Citations

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.

Background: The relationship between circulating ACTH levels and cortisol secretion in Cushing's disease is not precisely known. Hypothesis: Chronic ACTH hyperstimulation leads to decreased adrenal potency and is restored after normalization of ACTH secretion. Subjects: Subjects included 20 patients with Cushing's disease, eight patients in long-term remission, and 36 healthy controls. Outcomes: ACTH and cortisol secretion rates and analytical dose-response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH-cortisol profiles were evaluated. Results: Both basal and pulsatile secretion of ACTH and cortisol were increased in patients with active disease but normal in cured patients. ACTH, but not cortisol pulse frequency, was amplified in patients and restored after successful surgical treatment. ACTH EC50, an inverse measure of potency, was higher during pulse onset in Cushing's disease (59 ± 7.4 ng/liter) than in controls (20 ± 3.7 ng/liter) (P < 0.0001) and remitted patients after surgery [15 ± 3.2 ng/liter, P value not significant (NS) vs. controls] and during pulse recovery phases [128 ± 18 (P <0.0001), 70 ± 8.4, and 67 ± 17 ng/liter (NS vs. controls), respectively]. Efficacy was increased in active disease and normalized after surgical treatment [patients, 38 ± 8.3 nmol/liter · min, vs. controls, 21 ± 2.3 nmol/liter · min (P <0.0001), and cured patients, 15 ± 3.2 nmol/liter · min (NS vs. controls)]. Sensitivity to endogenous ACTH did not differ among the three groups. Conclusion: The adrenal gland in Cushing's disease exhibits decreased responsiveness to submaximal ACTH drive and amplified efficacy, with unchanged sensitivity. These target-gland abnormalities are reversible in long-term remission after pituitary surgery.

Negative-feedback (inhibitory) and positive-feedforward (stimulatory) processes regulate physiological systems. Whether such processes are themselves rhythmic is not known. Here, we apply cross-approximate entropy (cross-ApEn), a noninvasive measurement of joint (pairwise) signal synchrony, to inferentially assess hypothesized circadian and ultradian variations in feedback coupling. The data comprised simultaneous measurements of three pituitary and one peripheral hormone (LH, FSH, prolactin, and testosterone) in 12 healthy men each sampled every 10 min for 4 days (5,760 min). Ergodicity, due to the time series stationarity of the measurements over the 4 days, allows for effective estimation of parameters based upon the 12 subjects. Cross-ApEn changes were quantified via moving-window estimates applied to 4-day time series pairs. The resultant ordered windowed cross-ApEn series (in time) were subjected to power spectrum analysis. Rhythmicity was assessed against the null hypothesis of randomness using 1,000 simulated periodograms derived by shuffling the interpulse-interval hormone-concentration segments and redoing cross-ApEn windows and spectral analysis. By forward cross-ApEn analysis, paired LH-testosterone, LH-prolactin, and LH-FSH synchrony maintained dominant rhythms with periodicities of 18–22.5, 18, and 22.5 h, respectively (each P < 0.001). By reverse (feedback) cross-ApEn analysis, testosterone-LH, testosterone-prolactin, and testosterone-FSH synchrony cycles were 30, 18, and 30–45 h, respectively (each P ≤ 0.001). Significant 8- or 24-h rhythms were also detected in most linkages, and maximal bihormonal synchrony occurred consistently at ∼0400–0500. Collectively, these analyses demonstrate significant ultradian (<24 h), circadian (∼24 h), and infradian (>24 h) oscillations in pituitary-testis synchrony, wherein maximal biglandular coordination is strongly constrained to the early morning hours.

Although stimulatory (feedforward) and inhibitory (feedback) dynamics jointly control neurohormone secretion, the factors that supervise feedback restraint are poorly understood. To parse the regulation of growth hormone (GH) escape from negative feedback, 25 healthy men and women were studied eight times each during an experimental GH feedback clamp. The clamp comprised combined bolus infusion of GH or saline and continuous stimulation by saline GH-releasing hormone (GHRH), GHRP-2, or both peptides after randomly ordered supplementation with placebo (both sexes) vs. E2 (estrogen; women) and T (testosterone; men). Endpoints were GH pulsatility and entropy (a model-free measure of feedback quenching). Gender determined recovery of pulsatile GH secretion from negative feedback in all four secretagog regimens (0.003 ≤ P ≤ 0.017 for women>men). Peptidyl secretagog controlled the mass, number, and duration of feedback-inhibited GH secretory bursts (each, P < 0.001). E2/T administration potentiated both pulsatile ( P = 0.006) and entropic ( P < 0.001) modes of GH recovery. IGF-I positively predicted the escape of GH secretory burst number and mode ( P = 0.022), whereas body mass index negatively forecast GH secretory burst number and mass ( P = 0.005). The composite of gender, body mass index, E2, IGF-I, and peptidyl secretagog strongly regulates the escape of pulsatile and entropic GH secretion from autonegative feedback. The ensemble factors identified in this preclinical investigation enlarge the dynamic model of GH control in humans.

BackgroundThe cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch‐to‐batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.MethodsThe program is open for laboratories using commercially available kits for Aβ, T‐tau, or P‐tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Mölndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples.ResultsForty laboratories participated. Twenty‐six used INNOTEST enzyme‐linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO‐BIA AlzBio3 kit (both measure Aβ‐(1‐42), P‐tau(181P), and T‐tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN‐42, AβN‐40, and AβN‐38) or T‐tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within‐laboratory precisions differed considerably between biomarkers within individual laboratories.ConclusionsMeasurements of CSF AD biomarkers show large between‐laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.

A primary arteriopathy is suspected in most patients with spontaneous dissections of the carotid artery, although the nature of this arteriopathy usually remains elusive. Angiographic changes of fibromuscular dysplasia (FMD), however, are found in 10% to 20% of patients with carotid dissections. A 26-year-old woman with Marfan's syndrome presented with bilateral amaurosis fugax after surgical repair of an aortic dissection. Angiography revealed a dissection extending from the ascending aorta into the right internal carotid artery and, separate from the aortic dissection, a dissection of the left internal carotid artery. After surgery, microscopic examination of the right carotid artery revealed a medial dissection but no evidence of an underlying arteriopathy, while the left internal carotid artery displayed the typical features of FMD. Eighteen months later the patient died after resection of a large thoracoabdominal aortic dissecting aneurysm. Microscopic examination of the aorta revealed moderately extensive cystic medial necrosis. Carotid dissections associated with Marfan's syndrome may be the result of an extension of an aortic dissection or occur isolated from the aorta, even in the same patient. The occurrence of FMD in a patient with Marfan's syndrome in conjunction with previous reports of FMD in a variety of connective tissue disorders suggests that FMD, like cystic medial necrosis, may be a nonspecific disease entity.

OBJECTIVE In patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known. RESEARCH DESIGN AND METHODS Twelve patients with type 2 diabetes and 13 nondiabetic individuals were examined in the fasting state and after mixed meal ingestion. Deconvolution analyses were performed on insulin and glucagon concentration time series sampled at 1-min intervals. RESULTS Both insulin and glucagon were secreted in distinct pulses, occurring at ∼5-min intervals. In patients with diabetes, postprandial insulin pulse mass was reduced by 74% (P &lt; 0.001). Glucagon concentrations were increased in the patients during fasting and after meal ingestion (P &lt; 0.05), specifically through an increased glucagon pulse mass (P &lt; 0.01). In healthy subjects, the increase in postprandial insulin levels was inversely related to respective glucagon levels (P &lt; 0.05). This relationship was absent in the fasting state and in patients with diabetes. CONCLUSIONS Glucagon and insulin are secreted in a coordinated, pulsatile manner. A plausible model is that the postprandial increase in insulin burst mass represses the corresponding glucagon pulses. Disruption of the insulin–glucagon interaction in patients with type 2 diabetes could potentially contribute to hyperglucagonemia.