupling of testosterone release and deep sleep, and 4) abrogation of the linkage between LH secretion and penile detumescence. In summary, high intensity overnight monitoring of multiple reproductive neuroendocrine outflow measures simultaneously in young men delineates prominent neurophysiological coupling among sleep transitions and NPT activity, LH and testosterone secretion or NPT oscillations, and testosterone secretion and deepening sleep stage. In contrast, healthy older men exhibit near-universal disruption of physiological young adult synchronicity. Thus, we conclude that male reproductive aging is marked by erosion of coordinate regulation among sleep transitions, central nervous system-directed NPT activity, and hypothalamically driven episodic GnRH/LH (and thereby Leydig cell testosterone) secretion. Whether analogous multifold uncoupling of neurohormone signals emerges in the course of reproductive aging in women or in nonhuman species is not yet known.

Synthetic somatostatin analog (octreotide) suppresses daytime growth hormone secretion equivalently in young and older men: preserved pituitary responsiveness to somatostatin's inhibition in aging.

OBJECTIVE: To gain greater insight into the mechanisms controlling the low daytime rate of growth hormone (GH) secretion in older men. DESIGN: We conducted a randomized, controlled study of GH secretion during inhibition by octreotide, a somatostatin analog. PARTICIPANTS: Nine young (35-44 years) and ten older (62-79 years) healthy men participated. INTERVENTION: Octreotide versus nothing, while subjects were on a standardized diet. MEASUREMENTS: All subjects were assessed on two separate occasions: baseline and at time of the intervention of octreotide (100 microg subcutaneously); the order of the intervention was randomly assigned. Octreotide was administered at 8:00 a.m. Venous sampling was performed every 10 minutes for 8 hours (8:30 a.m. to 4:30 p.m.). To estimate the joint parameters of pulsatile and basal (between secretory pulses) GH secretion, we used an ultrasensitive chemiluminescence-based GH assay and multiparameter deconvolution analysis. RESULTS: Compared with baseline, octreotide markedly reduced mean (8-hour) serum GH concentrations in both young (0.585+/-0.255 microg/L vs 0.070+/-0.029 microg/L; P = .008) and older (0.397+/-0.107 microg/L vs 0.087+/-0.027 microg/L; P = 0.005) men. In younger men, octreotide decreased the serum GH concentration primarily by suppressing the mass of GH released per secretory pulse (2.4+/-0.9 microg/L vs 1.0+/-.7 microg/L; P = .015) and the interpulse (basal) rate of GH release (0.0014+/-0.0003 microg/L/min vs 0.0006+/-0.0002 microg/L/min; P = .051). In older men, octreotide also restrained the mass of GH per secretory pulse (1.5+/-0.4 microg/L vs 0.4+/-0.1 microg/L; P = .028) and lowered basal GH release (0.0014+/-0.0003 microg/L/min vs 0.0004+/-0.0001 microg/L/min; P = .007). There were no significant differences when the older men were compared with the young controls. CONCLUSIONS: Our data suggest that the daytime relative GH deficiency seen in older men is not a result of excessive pituitary susceptibility to the inhibitory capabilities of somatostatin, but more likely reflects impoverished endogenous GHRH drive and/or heightened release of brain somatostatin.

Disruption of the young-adult synchrony between luteinizing hormone release and oscillations in follicle-stimulating hormone, prolactin, and nocturnal penile tumescence (NPT) in healthy older men.

The healthy human male hypothalamo-pituitary-gonadal axis exhibits age-dependent loss of coordinate LH-testosterone secretion. A putative independent defect in Leydig-cell steroidogenesis with aging would confound the attribution of such LH-testosterone asynchrony to a hypothalamo-pituitary locus per se. Accordingly, here we appraise by sampling every 2.5 min overnight the joint synchrony of moment-to-moment LH release with simultaneously monitored pituitary FSH secretion, prolactin release, and nocturnal penile tumescence (NPT) oscillations, as a neurophysiological correlate of sleep regulation) in 10 young (ages 21-34) and 8 older (ages 62-72) healthy men. Joint synchrony for paired LH-FSH, LH-prolactin, and LH-NPT observations in young vs. older individuals was quantified by the cross-approximate entropy (cross-ApEn) statistic, with larger cross-ApEn values indicating greater two-variable asynchrony. Concomitantly, we assessed (possible) univariate changes with age for each of LH, FSH, prolactin, and NPT, as quantified by approximate entropy (ApEn). Hormone assays were performed by random-access direct chemiluminescence analyzer. Overnight mean (+/- SEM) serum LH concentrations (IU/L) were equivalent in older (3.1 +/- 0.31 IU/L) and younger (2.9 +/- 0.29) men, as were their serum total testosterone concentrations; viz., 425 +/- 48 (older) and 523 +/- 40 (younger) ng/dL. However, all three sets of paired time-series were significantly more asynchronous in the older cohort. First, cross-ApEn of paired LH-FSH release was significantly higher (or more asynchronous) in older subjects; viz., 1.902 +/- 0.022 in older men vs. 1.607 +/- 0.058 in younger individuals (P = 0.0005). Second, cross-ApEn of paired LH and prolactin release was 1.744 +/- 0.085 in older volunteers vs. 1.346 +/- 0.084 in younger subjects (P = 0.0046). Third, and most notably, cross-ApEn for the joint LH-NPT observation time-series was significantly greater in older subjects at 1.771 +/- 0.056 vs. 1.223 +/- 0.086 (young) (P = 0.0001), thereby denoting loss of coordination between (neural) signals directing intermittent LH secretion and those governing sleep-associated penile tumescence in older men. Among one-variable results, only ApEn of LH release was significantly higher in older individuals at 1.323 +/- 0.058 vs. 0.897 +/- 0.089 in younger subjects (P = 0.0019), signifying greater disorderliness of the LH secretory process in aged men. Individual ApEn values of FSH and prolactin release and NPT were age-invariant. In ensemble, the present clinical experiments indicate that, within the aging male reproductive axis, bihormonal network disruption is more pronounced than individual signal disruption. We suggest that abrogation of joint synchrony among hypothalamically directed pituitary hormones and a neurogenically organized sexual response (nocturnal penile tumescence) can be unified thematically under an hypothesis of disrupted central nervous system hypothalamo-pituitary network coordination in human aging. Such implicit disarray of multinodal communication is of consequence both scientifically and clinically, especially in proposing aging theories and intervention strategies.

Joint basal and pulsatile hypersecretory mechanisms drive the monotropic follicle-stimulating hormone (FSH) elevation in healthy older men: concurrent preservation of the orderliness of the FSH release process: a general clinical research center study.

To appraise the neuroendocrine mechanisms that underlie a selective (monotropic) elevation of serum FSH concentrations in healthy older men, we sampled blood in 11 young (ages 21-34) and 8 older men (ages 62-72) men every 2.5 min overnight. Serum FSH concentrations were quantitated in an automated, high-sensitivity, chemiluminescence-based assay. Rates of basal and pulsatile FSH secretion were estimated by deconvolution analysis, and the orderliness of the FSH release process via quantitated the approximate entropy statistic. Statistical analysis revealed that healthy older men manifest dual neuroendocrine hypersecretory mechanisims; specifically, a 2-fold increase in the basal (nonpulsatile) FSH secretion rate, and a concurrent 50% amplification of FSH secretory burst mass (and amplitude). The regularity or orderliness of ad seriatim FSH release is preserved in older individuals. We postulate that higher basal FSH secretion in older men is a consequence of reduced testosterone negative feedback, whereas amplified FSH secretory burst mass reflects net enhanced stimulation of gonadotrope cells by endogenous FSH secretagogues (e.g. GnRH and/or activin). The foregoing specific mechanisms driving heightened FSH secretion in older men contrast with the lower-amplitude pulsatility and more disorderly patterns of LH release in the same individuals. Thus, the present data illuminate an age-dependent disparity in the disruption of FSH neuroregulation in the aging male.

Two-week pulsatile gonadotropin releasing hormone infusion unmasks dual (hypothalamic and Leydig cell) defects in the healthy aging male gonadotropic axis.

OBJECTIVE: To examine the possibility that lower serum bioavailable testosterone concentrations, without increased LH release, in healthy older men, reflects hypothalamic GnRH deficiency. DESIGN: We used a randomized, double-blind, placebo-controlled design. METHODS: We treated each of five young (ages 20-34 years) and five older (ages 60-78 years) men with 2 weeks of randomized infusions of saline or pulsatile GnRH (100 ng/kg i.v. every 90 min). RESULTS: At baseline (saline infusion), older men had more LH pulses (young compared with old, 10 +/- 0.6 compared with 15 +/- 1, P = 0.0026) per 24h, reduced fractional LH pulse amplitude (219 +/- 17% compared with 167 +/- 40%, P = 0.0376), and more disorderly hormone release as judged by approximate entropy (ApEn) (LH, P < or = 0.0001; testosterone, P < or = 0.0047). In response to pulsatile i.v. GnRH infusions, serum 24-h LH concentrations (measured by immunoradiometric assay (IRMA)), increased equivalently in young and older men (to 7.3 +/- 1.2 and 7.2 +/- 1.8 IU/l respectively). GnRH treatment also normalized LH pulse frequency and amplitude, ApEn, and plasma biologically active LH (pooled) concentrations. In contrast, 24-h testosterone concentrations failed to increase equivalently in older men (young compared with old, 869 +/- 88 compared with 517 +/- 38 ng/dl, P = 0.0061), reflecting lower testosterone peak maxima (995 +/- 108 compared with 583 +/- 48 ng/dl, P = 0.0083) and interpeak nadirs (750 +/- 87 compared with 427 +/- 26 ng/dl, P = 0.0073). CONCLUSIONS: We have demonstrated that, in older men, successful reconstitution of 24-h pituitary (bioactive) LH output and pulsatile (IRMA) LH release patterns could be achieved by a fixed exogenous GnRH pulse signal, thereby implicating altered endogenous hypothalamic GnRH release in the relative hypogonadotropism of aging. The failure of testosterone concentrations to increase concomitantly points to a simultaneous Leydig cell defect. We conclude that aging in men is marked by a dual defect in the central nervous system-pituitary-Leydig cell axis.

Religious activity improves life satisfaction for some physicians and older patients.

OBJECTIVE: To assess religious perceptions and activities of physicians and older patients and to determine whether religious activities are associated with life satisfaction. DESIGN AND SETTING: A cross-sectional survey of practicing Virginia internists and psychiatrists and hospitalized or institutionalized (nursing home) older adults. PARTICIPANTS: One hundred randomly sampled practicing physicians and 55 hospitalized or institutionalized older patients. METHODS: A mailed survey was used for the physicians and a structured interview for the patients. All subjects provided information pertaining to demographics and life satisfaction using the Life Satisfaction Index (LSI-B). For physicians or patients who engaged in any religious activity, the Intrinsic/Extrinsic Religiosity (I/E-R) scale was used. RESULTS: Of the 100 physicians (49 internists and 51 psychiatrists) who answered the survey (50% response rate), 75% used religious activity as a coping resource (39% somewhat, 36% definitely). There was a positive correlation between intrinsic religious activity (e.g., prayer, Bible reading) and life satisfaction (r = .293, P = .042). Of the 55 patients interviewed, 47 (86%) used religion as a coping resource, and intrinsic religious activity was positively associated with life satisfaction (r = .843, P < .001). Even after controlling for age, gender, health, and marital status, intrinsic religious activity remained a predictor of higher life satisfaction. CONCLUSIONS: Intrinsic religious activity is associated positively with life satisfaction in physicians and ill older adults.

Influence of the antacid Maalox on the pharmacokinetics of capecitabine in cancer patients.

PURPOSE: In the present study the possible influence of the antacid Maalox on the pharmacokinetics of capecitabine (Xeloda) and its metabolites was investigated in cancer patients. METHODS: A total of 12 patients with solid, predominantly metastatic tumors of various origin received a single oral dose of 1250 mg/m2 of capecitabine (treatment A), a single oral dose of 1250 mg/m2 of capecitabine followed immediately by 20 ml of Maalox (treatment B), and a single oral dose of 1250 mg/m2 of capecitabine followed 2 h later by 20 ml of Maalox (treatment C) in an open, randomized, three-way cross over fashion. Serial blood and urine samples were collected for up to 24 h after each administration. Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chromatography/mass spectrometry and in urine using nuclear magnetic resonance spectroscopy. RESULTS: Administration of Maalox either concomitantly with capecitabine or delayed by 2 h did not influence the time to peak plasma concentrations (Cmax) or the elimination half-lives of capecitabine and its metabolites. Unexpectedly, moderate increases in the Cmax and AUC0-infinity values obtained for capecitabine and 5'-deoxy-5-fluorocytidine were observed when Maalox was given together with capecitabine. However, these increases, which ranged between 10% and 31%, were not statistically significant (P > 0.05) and are not of clinical significance. There was no indication of consistent changes in the plasma concentrations of the other metabolites 5'-deoxy-5'-fluorouridine (5'-DFUR), 5-fluorouracil, and alpha-fluoro-beta-alanine. The Cmax and AUC0-infinity values recorded for these three metabolites increased and decreased in a stochastic manner. The magnitude of these changes was low (<13%) and not statistically significant. The primary statistical analysis of the AUC0-infinity obtained for 5'-DFUR provided a P value of 0.4524 and clearly indicated no significant difference between the treatments. The addition of Maalox had no influence on the overall urinary recovery or the proportion of the dose recovered as capecitabine or its metabolites from urine. CONCLUSION: At the dose used in this study, the effect of concomitantly delivered Maalox on the extent and rate of gastrointestinal absorption of capecitabine is not clinically significant. Therefore, there is no need to adjust the dose or timing of capecitabine administration in patients treated with Maalox.