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Biomedical subjects

Paul Y Takahashi

Publications and source records attributed to Paul Y Takahashi.

13 recordsLinked to original sources
PubMed2006

Age or factors associated with aging attenuate testosterone's concentration-dependent enhancement of the regularity of luteinizing hormone secretion in healthy men.

BACKGROUND: Healthy older men have reduced testosterone (Te) production and frequent, small irregular LH pulses. Which is cause and which is effect are not known. RATIONALE: In model systems, frequent and irregular LH pulses reflect attenuated feedback inhibition by Te. HYPOTHESIS: Factors associated with aging impair negative feedback by Te. SUBJECTS AND SETTING: Healthy men at an academic medical center were studied. METHODS: The study used quantification of the regularity of LH release patterns during blockade of gonadal steroidogenesis and graded transdermal Te addback in 18 healthy men aged 18-65 yr. RESULTS: In the cohort as a whole, stepwise Te repletion repressed LH concentrations (P = 0.001) and enhanced the quantifiable orderliness of LH release patterns (P < 0.001). By regression analysis, age attenuated the capability of increasing Te concentrations to regularize LH secretion patterns (P = 0.019). However, after a fixed GnRH stimulus, the effect of Te on LH regularity was invariant of the age factor (P = 0.16), thus pointing to a hypothalamic locus of impaired Te feedback. SUMMARY: Aging disrupts the capability of systemic Te concentrations to maintain orderly LH secretion under endogenous, but not exogenous, GnRH drive. CONCLUSIONS: Age or factors associated with increased age reduce negative feedback by any given total Te concentration on hypothalamopituitary GnRH-LH outflow, thus contributing to disorderly LH secretion.

Adult↗
PubMed2006

An ensemble model of the male gonadal axis: illustrative application in aging men.

Testosterone (Te) production declines in the aging male, albeit for unknown reasons. Plausible mechanisms include reduced secretion of GnRH, less feedforward by LH, and/or altered feedback by systemic Te. The present study tests all three postulates in a cohort of 10 young (20-35 yr old) and eight older (50-72 yr old) men. The experimental paradigm comprised graded blockade of the GnRH receptor to create four distinct strata of LH and Te pulsatility in each subject. A novel analytical formalism was developed to reconstruct implicit dose-response functions linking 1) virtual GnRH outflow positively to LH secretion, 2) LH pulses positively to Te secretion, and 3) Te concentrations negatively to the size and number of LH secretory bursts. Validation was by direct pituitary sampling in the horse and sheep. Statistical comparisons disclosed that age decreased the efficacy of each of 1) virtual GnRH outflow (P < 0.01), 2) LH drive of Te secretion (P < 0.01), and 3) total, bioavailable and free Te feedback on GnRH-driven LH secretion (P = 0.015). In contrast, age increased the potency of virtual GnRH feedforward (P = 0.013) and did not affect Te's inhibition of LH pulse frequency. Unexplained variance was less than 10%. Robustness was shown by resampling techniques. Accordingly, competitive silencing of one locus of control and ensemble-based analyses identified triple regulatory deficits in the aging male gonadal axis. The generality of the present integrative model suggests utility in parsing interlinked adaptations in other physiological networks.

Adult↗
PubMed2006

Aging attenuates both the regularity and joint synchrony of LH and testosterone secretion in normal men: analyses via a model of graded GnRH receptor blockade.

Testosterone (T) secretion declines in the aging male, albeit for unknown reasons. From an ensemble perspective, repeated incremental signaling among gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and T is required to maintain physiological androgen availability. Pattern-regularity statistics, such as univariate approximate entropy (ApEn) and bivariate cross-ApEn, provide specific and sensitive model-free measurement of altered multi-pathway control. The present study exploits partial muting of one pathway (GnRH drive) to appraise adaptive regulation of LH and T secretion in young and aging individuals. Analyses comprised 100 paired 18-h LH and T concentration time series obtained in 25 healthy men ages 20-72 yr each administered placebo and three graded doses of a specific GnRH-receptor antagonist. Graded blockade of GnRH drive increased the individual regularity of LH and T secretion and the synchrony of LH-T feedforward and T-LH feedback in the cohort as a whole (P<0.001 for each). However, age markedly attenuated ganirelix-induced enhancement of univariate T orderliness and bivariate LH-T feedback and T-LH feedback synchrony (P <or= 0.0025). In summary, the present analyses support the thesis that aging disrupts coordinate control of T secretion, LH-T feedforward, and T-LH feedback in healthy men. Thus the experimental strategy of stepwise silencing of an agonistic pathway may have utility in dissecting the bases of altered neurohormonal linkages in other systems.

Adult↗
PubMed2005

Aging in healthy men impairs recombinant human luteinizing hormone (LH)-stimulated testosterone secretion monitored under a two-day intravenous pulsatile LH clamp.

CONTEXT: Testosterone (Te) depletion in aging men in principle could reflect deficits in the hypothalamus, pituitary gland, or testis. Available pharmacological studies of possible failure of Leydig cell steroidogenesis remain inconclusive. OBJECTIVE: The objective of the study was to assess Te secretion in older and young men in response to near physiological LH stimulation. INTERVENTION: Pulsatile i.v. infusion of recombinant human LH was administered for 2 d to stimulate Te secretion during suppression of endogenous LH concentrations with a potent selective GnRH receptor antagonist (ganirelix). SUBJECTS/CONTEXT: Healthy older (aged 60-73 yr, n = 8) and young (19-30 yr, n = 13) men were studied in an academic setting. MEASURES: Pulsatile LH and Te concentrations on the second day of exogenous LH stimulation were measured. RESULTS: Serum ganirelix concentrations and infused LH pulse increments were similar by age. In contrast, older subjects manifested: 1) reduced mean Te concentrations (P = 0.016), Te peak heights (P = 0.014), increments (P = 0.010), summed areas (P < 0.013), and interpeak Te concentrations (P = 0.023); 2) decreased Te to LH concentration ratios (P = 0.002); 3) diminished LH-Te feed-forward synchrony (P = 0.020); and 4) a blunted amplitude (P = 0.036) and advanced phase (P = 0.013) of diurnal Te rhythms. CONCLUSION: A novel regimen of pulsatile LH stimulation for 48 h during GnRH receptor blockade unmasks deficits in pulsatile, basal, synchronous, and nyctohemeral Te secretion in healthy older men. These findings do not exclude concomitant defects in GnRH outflow and/or Te-negative feedback in the aging male.

Adult↗
PubMed2005

Age-specific changes in the regulation of LH-dependent testosterone secretion: assessing responsiveness to varying endogenous gonadotropin output in normal men.

Pulsatile and thus total testosterone (Te) secretion declines in older men, albeit for unknown reasons. Analytical models forecast that aging may reduce the capability of endogenous luteinizing hormone (LH) pulses to stimulate Leydig cell steroidogenesis. This notion has been difficult to test experimentally. The present study used graded doses of a selective gonadotropin releasing hormone (GnRH)-receptor antagonist to yield four distinct strata of pulsatile LH release in each of 18 healthy men ages 23-72 yr. Deconvolution analysis was applied to frequently sampled LH and Te concentration time series to quantitate pulsatile Te secretion over a 16-h interval. Log-linear regression was used to relate pulsatile LH secretion to attendant pulsatile Te secretion (LH-Te drive) across the four stepwise interventions in each subject. Linear regression of the 18 individual estimates of LH-Te feedforward dose-response slopes on age disclosed a strongly negative relationship (r = -0.721, P < 0.001). Accordingly, the present data support the thesis that aging in healthy men attenuates amplitude-dependent LH drive of burst-like Te secretion. The experimental strategy of graded suppression of neuroglandular outflow may have utility in estimating dose-response adaptations in other endocrine systems.

Adult↗
PubMed2005

Graded inhibition of pulsatile luteinizing hormone secretion by a selective gonadotropin-releasing hormone (GnRH)-receptor antagonist in healthy men: evidence that age attenuates hypothalamic GnRH outflow.

Healthy older men manifest concomitant hypoandrogenemia and attenuation of LH pulse size. Because exogenous GnRH remains effective, a plausible intuition is that aging reduces hypothalamic GnRH secretion, thus mediating relative hypogonadotropic hypogonadism. To assess the impact of age on central GnRH outflow indirectly, we quantitated graded suppression of pulsatile LH secretion by saline and escalating doses of a potent and selective GnRH-receptor antagonist, ganirelix, in 18 healthy men ages 23-72 yr. The rationale is that ganirelix should reduce the amplitude of LH pulses in proportion to both drug concentration and endogenous GnRH feedforward. To this end, blood was sampled every 10 min for 2 h before and 16 h after sc administration of saline or ganirelix and for 3 additional hours after iv injection of a fixed dose of GnRH (100 ng/kg); concentrations of LH and ganirelix were measured by immunochemiluminometry and RIA, respectively; and pulsatile LH secretion was quantitated by a deconvolution procedure. Log-linear regression analysis was used to estimate the sensitivity of pulsatile LH secretion to inhibition by a unit increase in serum ganirelix concentrations in each subject. Statistical analyses revealed that increasing age markedly attenuated the capability of ganirelix to decrease LH pulse size (viz., r = -0.648; P = 0.004). In contrast, age did not modify the competitive interaction between injected GnRH and ganirelix. These joint outcomes support the clinical hypothesis that age diminishes hypothalamic GnRH outflow without impairing GnRH action in healthy men.

Adult↗
PubMed2005

Inappropriate medication use in the elderly.

Medications are commonly used in the elderly population. Because of a variety of treatments now available, many disease states now have very effective treatment. As a result, our elderly patients often take multiple medications. Due to various changes that occur, the elderly are at increased risk of adverse drug effects and drug toxicity potentially resulting in serious complications. Some medications have a greater potential to cause harm and these should be made aware to those who prescribe to elderly patients. Some of these medications should not be used if at all possible, while others, if used, need to be used with great caution, watching carefully for signs of problems. This article describes a variety of medications which have an increased potential for causing harm in elderly patients and gives alternatives of safer medications consideration.

Aged↗
PubMed2004

Intracerebral hemorrhage associated with use of an imported medication.

INTRODUCTION: The importation of medications is strongly discouraged in the United States. However, with the cost of prescription medications on the rise, an increasing number of patients are seeking alternative ways of obtaining drugs. Although medication errors involving imported drugs have been described in the literature, there is little available information on the prevalence of such problems. CASE SUMMARY: A 74-year-old woman who had been taking warfarin therapy for >2 years presented to the emergency department with new-onset headache. She was found to have a small subdural hematoma on computed tomography and a prothrombin time >120 seconds. Warfarin was stopped and anticoagulation was corrected with fresh frozen plasma. At follow-up testing, the international normalized ratio (INR) continued to be >2 despite vitamin K therapy and the patient's insistence that she had discontinued warfarin. Further evaluation by a hematologist detected warfarin in the blood. Subsequent inspection of her medications revealed unmarked white tablets labeled "phenytoin" that had been dispensed by a pharmacy in another country. The INR normalized after these tablets were discarded and a new prescription for phenytoin was started. DISCUSSION: Application of the Naranjo scale to this case suggested a high likelihood of an adverse drug reaction (ADR). Potential causes of the ADR included the placement of warfarin in a bottle mislabeled "phenytoin" and contamination of phenytoin with warfarin. CONCLUSIONS: Obtaining medications from pharmacies in or by mail order from other countries means that patients miss the opportunity to ask questions and receive counseling from a pharmacist. Physicians and pharmacists should inspect patients' medications to ensure product legitimacy and confirm that the indications, dispensing, and labeling are accurate.

Aged↗
PubMed2004

Inappropriate medications for elderly patients.

The use of medications is common in elderly persons, and this population has the highest risk of medication-related problems. Elderly persons are more susceptible to the effects of various medications for a number of reasons. It is well known that polypharmacy is one of the most serious problems in caring for elderly persons; however, many of these patients continue to receive medications that have an increased risk of causing harm. In 1991, an important article was published about inappropriate medication use in the elderly population. This article raised awareness of the problem and presented explicit criteria for determining which medications were inappropriate for elderly patients residing in long-term care facilities. This list of drugs is still used for evaluating medications taken by elderly persons and for determining whether satisfactory prescribing practices are being used. We reviewed the medications described as inappropriate for elderly persons and searched the scientific literature to determine whether evidence exists to defend or refute the labeling of particular drugs. At times, evidence was difficult to find, and many of the original studies were dated. For most medications listed as inappropriate, we found evidence to support these designations.

Aged↗
PubMed2004

Wound care for elderly patients: advances and clinical applications for practicing physicians.

Chronic ulcers (wounds) are commonly encountered in medical practice, particularly in elderly patients who have chronic medical conditions. Health care providers must be adept at diagnosing chronic ulcers and optimizing medical treatment. We describe the best medical practice for the 4 common types of chronic ulcers: pressure ulcers, ischemic ulcers, venous ulcers, and neuropathic ulcers. We emphasize the importance of nutrition and proper wound care as a foundation for the management of all chronic ulcers. There is a unique therapeutic goal for each chronic ulcer. Pressure relief should be provided for both pressure ulcers and neuropathic ulcers. Ischemic ulcers require revascularization. Patients with venous ulcers need adequate edema control. We outline advances in each of these areas and discuss the newest developments in wound care, including growth factors, hyperbaric oxygen, and vacuum-assisted devices. Chronic ulcers in elderly patients can heal with proper diagnosis and good medical care.

Aged↗
PubMed2004

Preventive health care in the elderly population: a guide for practicing physicians.

Preventive medicine provides important benefits to all persons, including older adults; however, these benefits may be seen more clearly in younger adults than in older persons. Smoking cessation, proper nutrition, exercise, and immunizations are important regardless of age. The prevalence of illness increases as we age; at the same time, life expectancy decreases. All physicians and patients should consider the potential benefits of screening and treatment vs conservative management. We discuss lifestyle recommendations such as smoking cessation, exercise, and good nutrition, as well as the role of screening for cardiovascular disease, cancer, and sensory and other disorders. These recommendations are derived from evidence-based guidelines when available; issues not associated with established guidelines are discussed on the basis of best current thinking.

Advance Directives↗