Spectrum of the pulsatile characteristics of LH release in normal men

To assess the spectrum of LH pulse characteristics in normal men, blood samples from 36 individuals were drawn at 20-minute intervals for 8 hours. The subsequent immunoactive LH concentrations were analyzed by computer algorithms to delineate the frequency and amplitude characteristics of pulsatile LH secretion. The absolute range for LH pulse frequency estimated by a modified threshold method was 1-6 pulses/8 hr, with a mean (+/- SEM) of 3.36 +/- 0.17 (median -3)pulses/8 hr. The distribution differed significantly from a Gaussian pattern. The mean LH pulse amplitude expressed as a percent increase above nadir was 92.1 +/- 6.1 (median-91.5%). When LH pulse amplitude was defined as an increment (mIU/ml) above nadir, the mean value was 5.13 +/- 0.4 (median -4.8) mIU/ml. These two expressions of amplitude were positively correlated (P less than 0.01), while the incremental (mIU/ml) pulse amplitude correlated inversely with pulse frequency (P less than 0.01). To examine the influence of more intensified rates of venous sampling on the spectrum of LH pulse properties, blood was sampled at 4-minute intervals for 8 hours in a subgroup of 13 men. Under these conditions, estimated LH pulse frequency was significantly higher, with a mean of 10.31 +/- 1.87 (median -9) pulses/8 hr compared with 20-minute sampling in the same individuals (P less than 0.001). Although the estimates of LH pulse frequency at 4-minute and 20-minute sampling intervals were significantly correlated (P less than 0.01), the dispersion of the LH pulse frequency estimates was considerably larger at more rapid rates of sampling. There was an absolute range of 2-20 pulses/8 hr for the 4-minute sampling, and 1-6 pulses/8 hr for the 20-minute sampling in the same individuals. This increase in LH pulse frequency and the broader dispersion of the range of frequencies estimated at 4-minute compared with 20-minute sampling intervals were confirmed using either another pulse detection algorithm, or separate criteria designed to adjust false-positive error rates in relation to sampling intensity. It was concluded that eugonadal men exhibit a broad spectrum of pulsatile LH characteristics, and the range of LH pulse attributes is even greater at more intensive rates of venous sampling. The results of this study in normal men demonstrate that a wider dispersion of physiologic LH pulse characteristics must be recognized in man.(ABSTRACT TRUNCATED AT 400 WORDS)     

Nature of alpha subunit secretion in men: circadian rhythms, pulsatile release and secretory profiles

Alpha subunit complements LH as a marker of the activity of the hypothalamic GnRH pulse generator. To characterize episodes of alpha subunit release and to determine if a circadian pattern of alpha subunit secretion is present in man, spontaneous alpha subunit pulsatility was analyzed in six healthy young men by blood sampling every 5 min for 24 h. The resulting alpha subunit concentration time series were analyzed by two statistically based independent peak detection methods, and subjected to Fourier transformation to assess underlying circadian rhythms. Cross-correlation analyses and multiple parameter deconvolution were used to estimate the concordance of spontaneous and exogenous GnRH-stimulated LH and alpha subunit secretion. These analyses revealed that two independent discrete peak detection algorithms yielded similar estimates of spontaneous alpha subunit pulse frequency, namely, 21 +/- 1.1 (Cluster) and 21 +/- 1.5 (Detect) alpha subunit peaks/24 h. Sampling intensity markedly influenced the estimate of endogenous alpha subunit pulse frequency, inasmuch as estimates from 5-min sampling were significantly greater than those of 10-min or 20-min sampling. Fourier transformation unmasked a significant circadian alpha subunit rhythm in all six men, with maximal concentrations at 0836 h and an average amplitude of 28% of the 24-hr mean hormone concentration. Cross-correlation analysis of spontaneous glycoprotein release revealed that serum LH and alpha subunit concentrations were highly cross-correlated when considered simultaneously, but not at various lags. Finally, deconvolution analysis of exogenous GnRH-stimulated glycoprotein release disclosed distinct half-times of alpha subunit and LH clearance with virtually simultaneous underlying secretory bursts. These data indicate that human alpha subunit is secreted in both a circadian and a discrete pulsatile fashion at a pulse frequency that is significantly underestimated at conventional sampling rates. The approximately hourly alpha subunit interpulse interval (68 +/- 4.6 min) is similar to that reported earlier for LH in peripheral blood and for testosterone in gonadal vein blood in healthy men. Moreover, cross-correlation analysis of endogenous GnRH-driven alpha subunit and deconvolution analysis of exogenous GnRH-stimulated alpha subunit and LH secretion suggest that these glycoproteins are secreted virtually simultaneously, but have significantly different endogenous clearance properties. The remarkably similar in vivo pulse frequencies for alpha subunit, LH, and testosterone in man suggest that the release of these three hormones is coordinately regulated.     

健康成年男子黄体生成素脉冲释放分析

对７名健康男子每１０分钟采血一次，历时２４小时，测定血清ＬＨ浓度并进行脉冲分析。结果平均ＬＨ脉冲频率为１６．９±２．１次／２４ｈ，周期为８７±ｌ０ｍｉｎ／次，脉冲间期为３０～３００分钟不等，幅度为１．０±０．６ＩＵ／Ｌ。采血间期为５分钟的另外３名健康男子１２小时ＬＨ脉冲频率为１０．３±０．９次，周期为６９±８分钟，间期为６２±３７分钟，幅度为１３±０．４ＩＵ／Ｌ。采血间期和设定的脉冲阈值不同对ＬＨ脉冲频率和脉冲周期均有影响，但对平均浓度和脉冲幅度的影响不明显     

Pulsatile secretion of gonadotropins and prolactin in male marathon runners. Relation to the endogenous opiate system

We tested the hypothesis that sustained, strenuous physical training alters the neuroendocrine regulation of pulsatile gonadotropin and/or prolactin secretion in men. Blood was sampled at 20-minute intervals over 8 hours in five endurance-trained men after a 10-15 mile run in the middle of the active training season, and in 11 nonendurance trained normal controls. In these two groups, basal patterns of physiologically pulsatile secretion of LH, FSH, and prolactin (PRL) were not significantly different in relation to the following parameters: mean serum concentration of each of the three hormones (N = 25 samples); areas under the hormone concentration vs. time curves; fractional, incremental, and absolute pulse amplitudes; and pulse frequency, or periodicity. To test for enhanced suppressive effects of endogenous opiates in trained male marathon runners, subjects were administered the potent opiate-receptor antagonist, naltrexone (1 mg/kg). This antagonist significantly stimulated pulsatile LH secretion by increasing mean serum LH values from 10.94 to 13.58 mIU/ml (P = 0.007); area under the LH concentration vs. time curve increased from 5370 to 6510 mIU/ml X 8 hours (P = 0.05) and, pulse frequency rose from 2.8 to 4.9 pulses/8 hours (P = 0.006). Naltrexone also enhanced pulse frequency of FSH secretion from 3.4 to 5.4 pulses/8 hours (P = 0.009), but did not alter serum prolactin concentrations. None of these responses differed significantly from those in normal sedentary controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulse pattern of luteinizing hormone (LH) in patients with varicocele: a preliminary report

Serum concentrations of LH were measured every 20 minutes for 6 hours in 4 varicocele patients and 4 control subjects. In both groups, a pulsatile pattern of LH secretion was observed. Also in the two groups, LH pulse rate (2-5/6 hour) and amplitude (23.5-61%) were identical. These findings suggest that Gonadotrophin releasing hormone (Gn RH) and LH secretions have no role in the deranged sperm parameters often found in infertile men with varicocele.     

Effects of short-term stimulation of serotoninergic pathways on the pulsatile secretion of luteinizing hormone in the absence and presence of acute opiate-receptor blockage

To investigate the role of the serotoninergic system in regulating pulsatile gonadotropin secretion in man, we tested the influences of a novel selective serotonin re-uptake inhibitor (fluoxetine HCl) on episodic LH release in men. Spontaneous LH pulsatility was assessed by computerized analysis of serial LH concentrations measured in blood samples withdrawn at 10 min intervals for 24 h. Possible alterations in pituitary responsiveness were tested by administering three consecutive two-hourly intravenous pulses of GnRH (10 micrograms, 10 micrograms, and 100 micrograms). The effects of fluoxetine (20 mg orally three times daily for one wk) were assessed in a double-blind, placebo-controlled design. Compared with the placebo, fluoxetine elicited no changes in 24 h mean serum LH concentrations, LH pulse characteristics (Cluster analysis), or LH secretion and clearance parameters assessed in response to exogenous GnRH administration (deconvolution analysis) in the presence of normal opiatergic tone (nine healthy young men), and during acute blockade of the opiatergic system (seven young men treated with the mu-opiate receptor antagonist, naltrexone). In summary, a selective enhancer of serotoninergic activity (fluoxetine HCl) does not affect pulsatile LH release basally or in the presence of acute inhibitory opiatergic tone. Since this probe does modify prolactin secretion in man, we conclude that stimulation of the serotoninergic system by this selective neuroendocrine probe shows no demonstrable coupling between the serotoninergic and the opiatergic pathways that modulate pulsatile LH release in man.     

Long-term effects of a short course of neoadjuvant luteinizing hormone-releasing hormone analogue and radical radiotherapy on the hormonal profile in patients with localized prostate cancer

OBJECTIVE: To assess whether a long-term follow-up shows any reduction in the level of luteinizing hormone (LH) secretion, which could result in declining testosterone levels in men with localized prostate cancer, as most (96%) men have testosterone levels within the normal range by 1 year after treatment with a short course of LH-releasing hormone analogue (LHRHa) and radiotherapy, and LH and follicle stimulating hormone (FSH) remain high at 1 year after treatment, maintaining the testosterone levels. PATIENTS AND METHODS: We prospectively evaluated 55 patients who previously had a short course of LHRHa (median 97 days, range 28-167) and radiotherapy for localized prostate cancer. Eligible patients had documented normal testosterone, LH and FSH levels at baseline and at 1-3 years after radiotherapy. LH, FSH and testosterone were then measured at 5 years after treatment. RESULTS: The mean hormone levels before, at 1-3 years and at 5 years after treatment, respectively, were: testosterone (nmol/L), 15.33, 13.98, 12.97; LH (U/L), 5.51, 9.95, 6.95; and FSH (U/L), 7.95, 22.40, 17.00. The decrease in testosterone level at 5 years vs 1-3 years was not statistically significant and was of little clinical relevance (P = 0.057). LH and FSH levels were higher at 1-3 years than at baseline and decreased significantly (P < 0.001) at 5 years towards the baseline value. The decrease in FSH level was less marked than for LH. CONCLUSION: After a short course of LHRHa and radiotherapy, the testosterone level was maintained at 5 years. LH levels decreased towards the baseline value, suggesting recovery of Leydig cell function. FSH levels remained high, suggesting persistent Sertoli cell damage from treatment.     

Impact level of dihydrotestosterone on the hypothalamic-pituitary-leydig cell axis in men

Dihydrotestosterone (DHT) the physiologically most potent androgen cannot be aromatised into oestrogen. DHT is used as a treatment for idiopathic gynaecomastia. In order to investigate the different sites of action of DHT on the hypothalamic-pituitary-testicular axis, two groups of adult men were studied. Group I included 10 gonadotropin-releasing hormone (GnRH)-deficient men who were evaluated before and during a pulsatile infusion of GnRH alone for 2 weeks and then in association with DHT given transdermally at doses used in the treatment of gynaecomastia for further two weeks. Luteinizing hormone (LH) pulsatility was assessed at the end of each step of the study. Plasma LH levels were measured every 15 min. Plasma testosterone (T), DHT, oestradiol (E2), free alpha-subunit (FAS) of glycoproteic hormones and LH bioactivity were measured on pooled plasma samples. Group II included 12 healthy men in whom plasma T, DHT and E2 were measured before and then 24, 48 and 72 h after the injection of 5000 IU hCG alone or in combination with either DHT or the pure anti-androgen nilutamide. Two weeks separated each of the 3 hCG testing. In group I, except for bioactive/immunoreactive (B/I) LH ratio which was unchanged, GnRH treatment induced significant rises (p < 0.01) in all plasma hormone levels, LH pulse amplitude and frequency. During treatment with GnRH+DHT, plasma DHT levels increased up to 16.8 +/- 2.5 nm, while plasma hormone levels, B/I LH ratio, LH pulse amplitude and frequency were similar to those obtained with GnRH alone. In group II, the peak of hCG-induced T rise was not modified by either DHT or nilutamide. In contrast, DHT reduced by 50% (p < 0.01) the E2 peak in response to hCG. These data show that DHT exerts no direct action on the pituitary to retroregulate LH secretion and to modify either B/I LH ratio or FAS secretion. Its reducing effect on LH secretion is likely mediated at the hypothalamic level. DHT does not appear to have a physiological influence on Leydig cells steroidogenesis. Administered at therapeutic doses, DHT directly reduces testicular aromatase activity that combined with its antigonadotropic effect leads to the gain in the symptomatic treatment of gynaecomastia.     

Peripheral hemodynamic stability during prolonged anesthesia in the rat

The present study tests the hypothesis that peripheral hemodynamics in the rat femoral artery remain relatively stable during 3 hours of general anesthesia. Hemodynamic variables (pulse period, maximal centerline velocity, lumen diameter, and mean volumetric flow) were measured by the 20 MHz-pulsed ultrasonic Doppler velocimeter method at 30-minute intervals. The hemodynamic variables were not statistically different during the duration of the study. The mean values were pulse period 160 +/- 2 msec, maximal centerline velocity 37.0 +/- 1.9 cm/sec, lumen diameter 0.94 +/- 0.03 mm, and mean volumetric flow 1.92 +/- 0.19 cc/min.     

Specific regulatory actions of dihydrotestosterone and estradiol on the dynamics of FSH secretion and clearance in humans

The authors investigated immunoactive and bioactive follicle-stimulating hormone (FSH) secretion and clearance in six healthy young men during steady-state infusions of vehicle (basal, B, 28 hours), dihydrotestosterone (DHT, 4.5 days), or estradiol (4.5 days) accompanied by blood sampling at 10-minute intervals for 28 hours. Serum FSH concentrations were assayed by a two-site immunoradiometric assay (IRMA) and two separate in vitro bioassays (rat granulosa and Sertoli cell systems). FSH measurements included: 24-hour mean serum concentrations (IRMA and bioassay), multiple-parameter deconvolution of 24-hour pulsatile FSH time series and FSH release in response to exogenous gonadotropin-releasing hormone (GnRH) boluses (IRMA) to assess secretion and clearance, and circadian serum FSH concentration rhythms by cosinor analysis (IRMA). We found: 1) a significant decrease in 24-hour mean IRMA FSH concentrations during DHT infusion while both in vitro estimates of FSH bioactivity were unchanged; 2) significant decreases in the mass of IRMA FSH secreted per 24 hours during DHT infusion; 3) significant decreases in the IRMA FSH half-life during estradiol infusion without any change in FSH interpulse interval; 4) no steroidal effects on FSH secretory responses to exogenous GnRH; and 5) abolition of basal circadian FSH rhythms during sex-steroid infusions. Based on these findings, we conclude that steady-state sex-steroid hormone infusions selectively alter IRMA FSH secretion and clearance without affecting IRMA FSH pulse frequency or mean concentrations of bioactive FSH.     

Alterations in the pulsatile properties of gonadotropin secretion in alcoholic men

The functional characteristics of the hypothalamic-pituitary-testicular axis were examined quantitatively in 10 chronic alcoholic men without hepatic dysfunction or clinical nutritional deficiencies. Spontaneous gonadotropin pulsatility was analyzed in blood sampled every 20 minutes over a 24-hour period 3 to 16 days after abstinence from alcohol and again 29 to 39 days later. The numbers of LH and FSH pulses per 24 hours were normal in these alcoholic men compared with controls. However, we found increased mean 24-hour concentrations of immunoactive LH (P = 0.012) and FSH (P = 0.018), increased peak heights for LH (P = 0.035) and FSH (P = 0.004), decreased fractional LH (P = 0.002) and FSH (P = 0.044) pulse amplitudes and increased interpulse valley mean LH (P = 0.010) and FSH (P = 0.018) concentrations. Serum levels of total testosterone, total estradiol and estrone were normal, whereas concentrations of free testosterone and free estradiol were increased. Pituitary release of LH and FSH was normal in response to low (5-micrograms) and high (95-micrograms) doses of GnRH given intravenously. The present observations indicate that in chronically alcoholic men, acute abstinence from ethanol is associated with elevated circulating concentrations of immunoactive gonadotropins in the presence of intact spontaneous gonadotropin pulsatility, preserved pituitary responsiveness to exogenous GnRH, and increased concentrations of free testosterone and free estradiol. Such findings are consistent with alterations in the endogenous feedback actions of sex steroid hormones in this setting.     

The pattern of LH release in the adult ram influences the testicular steroidogenic response to individual LH pulses and is regulated by testosterone negative feedback

Two experiments were conducted with adult intact rams (approximately 58 kg in body weight) in the nonbreeding season to investigate interrelationships between LH and testosterone secretion. In Experiment 1, LH pulse frequency was increased from approximately two to six peaks per 8 hours (for 56 hours) by injecting (iv) 10 micrograms NIH-LH-S18 every 80 minutes. Induction of a breeding season peak frequency produced a progressive 3-fold increase (P less than 0.01) in mean serum testosterone levels to values during the last 8 hours of treatment (12.6 +/- 1.2 ng/ml) that were 50% of those in the fall. In response to LH pulsing, testosterone peak amplitude increased (P less than 0.05) from 3.5 +/- 0.8 ng/ml to 6.7 +/- 0.7 ng/ml. In Experiment 2, the mean testosterone level was increased to breeding season values (for 96 hours) by injecting (im) 5 mg testosterone every 4 hours. Mean LH levels and LH peak frequency were decreased (approximately 70%, P less than 0.01) following 36 hours of treatment, and the LH response to exogenous GnRH was decreased (approximately 45%, P less than 0.01) by the final 4 hours Results indicate that for rams in the nonbreeding season, the testicular steroidogenic response to individual LH pulses is enhanced when pulse frequency is increased. When blood testosterone is elevated to breeding season levels, LH pulse frequency is severely impaired, while pituitary responsiveness to GnRH is diminished, as in the fall.     

Quantification of pulsatile flow during cardiopulmonary bypass to permit direct comparison of the effectiveness of various types of "pulsatile" and "nonpulsatile" flow

The relative merits of adding a "pulsatile" component to flow during cardiopulmonary bypass (CPB) has long generated controversy, the resolution of which has been hampered by lack of quantification of the "pulsatility" delivered by different devices. The present experimental series had two goals: to quantify the "pulsatility" of blood flow during CPB in terms of pulse rate and pulsatility index (PI) and to examine which aspects of a "pulsed flow" provide clinical benefits. A flow waveform can be expressed in terms of its baseline rate and its PI, the sum of the square of its harmonics components divided by the square of the mean flow. We used PI to quantify the pulsatility of blood flow in the descending thoracic aorta and used changes in the serum lactate level as an indication of end organ flow. In one experimental series seven adult mongrel dogs were placed on roller pump CPB at a constant flow of 100 ml/kg/min. After a 20-minute stabilization period a roller pump wave and three different pulse shapes (generated by a computer-controlled hydraulic pump) were evaluated for 15 minutes each. The pulse wave shapes were graded, with C being the sharpest and A the least sharp. In a second series six other dogs were placed on CPB and were subjected to roller pump perfusion and three pulse waves of identical shape but at different rates. The results indicated that a combination of a minimum PI of 1.88 and a minimum rate of 80 bpm were necessary to significantly reduce lactate production as compared with roller pump perfusion. Thus the same mean flow can have very different physiologic effects depending on how it is delivered. This quantification method permits direct comparison of different "pulsatile waveforms" and provides a means for identification of optimal pulsatile flow.     

Luteinizing hormone pulse frequency and amplitude in azoospermic,oligozoospermic and normal fertile men in Turkey

AIM: To investigate the LH pulse frequency and amplitude in azoospermic and oligozoospermic patients and to compare them with normal fertile subjects. METHODS: In this controlled clinical study, 10 normal fertile male volunteers and 20 infertile patients (10 oligozoospermic and 10 azoospermic) were enrolled. Blood samples were taken every 30 minutes for 12 hours. FSH, LH and T levels were determined. LH was observed at all the blood samples, but FSH and testosterone only at the first, middle and last samples. RESULTS: The mean LH levels were significantly different between all the groups, but there was no statistical difference in the FSH levels between the fertile and oligozoospermic groups. The mean LH levels increased from the fertile towards the azoospermic groups (P<0.01). The LH pulse amplitude and frequency were significantly different between all the 3 groups. The former increased while the latter decreased from the fertile to the azoospermic groups. The T levels were different statistically only between the fertile and the azoospermic groups. CONCLUSION: The more prominent is the testicular defect, the lower will be the LH pulse frequency and the higher the amplitude.     

Changes in intratesticular testosterone, cytoplasmic androgen receptors and ABP content of the ram testis after a single endogenous pulse of LH

The effects of an endogenous LH pulse on the testicular concentration of testosterone, cytoplasmic androgen receptor content and androgen binding protein (ABP) content was studied in rams. Blood was collected from 36 rams for at least 14 h and their testes then removed. Animals were then grouped according to the interval from their last LH pulse and the time of slaughter. The concentration of testosterone in the testis was highest during the first h following the LH pulse and returned to its baseline within 5 h. There was a 60% reduction in the testicular content of cytoplasmic androgen receptors at 3 h after the LH pulse, followed by slow replenishment. The testicular content of ABP was highest at 4 h after the LH pulse. It is in the testis concluded that the pulsatility of LH and testosterone induces a pulsatile translocation of cytoplasmic androgen receptors.     

Luteinizing hormone pulsatility in men with damage to the germinal epithelium

Bioactive-LH (B-LH) was measured in plasma by in-vitro bioassay and immunoactive-LH (I-LH) by immunoassay at 10 min intervals for 6 h in five men after standard chemotherapy for Hodgkin's disease. Eleven normal men acted as controls. Follicle-stimulating hormone (FSH) was markedly raised in the treated patients (mean +/- SEM; 12.8 +/- 2.8 vs. 2.7 +/- 0.4 IU l-1, P less than 0.006) reflecting damage to the germinal epithelium. Bioactive (27.4 +/- 2.8 vs. 12.9 +/- 1.3 IU l-1) and I-LH (9.6 +/- 2.0 vs. 4.9 +/- 0.4 IU l-1) were elevated (P less than 0.006) in the patient group whilst testosterone levels (24.0 +/- 3.8 vs. 19.6 +/- 2.4 nmol l-1) were normal. The testosterone I-LH ratio, a putative index of Leydig cell dysfunction, was negatively correlated with FSH levels (r = -0.85, P less than 0.02). Bioactive and I-LH pulse peak amplitude were elevated, as were pulse maxima (P less than 0.05). In contrast, B-LH pulse frequency was similar between the patients (2 pulses per 6 h) and controls (median 2, range 1-3 pulses per 6 h) as was the I-LH pulse frequency (median 2, 1-2 pulses per 6 h in both groups). The mean B:I LH ratios were similar (2.94 +/- 0.09 vs. 2.63 +/- 0.14) in both groups, although the inter-pulse B:I ratio was increased (P less than 0.007) in the patient group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diurnal variations of pituitary and testicular hormones in paraplegic men

The effect of the neuro-spinal cord injury upon testicular physiology was evaluated in six adult paraplegic (PPG) men by measuring the circulating levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), androstenedione, testosterone, and dihydrotestosterone every 4 hr throughout a 24-hr period. Three PPG men were studied within the first 3 months (acute period) and the other three patients 39-79 months (stabilized period) after trauma. Hormonal values were compared with eight age-matched normal adult males. Plasma FSH and LH were constantly above normal concentrations regardless of the sampling time and period of observation, whereas prolactin was higher than normal only during the first two months after trauma, returning to normal afterwards. Plasma androgens were consistently below normal during the first 3 months after injury, and returned toward normal thereafter. There may be a direct relationship between the time elapsed after the spinal cord injury and the plasma androgens concentrations. A possible role of PRL in testicular steroidogenesis is suggested.     

Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans

In health, insulin is secreted in discrete pulses into the portal vein, and the regulation of the rate of insulin secretion is accomplished by modulation of insulin pulse mass. Several lines of evidence suggest that the pattern of insulin delivery by the pancreas determines hepatic insulin clearance. In previous large animal studies, the amplitude of insulin pulses was related to the extent of insulin clearance. In humans (and in large animals), the amplitude of insulin oscillations is approximately 100-fold higher in the portal vein than in the systemic circulation, despite only a fivefold dilution, implying preferential hepatic extraction of insulin pulses. In the present study, by direct hepatic vein sampling in healthy humans, we sought to establish the extent of first-pass hepatic insulin extraction and to determine whether the pattern of insulin secretion (insulin pulse mass and amplitude) dictates the hepatic insulin clearance and thereby delivery of insulin to extrahepatic insulin-responsive tissues. Five nondiabetic subjects (two men and three women, mean age 32 years [range 25-39], BMI 24.9 kg/m(2) [21.2-27.1]) participated. Insulin and C-peptide delivery from the splanchnic bed was measured in basal overnight-fasted state and during a glucose infusion of 2 mg . kg(-1) . min(-1) by simultaneous sampling from the hepatic vein and an arterialized vein along with direct estimation of splanchnic blood flow. Fractional insulin extraction was calculated from the difference between the C-peptide and insulin delivery rates from the liver. The time patterns of insulin concentrations and hepatic insulin clearance were analyzed by deconvolution and Cluster analysis, respectively. Cross-correlation analysis was used to relate C-peptide secretion and insulin clearance. Glucose infusion increased peripheral glucose concentrations from 5.4 +/- 0.1 to 6.4 +/- 0.4 mmol/l (P < 0.05). Likewise, insulin and C-peptide concentrations increased during glucose infusion (P < 0.05). Hepatic insulin clearance increased with glucose infusion (1.06 +/- 0.18 vs. 2.55 +/- 0.38 pmol . kg(-1) . min(-1); P < 0.01), but fractional hepatic insulin clearance was stable (78.2 +/- 4.4 vs. 84 0. +/- 3.9%, respectively; P = 0.18). Insulin secretory-burst mass rose during glucose infusion (P < 0.05), whereas the interburst interval remained unchanged (4.4 +/- 0.2 vs. 4.5 +/- 0.3 min; P = 0.36). Cluster analysis identified an oscillatory pattern in insulin clearance, with peaks occurring approximately every 5 min. Cross-correlation analysis between prehepatic C-peptide secretion and hepatic insulin clearance demonstrated a significant positive association without detectable (<1 min) time lag. Insulin secretory-burst mass strongly predicted insulin clearance (r = 0.81, P = 0.0043). In conclusion, in humans, approximately 80% of insulin is extracted during the first liver passage. The liver rapidly responds to fluctuations in insulin secretion, preferentially extracting insulin delivered in pulses. The mass (and therefore amplitude) of insulin pulses traversing the liver is the predominant determinant of hepatic insulin clearance. Therefore, through this means, the pulse mass of insulin release dictates both hepatic (directly) as well as extra-hepatic (indirectly) insulin delivery. These findings emphasize the dual role of the liver and pancreas and their relationship mediated through magnitude of insulin pulse mass in regulating the quantity and pattern of systemic insulin delivery.     

Physiologic responses to electrically assisted and frame-supported standing in persons with paraplegia

BACKGROUND: Systems of functional electrical stimulation (FES) have been demonstrated to enable some persons with paraplegia to stand and ambulate limited distances. However, the energy costs and acute physiologic responses associated with FES standing activities have not been well investigated. OBJECTIVE: To compare the physiologic responses of persons with paraplegia to active FES-assisted standing (AS) and frame-supported passive standing (PS). METHODS: Fifteen persons with paraplegia (T6-T11) previously habituated to FES ambulation, completed physiologic testing of PS and AS. The AS assessments were performed using a commercial FES system (Parastep-1; Altimed, Fresno, Calif); the PS tests used a commercial standing frame (Easy Stand 5000; Altimed, Fresno, Calif). Participants also performed a peak arm-cranking exercise (ACE) test using a progressive graded protocol in 3-minute stages and 10-watt power output increments to exhaustion. During all assessments, metabolic activity and heart rate (HR) were measured via open-circuit spirometry and 12-lead electrocardiography, respectively. Absolute physiologic responses to PS and AS were averaged over 1-minute periods at 5-minute intervals (5, 10, 15, 20, 25, and 30 minutes) and adjusted relative to peak values displayed during ACE to determine percentage of peak (%pk) values. Absolute and relative responses were compared between test conditions (AS and PS) and across time using two-way analysis of variance. RESULTS: The AS produced significantly greater values of VO2 (43%pk) than did PS (20%pk). The mean HR responses to PS (100-102 beats per minute [bpm] throughout) were significantly lower than during AS, which ranged from 108 bpm at 5 minutes to 132 bpm at test termination. CONCLUSION: Standing with FES requires significantly more energy than does AS and may provide a cardiorespiratory stress sufficient to meet minimal requirements for exercise conditioning.     

A comparison of transcutaneous PO2 in patients sedated with diazepam-fentanyl or midazolam-fentanyl

Fifty oral and maxillofacial surgery patients undergoing outpatient surgical removal of third molars under intravenous conscious sedation comprised the study group. All patients received 1 microgram/kg of fentanyl prior to receiving either diazepam or midazolam. The results show no statistically significant differences in blood pressure or pulse over time between the two groups, nor was there a statistically significant difference between the transcutaneous PO2 responses of the groups. However, a statistically significant time effect as well as a group by time interaction was present. Both groups show respiratory depression at the 8- and 10-minute time intervals. The use of supplemental oxygen and monitoring of respiration is recommended with the use of these drug combinations.