Takahashi, Paul

SummaryTestosterone (T) impacts luteinizing hormone (LH) secretion through negative feedback via the androgen receptor (AR) in the hypothalamo‐pituitary system. An untested postulate is that increasing body mass index (BMI), abdominal visceral fat (AVF) or total abdominal fat (TAF) with ageing decreases LH secretion by heightening T negative feedback via AR. This hypothesis was tested in a prospective, randomized double‐blind cross‐over study of 19 healthy men comparing the effects of flutamide, a selective non‐steroidal AR antagonist and placebo administration on basal and pulsatile LH secretion as a function of age and obesity measures. To this end, serum levels of 2‐hydroxyflutamide (2‐OHF), a major active flutamide metabolite, were measured by mass spectrometry, and AVF/TAF quantified by abdominal computerized tomography. Statistical analysis showed that antiandrogen administration elevated 6‐h mean LH concentrations to 5.4 ± 1.3 IU/L compared with 3.3 ± 1.2 IU/L for placebo (p < 10−3), and total T by 35% (p < 10−4). The LH‐T concentration product doubled (p < 10−8). According to deconvolution analysis, flutamide exposure increased total LH secretion (p < 10−3) and pulsatile LH secretion (p = 0.0077), along with LH pulse frequency (p = 0.019). Despite feedback inhibition, the LH‐T product declined as a linear function of AVF (p = 0.021) and TAF (p = 0.017). This was explained by the fact that higher BMI was associated with lower 2‐OHF concentrations (R = −0.562, p = 0.012). In contrast, age was associated with less pulsatile LH secretion (R = −0.567, p = 0.011) even when LH responses were normalized to antiantrogen levels. In conclusion, increased AVF, TAF and BMI predict decreased LH and flutamide blood levels, whereas older age is marked by impaired stimulation of pulsatile LH secretion even when normalized for antiandrogen levels, suggesting different mechanisms of regulation by adiposity and age.

AbstractWe provide a mini‐review of how biobanks can support clinical genetics in the era of personalized medicine. We discuss types of biobanks, including disease specific and general biobanks not focused on one disease. We present considerations in setting up a biobank, including consenting and governance, biospecimens, risk factor and related data, informatics, and linkage to electronic health records for phenotyping. We also discuss the uses of biobanks and ongoing considerations, including genotype‐driven recruitment, investigations of gene–environment associations, and the re‐use of data generated from studies. Finally, we present a brief discussion of some of the unresolved issues, such as return of research results and sustaining biobanks over time. In summary, carefully designed biobanks can provide critical research and infrastructure support for clinical genetics in the era of personalized medicine.

Telemedicine practitioners are familiar with multiple barriers to delivering care at a distance. Licensing and reimbursement barriers are well known and are being addressed at national and state levels by the American Telemedicine Association. Another telemedicine barrier comes in the form of quality measures for diabetes. Minnesota medical practices are currently being compared on the proportion of their patients with diabetes who have attained goals for blood pressure, low-density lipoprotein cholesterol, and hemoglobin A1C. The quality measure for blood pressure specifically excludes measurements taken by the patient, thus precluding blood pressure telemonitoring as a way to meet the blood pressure goal. To counter this barrier, advocacy in telemedicine is needed so that telemonitoring as a data collection tool is included in quality measures.

Gonadotrophin-releasing hormone (GnRH) pulsatility is required for optimal luteinizing hormone (LH) secretion, but whether LH pulsatility is required for physiological testosterone (T) secretion is not known. To test the postulate that pulses of recombinant human (rh) LH stimulate greater T secretion than continuous infusion of the same dose, a potent selective GnRH antagonist was administered overnight to 19 healthy men ages 18–49 yr. Subjects then received saline or rhLH intravenously continuously or as 6-min pulses intravenously every 1 or 2 h at the same total dose. Blood was sampled every 10 min for 10 h to quantify T responses. For the four interventions, the descending rank order of mean LH and mean T concentrations was 1-h = 2-h rhLH pulses > continuous rhLH > saline ( P < 10−3). Plateau LH and T concentrations correlated positively ( R2 = 0.943, P = 0.029) as did LH concentrations and LH half-lives ( R2 = 0.962, P = 0.019). Percentage pulsatile T secretion assessed by deconvolution analysis (Keenan DM, Takahashi PY, Liu PY, Roebuck PD, Nehra AX, Iranmanesh A, Veldhuis JD. Endocrinology 147: 2817–2828, 2006) was the highest ( P = 0.019), and half-time to attain peak T concentrations was the shortest ( P < 10−6), for 1-h rhLH pulses. Approximate entropy (a pattern-regularity measure) revealed more orderly T secretion for 1- than 2-h rhLH pulses ( P = 0.0076). Accordingly, a pulsatile LH signal, while not obligatory to maintain mean T concentrations, controls the mean plasma LH concentration and determines quantifiable patterns of T secretion. These data introduce the question whether blood T patterns in turn supervise distinctive target-tissue responses.

The long-lived glycoprotein hormone, human chorionic gonadotropin (hCG), downregulates testosterone (T) biosynthesis in vitro and in vivo in animals and humans. The degree to which short-lived pulses of pituitary luteinizing hormone (LH) do so, particularly at physiological concentrations, is not known. We test the hypothesis that continuous LH infusion compared with bolus injections of LH every 1 h or every 2 h overnight downregulates T secretory responses to a subsequent fixed template of three consecutive intravenous pulses of a physiological amount of recombinant human (rh) LH (triple stimulus). Nineteen healthy men ages 18–49 yr each underwent four separate randomly ordered overnight gonadotropin-releasing hormone-receptor antagonist treatments with superimposed intravenous infusions of saline or rhLH (1-h pulses, 2-h pulses, or continuously). Each 12-h infusion protocol was followed by the triple rhLH-pulse stimulus the next morning. During the triple stimulus, basal (nonpulsatile) as well as total (basal plus pulsatile) T secretion was higher after overnight 2- and 1-h rhLH pulses than after continuous rhLH or saline delivery. Approximate entropy, a probabilistic measure of feedforward-induced irregularity of T concentration time series, was higher after 1-h rhLH pulses than after continuous rhLH. Analytical estimation of pulsatile rhLH-T dose-response measures revealed higher T secretory sensitivity and greater rhLH potency (lower EC50) after exposure to 1-h than 2-h rhLH pulses. Collectively, these data indicate that in vivo dynamics of LH-stimulated T secretion under standardized conditions in men depend on the prior time mode of LH delivery in the bloodstream.

Health care provider’s acceptance of telemonitoring is pivotal for implementation. The aim of this study was to determine provider’s feelings about telemonitoring using a qualitative method. In regard to method, we interviewed physicians, nurse practitioners, and registered nurses to explore their attitudes toward telemonitoring. Thematic and content analysis strategies were used to identify core concepts and develop categories for coding interview data. Results reveal that providers view telemonitoring as most appropriate for specific types of patients, especially older patients with chronic medical conditions. Telemonitoring offers reassurance to patients and providers. Some providers expressed concerns about excessive information that at times may not be clinically useful. In conclusion, home telemonitoring provides reassurance to patients and health care providers. Taking provider preferences into consideration when implementing telemonitoring may improve provider acceptance of this form of care.

Direct sampling of the human spermatic veins has disclosed concomitant LH and testosterone (T) pulses, suggesting pulsatile LH concentration-dependent stimulation of T secretion. However, studies to date have examined this hypothesis using only pharmacological stimulation with hCG. The present study tests the hypothesis that age is marked by decreased T secretory responses to repeated near-physiological iv pulses of recombinant human LH administered in a Clinical Translational Science Center. Participants included 92 healthy men aged 18–75 yr with BMI 18–34 kg/m2. The contribution of endogenous LH pulses was minimized by combined injection of a selective GnRH receptor antagonist sc and successive pulses of biosynthetic LH iv. A new analytical dose response model was applied to estimate the properties of exogenous LH's drive of T secretion. Regression of LH-T dose response potency estimates on age showed that the efficacy of pulses of biosynthetic LH progressively decreased with age ( P = 0.014, r = 0.26). Testis sensitivity to exogenous LH pulses also declined with age ( P = 0.011, r = 0.27). Moreover, estimated Leydig cell downregulation by LH pulses rose significantly with age ( P = 0.039, r = 0.22). These outcomes were selective, since the recovery potency of infused LH was not affected by age but was reduced by increasing BMI ( P = 0.011, r = 0.27). Assuming stable bioactivity of infused recombinant human LH, these novel data indicate that factors associated with age and BMI attenuate LH efficacy and testis sensitivity and augment Leydig cell downregulation in healthy men.

Introduction: Telemonitoring is being increasingly used for chronic disease monitoring. Understanding elderly patients' feelings and perspectives toward telemonitoring is important to minimize any barriers to implementation in this population . Methods: Twenty Tele-Era Trial participants completed qualitative interviews assessing opinions about their telemonitoring experience. Participants also rated telemonitoring on burden, communication with clinicians, impact on medical condition knowledge, and confidence in using the monitor . Results: On an average, participants rated telemonitoring as minimally burdensome, rated themselves confident in using the monitor, and positively rated telemonitoring for clinical communication. Qualitative analysis revealed a predominant theme that telemonitoring increases patient awareness of their health and also that telemonitoring prompts action . Conclusion: Elderly patients find home telemonitoring to be an acceptable and satisfying experience that can increase their awareness of their health and provide a sense of safety in their home. Home telemonitoring can lead to earlier evaluation of decline in health status .

Testosterone (T) exerts negative feedback on the hypothalamo-pituitary (GnRH-LH) unit, but the relative roles of the CNS and pituitary are not established. We postulated that relatively greater LH responses to flutamide (brain-permeant antiandrogen) than bicalutamide (brain-impermeant antiandrogen) should reflect greater feedback via CNS than pituitary/peripheral androgen receptor-dependent pathways. To this end, 24 healthy men ages 20–73 yr, BMI 21–32 kg/m2, participated in a prospective, placebo-controlled, randomized, double-blind crossover study of the effects of antiandrogen control of pulsatile, basal, and entropic (pattern regularity) measurements of LH secretion. Analysis of covariance revealed that flutamide but not bicalutamide 1) increased pulsatile LH secretion ( P = 0.003), 2) potentiated the age-related abbreviation of LH secretory bursts ( P = 0.025), 3) suppressed incremental GnRH-induced LH release ( P = 0.015), and 4) decreased the regularity of GnRH-stimulated LH release ( P = 0.012). Furthermore, the effect of flutamide exceeded that of bicalutamide in 1) raising mean LH ( P = 0.002) and T ( P = 0.017) concentrations, 2) accelerating LH pulse frequency ( P = 0.013), 3) amplifying total (basal plus pulsatile) LH ( P = 0.002) and T ( P < 0.001) secretion, 4) shortening LH secretory bursts ( P = 0.032), and 5) reducing LH secretory regularity ( P < 0.001). Both flutamide and bicalutamide elevated basal (nonpulsatile) LH secretion ( P < 0.001). These data suggest the hypothesis that topographically selective androgen receptor pathways mediate brain-predominant and pituitary-dependent feedback mechanisms in healthy men.