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Biomedical subjects

D Heber

Publications and source records attributed to D Heber.

At least 109 records · Page 6Linked to original sources
PubMed1986

Influence of nandrolone decanoate on weight loss in advanced non-small cell lung cancer.

The short term addition of nandrolone decanoate to combination chemotherapy given to patients with unresectable non-small cell lung cancer was evaluated in a randomized, prospective trial. Patients were treated with doxorubicin 50 mg/M2 intravenously, cyclophosphamide 300 mg/M2 intravenously, CCNU 50 mg/M2 orally, vincristine 1.4 mg/M2 intravenously, with and without cisplatin 50 mg/M2 intravenously, all given every 28 days. In addition, patients were randomized to receive either nandrolone decanoate 200 mg intramuscularly weekly for 4 weeks or no additional therapy. Patient age, disease extent, performance score, and pretreatment weight loss were similar in the two treatment arms. Objective antitumor response frequency was comparable on both treatment arms with median survival somewhat longer for patients receiving the androgen (median survival 5.5 months without and 8.2 months with nandrolone decanoate). There was a trend for less severe weight loss on the nandrolone decanoate arm (average weight loss 0.8 +/- 0.15 kg versus 0.21 +/- 0.18 kg, respectively), with half as many patients experiencing weight loss on nandrolone decanoate (25% versus 12%). A separate concurrent study has demonstrated decreased free testosterone levels in 66% of patients with advanced cancer studied prior to chemotherapy treatment, therefore, further prospective studies in which pretreatment testosterone levels are used to guide androgen administration are needed to define more precisely a role for androgen replacement therapy in non-small cell lung cancer.

Anabolic Agents↗
PubMed1986

Metabolic abnormalities in cancer patients: carbohydrate metabolism.

Weight loss in patients with a variety of cancers is associated with a poor prognosis. Consistent abnormalities of carbohydrate metabolism are seen in cancer patients with weight loss and appear to represent derangements in host metabolism that are induced by the presence of cancer. To define therapeutic strategies to improve the poor clinical outcome for patients with cancer cachexia, investigations are under way to define the relationships among glucose metabolism, altered energy expenditure, caloric intake, weight loss, and clinical outcome.

Animals↗
PubMed1985

Metabolic abnormalities in the cancer patient.

Many malnourished patients with cancer fail to gain weight with what appears to be adequate nutritional support. Metabolic abnormalities resulting from remote effects of the tumor on host metabolism have been postulated to increase energy requirements in such cancer patients. In the current study, 44 patients with lung cancer who had significant weight loss (16 +/- 2% of usual body weight) were studied under metabolic ward conditions. Whole body glucose production rates were significantly elevated in cancer patients compared to age-matched healthy controls. Blood glucose levels 2 hours after a standard oral glucose challenge were also significantly increased, but insulin levels were not different at this time. Fasting glucose and insulin levels were not different. Fasting plasma alanine levels were significantly decreased in these patients, while branched-chain amino acids were not different. Increased alanine flux for gluconeogenesis is likely to reflect a basic metabolic abnormality in patients with cancer and could be explained on the basis of a resistance to insulin action in such patients.

Alanine↗
PubMed1985

Identification and partial characterization of gonadotropin-releasing hormone-like factors in human seminal plasma.

Gonadotropin-releasing hormone (GnRH)-like material was measured by radioimmunoassay in acid-ethanol-extracted human seminal plasma using radiolabeled D-[Leu6] GnRH ethylamide as labeled ligand, authentic GnRH as standard, and antibody raised against D-[Lys6] GnRH analog. The mean amount of GnRH-like material measured in the seminal plasma of semen samples with sperm counts greater than 20 X 10(6)/ml was 229.0 +/- 66 pg/ml, with sperm counts less than 20 X 10(6)/ml was 213 +/- 42 pg/ml, and from vasectomized samples was 252 +/- 36 pg/ml. There was no significant difference among the three groups. Scatchard analysis of radioreceptor binding data demonstrated significant displacement of GnRH agonist ligand from castrated male rat pituitary membrane preparations. Ultrafiltration and gel column chromatography of pooled extracted seminal plasma identified two compounds with apparent molecular weights of 2600 and 5000 that differ chemically and immunologically from native GnRH. Further characterization using affinity column chromatography suggests that at least one of these GnRH-like factors is a glycosylated protein.

Chromatography, Gel↗
PubMed1985

Postcastration rise in plasma gonadotropins is blocked by a luteinizing hormone-releasing hormone antagonist.

The dependence of the acute increases in plasma gonadotropins following castration on luteinizing hormone-releasing hormone (LHRH) was assessed with the use of a potent LHRH antagonist [ALHRH; (Nac-L-Ala1,p-Cl-D-Phe2,D-Trp3,6) LHRH]. Blood samples were collected from male and female rats at the time of castration and 2, 4, 8, 12, 24 and 48 h following and plasma gonadotropin levels were determined. Immediately following castration (diestrus I for females) animals received one of the following treatments: females-vehicle, 100 micrograms ALHRH, 50 micrograms estrogen benzoate (EB), or 100 micrograms ALHRH + 50 micrograms EB; males-vehicle, 100 micrograms ALHRH, 500 micrograms testosterone propionate (TP), or 100 micrograms ALHRH + 500 micrograms TP. ALHRH blocked the selective increase in plasma follicle-stimulating hormone (FSH) observed in female rats as well as the parallel increases in both gonadotropins seen in male rats following castration. Administration of EB or ALHRH + EB to females significantly suppressed both gonadotropins compared with control levels. However, EB alone did not completely block the rise in plasma FSH in females. In males, all three treatments significantly suppressed the increases in both gonadotropins when compared with control levels. These data demonstrate that hypothalamic LHRH plays an essential role in the acute elevations of plasma gonadotropins following castration in rats. In addition, these data suggest that the selective rise of FSH in females is dependent on LHRH stimulation of pituitary gonadotropes.

Animals↗
PubMed1985

Lactate, pyruvate, and lactate-to-pyruvate ratio during exercise and recovery.

The pattern of lactate increase and its relation to pyruvate and lactate-to-pyruvate (L/P) ratio were studied during exercise and early recovery in 10 normal subjects for incremental exercise on a cycle ergometer. Gas exchange was measured breath by breath. Lactate and pyruvate were measured by enzymatic techniques. Lactate and log lactate changed only slightly at low levels of O2 uptake (VO2) but both began to abruptly increase at approximately 40-55% of the maximal VO2. However, the point of abrupt increase in pyruvate occurred at higher work rates and the rate of increase was not as great as that for lactate. Thus L/P ratio increased at the same VO2 as the log lactate increase. Following the exercise, pyruvate continued to increase steeply for at least the first 5 recovery min, whereas at 2 min lactate increased only slightly or decreased. Thus arterial L/P ratio reversed its direction of change and decreased toward the resting value by 2 min of recovery. Lactate, as well as L/P ratios, decreased in all subjects by 5 min. This study demonstrates that lactate and pyruvate concentrations increase slightly at low levels of exercise without a change in L/P ratio until a threshold work rate at which lactate abruptly increases without pyruvate. The resulting increase in L/P ratio is progressive as work rate is incremented and abruptly reverses when exercise stops.

Adult↗
PubMed1985

Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in the human male. III. Effects of long term combined treatment with GnRH agonist and androgen.

Chronic treatment with agonist analogs of GnRH results in reversible oligospermia in man, but leads to impotence and decreased libido due to a concomitant fall in serum testosterone (T) concentrations. We, therefore, assessed the effects of combined treatment with a potent GnRH agonist and T on gonadotropins and spermatogenesis in normal men, anticipating that addition of androgen would prevent agonist-induced changes in libido. Seven normal men were treated with 200 micrograms of the GnRH agonist D-(Nal2)6GnRH (GnRH-A), sc, daily for 16 weeks. In addition, 200 mg T enanthate were administered every 2 weeks for the entire 16-week treatment period. Basal LH, FSH, and T concentrations were measured every week during a 5-week control period, daily on treatment days 0, 1-10, 14, 18, 22, 26, and 28, every week thereafter until day 56, and every 2 weeks thereafter for the remainder of the treatment and recovery phases. Detailed analysis of LH and FSH over the 24-h period was performed by multiple blood sampling on days 0, 1, 10, 28, 56, 84, and 112. Semen analyses were performed every week during the control phase and every 2 weeks during the treatment and recovery phases. The mean sperm count declined by 83%, to a nadir of 16.6 +/- 6.2 (+/- SEM) million/ml. One subject had no significant decrease in sperm count. Azoospermia was not achieved in any subject. Basal serum LH concentrations, after an early phase of stimulation, declined to near baseline by day 14. However, basal, 24-h integrated serum LH concentrations, and 24-h urinary LH excretion were not significantly lowered by combined treatment. Bioassayable serum LH concentrations, however, declined significantly from 20.4 +/- 6.3 to 4.5 +/- 0.5 mIU/ml, and the bioassayable to immunoassayable LH ratio decreased from 2.1 +/- 1.0 to 0.7 +/- 0.1 after 16 weeks of GnRH-A treatment. Basal and 24-h integrated FSH concentrations, after an initial period of stimulation, declined progressively to baseline by days 5-6 and were significantly below baseline by day 112. Serum T concentrations did not fall into the hypogonadal (less than 250 ng/dl) range in any subject at any time during the treatment period. After discontinuation of treatment, LH, FSH, and sperm counts returned to normal in all subjects. Thus, single daily injection of GnRH-A and T failed to predictably induce azoospermia in normal men over the 16-week treatment period.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1984

Counteractive effects of agonistic and antagonistic gonadotropin-releasing hormone analogs on spermatogenesis: sites of action.

Both gonadotropin-releasing hormone (GnRH) agonistic and antagonistic analogs have been shown to inhibit reproductive hormonal function. While predictable and complete suppression of spermatogenesis is the ultimate goal of a number of clinical studies aimed at developing male contraceptive agents based on GnRH analogs, neither class of analog has been shown to completely inhibit spermatogenesis in man. The potential for a synergistic interaction of submaximal doses of these two classes of GnRH analogs was investigated in the present studies. In these studies 200 ng/day of a potent agonist (D-Leu6des-Gly10GnRH ethylamide) and 100 micrograms/day of a potent antagonist (NAc-L-Ala1, pCl-D-Phe2, D-Trp3,6GnRH) were administered subcutaneously, both alone and in combination, to adult male rats for 21 days. Serum gonadotropins and testosterone, pituitary GnRH receptor content, gonadal gonadotropin receptors, and intratesticular sperm counts were quantitated in each treatment group. Despite the ability of both GnRH agonists and antagonists to inhibit reproductive function when administered as single agents in this study, combined treatment with the two classes of GnRH analogs was less effective than either agent alone at these doses in the pharmacologic suppression of spermatogenesis.

Animals↗
PubMed1984

Effects of chronic D-Leu6, des-Gly10-gonadotropin releasing hormone ethylamide on male sex tissues.

The chronic administration of superactive agonists of gonadotropin releasing hormone (GnRH-A) have been reported to have a direct inhibitory effect on the sex tissues of the male rat. In an attempt to confirm or refute this statement, adult male rats were either left intact or were castrated and then treated daily for 14 days with either testosterone (T), dihydrotestosterone (DHT) or sesame oil (vehicle). Half of the intact and castrate animals also received daily injections of 200 ng of the GnRH agonist, D-Leu6, des-Gly10-GnRH ethylamide for 14 days. Twenty-four hours after completing treatment, blood levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and T were measured by radioimmunoassay and the ventral prostate gland (VP), seminal vesicle (SV) and penis were weighed. After 2 weeks of GnRH-A treatment, the plasma T level was reduced from 2506 +/- 170 (pg/ml +/- SEM) in the intact, nontreated animals to 907 +/- 69 in the intact, GnRH-A-treated group, indicating that the dosage of GnRH-A used in this study had an inhibiting effect on T secretion. No differences were observed in the VP, SV and penile weights between the castrate, GnRH-A and the castrate, nontreated groups. When exogenous T or DHT was given for 14 days to these castrated animals, the concomitant administration of GnRH-A did not appear to have any effect on the plasma T levels or the sex accessory tissue weights. These data suggest that GnRH-A itself does not appear to have a direct inhibitory or stimulatory effect on the sex tissues of the adult male rat.

Animals↗
PubMed1984

Hormonal effects of GnRH agonist in the human male: II. Testosterone enhances gonadotrophin suppression induced by GnRH agonist.

Superactive analogues of gonadotrophin releasing hormone and testosterone, when administered together, synergistically inhibit gonadotrophin secretion and spermatogenesis in the rat. In order to determine whether testosterone also enhanced gonadotrophin suppression by GnRH agonist in the human male, two groups of four normal male volunteers first received either 10 or 100 micrograms of a GnRH agonist D(Nal2)6GnRH (GnRH-A) daily for 10 d. After at least a 50 d recovery period, the same subjects received a single injection of 200 mg of testosterone oenanthate (TE) on day 1 in addition to the same dose of GnRH-A daily for 10 d. Serum LH, FSH and testosterone (TS) concentrations were measured daily just prior to the next analogue dose, and on days 1 and 10 at 0, 1, 2, 4, 6, 8, 12, 16 and 24 h after the analogue injection. Daily administration of both 10 and 100 micrograms of GnRH-A alone resulted in an early phase of stimulation followed by progressive decline in LH, FSH and testosterone to levels below baseline by day 10 despite continued administration of GnRH-A. Addition of testosterone to 10 micrograms of GnRH-A resulted in hormonal responses identical to those seen with GnRH-A alone. Combined treatment of testosterone with 100 micrograms of GnRH-A did not blunt the peak LH and FSH responses on day 2, but resulted in significantly lower LH (mean integrated responses: 187 +/- 30 vs. 234 +/- 42 mIU-d/ml) and FSH (mean integrated responses: 20.6 +/- 3.3 vs. 32.8 +/- 4.2 mIU-d/ml) responses from days 3 to 11. By day 11, all subjects receiving combined treatment (GnRH-A 100 micrograms + testosterone oenanthate) had undetectable serum FSH levels. In contrast, serum FSH concentrations on day 11 after treatment with GnRH-A alone were 43.6 +/- 8.9% of control and none of the subjects had values below the limit of detection. Serum testosterone levels in the combined treatment group did not fall below baseline by day 10 in either the 10 (161.4 +/- 48%) or the 100 micrograms GnRH-A groups (104.6 +/- 11.2%), while in the group receiving GnRH-A alone, testosterone levels declined to 45.6 +/- 8.3% and 80 +/- 18.8% with the 10 and 100 micrograms dose respectively. We conclude that addition of a suppressive dose of testosterone to an appropriate dose of GnRN-A significantly enhances gonadotrophin suppression by GnRH-A in the human male.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1984

Differential gonadotropin secretion: blockade of periovulatory LH but not FSH secretion by a potent LHRH antagonist.

The dependence of periovulatory gonadotropin secretion on LHRH was assessed with the use of a potent LHRH antagonist [ ALHRH ; (Nac-L- Ala1 ,p-Cl-D-Phe2,D-Trp3,6)LHRH]. Blood samples were collected hourly from 14.00 h proestrus (P) through 09.00 h estrus (E) from intact cycling female rats. ALHRH was administered at 09.00 or 13.00 h P before the proestrous increases in gonadotropins had commenced or at 23.00 h P after the LH and primary FSH surges had occurred but preceding the secondary FSH surge. Antagonist given at 09.00 or 13.00 h P completely blocked the LH release with levels remaining undetectable in most animals (less than 30 ng/ml) throughout the sampling period. However, administration of antagonist at these times failed to block completely the primary FSH surge although peak values were reduced when compared with controls, which displayed normal gonadotropin surges. In addition, ALHRH administered at 23.00 h failed to alter the magnitude or other characteristics of the secondary FSH surge when compared with controls. The present study demonstrates that the estrous surge of FSH in the rat is independent of acute hypothalamic release of LHRH. Furthermore, although the proestrous release of FSH is to a large extent LHRH dependent, our data suggest that some other mechanism may also contribute to this primary FSH surge.

Animals↗
PubMed1984

The stimulatory and down-regulatory effects of a gonadotropin-releasing hormone agonist in man.

Synthetic long-acting agonistic analogs of GnRH both stimulate and paradoxically inhibit gonadotropin secretion in male animals and humans. To characterize the stimulatory and down-regulatory effects of such a superactive GnRH analog in man, either 10 or 100 micrograms D-( Nal2 ) 6GnRH were administered sc to two groups of seven normal men for 10 days. Serum LH, FSH, and testosterone were determined daily before analog injection and 1, 2, 4, 6, 8, 12, 16, and 24 h after analog injection on days 1 and 10. Both doses of analog led to initial increases in LH, FSH (peak, days 2-3), and testosterone (peak, days 3-4), but by day 10 of analog administration, serum levels of LH, FSH, and testosterone returned to pretreatment levels. The integrated 24-h responses above baseline of serum LH and FSH to both doses of GnRH analog were significantly decreased on day 10 compared to day 1 (P less than 0.05). The integrated 24-h responses of serum testosterone to both doses of agonist were not significantly decreased on day 10 of agonist treatment compared to those on day 1 (P greater than 0.2). Integrated serum testosterone responses above baseline in response to 3000 IU hCG administered 2 weeks before analog treatment and 24 h after the last analog injection were not different (P greater than 0.2). GnRH agonist treatment resulted in proportionate stimulation of LH, FSH, and testosterone consistent with a predominant pituitary effect of the analog at these doses given for 10 days. The stimulatory effects of daily GnRH agonist treatment in men are transient with some down-regulatory effects evident after 10 days of treatment.

Adult↗
PubMed1984

Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss.

Thirty-eight patients with advanced cancer and weight loss were tested in a prospectively randomized, double-blind, placebo-controlled trial to evaluate the influence of hydrazine sulfate on carbohydrate metabolism in cancer cachexia. All patients had an initial 3-day inpatient metabolic evaluation including: standard 5-hr p.o. glucose tolerance test, hormone studies, and total glucose production by infusion of [6-3H]glucose. After 30 days of treatment with capsules containing either placebo or hydrazine sulfate in a 60-mg, 3 times/day dosage, inpatient evaluation was repeated. A total of 62 metabolic inpatient evaluations were performed. The pretreatment characteristics of age, sex, prior therapy experience, nutritional parameters and tumor types were comparable in placebo and hydrazine treatment groups. On initial evaluation, abnormal glucose tolerance and increased glucose production were frequently seen. Serial assessment of glucose tolerance showed no improvement after 30 days of placebo treatment. However, the glucose tolerance was significantly improved in patients receiving 30 days of hydrazine sulfate [2-hr glucose; initial 169 +/- 24 (S.E.) mg/dl versus final 128 +/- 12 mg/dl; p less than 0.05]. In addition, the rate of total glucose production was significantly decreased after 30 days of hydrazine sulfate compared to placebo treatment (2.46 mg/kg/min versus 3.07 mg/kg/min, respectively; p less than 0.05). Toxic effects of hydrazine sulfate were minimal. Our results suggest that hydrazine sulfate can influence the abnormal carbohydrate metabolism associated with weight loss in patients with cancer.

Adult↗
PubMed1983

Effect of GnRH superactive analogs (alone and combined with androgen) on testicular function in man and experimental animals.

GnRH long acting agonists, when given chronically, are potent inhibitors of testicular function in both man and experimental animals. Administration of these agents to male rats and to men results in suppression of testosterone secretion and diminished sperm counts. Despite the similarity of these observations the mechanisms by which these agents effect the testes appear to be different in the two species. In man GnRH analogs have an early stimulatory effect on LH and FSH secretion with down regulation evident by the 10th day of daily treatment. Longer treatment results in suppressed LH, FSH and testosterone levels. In the rat the stimulatory phase of GnRH analogs on LH and FSH secretion persisted for a much longer period of time (20-60 days). In the rat, direct testicular effects of analogue were the most likely cause of early suppression of testosterone and impaired sperm production. In both species combined testosterone and GnRH analog had additive effects on gonadotropin hormone suppression; combined therapy is being tested as a male contraceptive regimen.

Animals↗
PubMed1983

Superactive gonadotropin-releasing hormone agonists.

Superactive GnRH agonists represent a new class of pharmacologic agents that inhibit reproductive function in both men and women when administered chronically. These hormonal drugs are being tested extensively as both male and female contraceptive agents, as a treatment for prostate cancer, and as a new treatment for idiopathic precocious puberty. Other potential uses include treatment for endometriosis, hirsutism, polycystic ovarian disease, and severe intractable androgen-related acne. This chapter reviews the effects of GnRH agonists on gonadotropin and steroid hormone secretion in both men and women, and assesses the potential of these agents in the varied clinical uses delineated above.

Animals↗
PubMed1983

Partial isolation and characterization of testicular GnRH-like factors.

We report here partial isolation and characterization of at least two GnRH-receptor binding factors from the ethanol: chloroform: acetic acid (ECA) extracts of rat testis. The displacement curve of defatted, steroid-free and desalted ECA extract was parallel to that of D-(leu)6-des (Gly)10-GnRH-EA in a GnRH-radioreceptor assay. Immunoaffinity chromatography on cyanogen bromide-activated Sepharose 4B beads covalently bound to an antibody raised against d-(lys)6-GnRH resulted in more than a hundredfold increase in receptor binding specific activity. Equivalent amounts of kidney extract after affinity chromatography showed no significant activity. Coincubation of the material purified by affinity chromatography with the labeled ligand did not result in significant peptidase degradation of the label, indicating that apparent displacement of the label in the receptor assay was not the result of cleavage of the ligand. HPLC of the material partially purified by affinity chromatography on a reverse phase 5 micron ODS column revealed two peaks of receptor binding activity. Preliminary estimates of molecular weights of these factors based on SDS-PAGE and gel filtration are 68,000 and 6,000 respectively. We conclude that there are at least two factors in rat testis with GnRH-receptor-binding properties that are chemically distinct from the native decapeptide.

Animals↗
PubMed1983

Whole body protein breakdown rates and hormonal adaptation in fasted obese subjects.

Fasting is known to result in marked decreases in urinary urea nitrogen excretion over a 7-day period. In the present studies, changes in whole body protein breakdown rates and in the circulating levels of a number of hormones involved in protein anabolism and catabolism were systematically studied in nine obese subjects after 12 h and after 7 days of fasting. Whole body protein breakdown rates, measured with a primed continuous infusion of L-[U-14C]lysine, were decreased after 7 days of fasting (1.54 +/- 0.12 g/kg . day) compared to those after 12 h of fasting (1.96 +/- 0.10 g/kg . day). Plasma insulin decreased and glucagon increased after 7 days of fasting, resulting in an increased glucagon to insulin molar ratio. Plasma cortisol, urinary free cortisol excretion plasma rT3 levels, and branched chain amino acid levels increased after 7 days of fasting. Serum lysine levels, used for the calculations of whole body protein breakdown rates, were not changed. We conclude: 1) decreased whole body protein breakdown contributes significantly to the decreased nitrogen excretion observed with fasting in obese subjects; and 2) a decrease in circulating levels of free T3 may lead to this adaptive decrease in protein breakdown in fasted obese subjects, since the other hormones measured either did not change or changed in a catabolic direction.

Adult↗