[Ischemic burden vs. coronary artery morphology : What is crucial for the indication of revascularization?]. / Ischämielast versus Koronarmorphologie : Was ist entscheidend für die Indikation zur Revaskularisation?

Ischemic heart disease still represents the leading cause of death in the western world despite a decrease of mortality in the last decade. For the diagnostics of coronary artery morphology, invasive coronary angiography represents the gold standard. Nevertheless, in recent years the importance of functional diagnostics of the coronary arteries has increased and various imaging procedures for the measurement of fractional flow reserve (FFR) during coronary angiography were established and recommended for ischemia testing in the actual guidelines on myocardial revascularization.Imaging modalities for diagnostics of the functional relevance of coronary artery disease include stress echocardiography, magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). These procedures enable advanced risk stratification and therapy guiding in patients with suspected or known coronary artery disease. In future algorithms, hybrid imaging may facilitate the determination of anatomical and functional aspects after only one investigation.In the present article, the role of ischemia testing is compared with morphological methods for the diagnosis of coronary artery disease, individual risk stratification, and therapy guiding.

Decrease of postprandial endothelial dysfunction by spice mix added to high-fat hamburger meat in men with Type 2 diabetes mellitus.

AIMS: Consumption of a high-fat diet has been demonstrated to promote endothelial dysfunction, possibly through an increase in lipid peroxidation and decrease in serum nitric oxide. The present study was designed to investigate whether consumption of a hamburger cooked with a polyphenol-rich spice mixture will reduce postprandial lipid oxidation and endothelial dysfunction in men with Type 2 diabetes. METHODS: Twenty-two subjects consumed burgers cooked with salt only (control burger) or with salt and spice mix (spice burger) in randomized order. The postprandial concentration of urinary malondialdehyde and nitrate/nitrite as well as the peripheral arterial tonometry score were determined. RESULTS: Eighteen subjects completed the study. Postprandial serum glucose, insulin and triglyceride concentrations were similar in all subjects after control burger or spice burger consumption. Urine malondialdehyde excretion in mmol/g creatinine was reduced by 31% (P < 0.001) after consuming the spice burger compared with the control burger. Two hours after consumption of the burgers, the peripheral arterial tonometry score was significantly different between control burger consumption (-9.7 ± 21.5%) and spice burger consumption (+18.0 ± 42.4%) (P = 0.025). Mean urinary nitrate/nitrite concentrations in urine collected during the 6 h after consumption of the control burger was 9.09 ± 5.7 mmol/g creatinine, but 12.37 ± 7.00 mmol/g creatinine after the spice burger (P = 0.053). CONCLUSION: Adding a spice mix to hamburger meat prior to cooking resulted in a reduction in urinary malondialdehyde, an increase in urinary nitrate/nitrite and improvement of postprandial endothelial dysfunction in men with Type 2 diabetes. Therefore, cooking a hamburger with a polyphenol-rich spice mixture may lead to potential cardiovascular benefits in patients with Type 2 diabetes mellitus.

Male contraception; synergism of gonadotropin-releasing hormone analog and testosterone in suppressing gonadotropin.

Long-term administration of either superactive analog's of gonadotropin-releasing hormone or of testosterone suppresses gonadotropin secretion in male animals and humans. Testosterone administered in combination with gonadotropin-releasing hormone analog further suppresses serum gonadotropin levels in male rats. This observation indicates synergistic activity and suggests that the gonadotropin-releasing hormone analog and testosterone act at independent sites within the hypothalamic-pituitary axis. The primary actions of superactive analog are probably mediated by changes at a postreceptor site in the pituitary gonadotropin-secreting cells.

Pituitary receptor site blockade by a gonadotropin-releasing hormone antagonist in vivo: mechanism of action.

Administration of a potent gonadotropin-releasing hormone (GnRH) antagonist [Nac-L-Ala1,pCl-D-Phe2,D-Trp3,6]GnRH as a single subcutaneous injection to castrated adult male rats reduced, by more than 90 percent, both serum luteinizing hormone concentrations and specific pituitary GnRH receptor binding. This effect persisted for 24 hours. The dissociation rate of the antagonist from pituitary membrane homogenates was fourfold slower than the dissociation rate of a potent agonist. The prolonged in vivo inhibition of pituitary GnRH receptor binding and luteinizing hormone secretion by the GnRH antagonist may be mediated by the slower dissociation rate of the antagonist from its specific pituitary membrane receptor site.

Feasibility of a low-fat/high-fiber diet intervention with soy supplementation in prostate cancer patients after prostatectomy.

OBJECTIVES: To evaluate the feasibility and long-term compliance with a low-fat diet supplemented with soy protein in men at increased risk for recurrence after radical prostatectomy. DESIGN: Randomized, control study. SETTING: Academic center in USA. SUBJECT: Forty men who had undergone radical prostatectomy and were at increased risk for recurrence. INTERVENTION: Low-fat (15% fat), high-fiber (18 g/1000 kcal) diet supplemented with 40 g soy protein isolate (n=26) was compared to USDA recommended diet (n=14). RESULTS: Over 4 years, subjects in the intervention group but not in the control group made and sustained significant changes in their diet as measured by the dietary assessment instruments and urinary isoflavone excretion. In the intervention group, dietary fat intake was reduced from 33.46+/-1.27% energy/day to 21.04+/-1.74% (P<0.05), fiber intake increased from 14.6+/-1.06 to 21.05+/-2.29 g/day. The insulin growth factor-1 (IGF-1) level was decreased from 260.4+/-8.6 ng/ml at baseline to 220.5+/-7.9 ng/ml at 6 months (P<0.05) in the intervention group with no significant change in the control group. An ex vivo assay demonstrated inhibition of LNCaP cell growth (-20.0+/-7.7%, P<0.05) by sera from patients in the intervention group after 6 months of dietary change compared to baseline. CONCLUSION: These data suggest that long-term low-fat dietary interventions as part of prospective randomized trials in prostate cancer survivors are feasible, and lead to reductions in circulating hormones or other growth factors stimulating prostate cancer growth ex vivo.

Pituitary gland: site of short-loop feedback for luteinizing hormone in the rabbit.

The development of a species specific radioimmunoassay for rabbit luteinizing hormone (LH) has permitted the direct demonstration of LH feedback control of LH secretion (short-loop feedback control). In previous studies we showed that small bolus injections of human LH (hLH) intravenously administered to castrate female rabbits suppressed rabbit LH for 20-30 min. Human LH had no effect on rabbit follicle-stimulating hormone secretion. This control system was responsive to amounts of hLH estimated to be present in blood of eugonadal men and women. These studies were designed to determine whether this feedback control was exerted at a pituitary or hypothalamic level. Two groups of studies were carried out: (a) in vivo studies: Rabbit LH was quantified in the blood of castrated female New Zealand White rabbits receiving either constant hLH perfusion (2.75 IU/min) or saline perfusion, plus a bolus injection of 0.5, 6, or 20 mug of gonadotropin-releasing hormone (GnRH). Human LH decreased the response to 6 and 20 mug of GnRH by 31 and 36%, respectively, and abolished the response to 0.5 mug, GnRH. (b) in vitro studies: Rabbit pituitary slices were incubated in the presence of medium alone, medium plus hLH (25 mIU/ml), medium plus GnRH (20 mug/ml), and medium plus both GnRH and hLH. hLH decreased basal rabbit LH release into the medium and abolished GnRH-stimulated rabbit LH release. hLH had no effect on rabbit follicle-stimulating hormone release. From these results we conclude that a direct and specific feedback control of LH on LH exists at a pituitary level.

Dietary modulation of omega-3/omega-6 polyunsaturated fatty acid ratios in patients with breast cancer.

BACKGROUND: Polyunsaturated fatty acids of the omega-6 (omega-6) class, as found in corn and safflower oils, can act as precursors for intermediates involved in the growth of mammary tumors when fed to animals, whereas polyunsaturated fatty acids of the omega-3 (omega-3) class, as found in fish oil, can inhibit these effects. The effects of dietary intervention on the ratios of these fatty acids in breast and other adipose tissues have not previously been prospectively studied. PURPOSE: The present investigation was conducted to study the impact on the ratio of omega-3 and omega-6 polyunsaturated fatty acid in plasma and in adipose tissue of the breast and buttocks when women with breast cancer consume a low-fat diet and fish oil supplements. METHODS: Twenty-five women with high-risk localized breast cancer were enrolled in a dietary intervention program that required them to eat a low-fat diet and take a daily fish oil supplement throughout a 3-month period. Breast and gluteal fat biopsy specimens were obtained from each woman before and after dietary intervention. The fatty acid compositions of specimens of plasma, breast fat, and gluteal fat were determined by gas-liquid chromatography. Statistical analysis involved use of a two-sided paired t test. RESULTS: After dietary intervention, a reduction in the level of total omega-6 polyunsaturated fatty acids in the plasma was observed (P<.0003); moreover, total omega-3 polyunsaturated fatty acids increased approximately three-fold (P<.0001) and the omega-3/omega-6 polyunsaturated fatty acids ratio increased approximately fourfold (i.e., mean values increased from 0.09 to 0.41; P = .0001). An increase in total omega-3 polyunsaturated fatty acids in breast adipose tissue was observed following dietary intervention (P = .04); the omega-3/omega-6 polyunsaturated fatty acid ratio increased from a mean value of 0.05 to 0.07 (P = .0001). An increase in total omega-3 polyunsaturated fatty acids was observed in gluteal adipose tissue following the intervention (P = .05); however, the ratio of omega-3 to omega-6 polyunsaturated fatty acids (mean ratio values of 0.036-0.045; P = .06) was unchanged. CONCLUSION: Short-term dietary intervention can lead to statistically significant increases in omega-3/omega-6 polyunsaturated fatty acid ratios in plasma and breast adipose tissue. Breast adipose tissue changed more rapidly than gluteal adipose tissue in response to the dietary modification tested in this study. Therefore, gluteal adipose tissue may not be a useful surrogate to study the effect of diet on breast adipose tissue.

Hypogonadism in male patients with metastatic cancer prior to chemotherapy.

Gonadal hormonal function was assessed in 44 adult males with disseminated cancer prior to chemotherapeutic treatment of their cancer by determination of plasma testosterone, free testosterone, and luteinizing hormone (LH) levels. Low values for both testosterone (43% decreased) and free testosterone (66% decreased) were seen in this largely malnourished cancer population, in which 82% of patients were less than 90% of ideal body weight. Four patients of serum testosterone and LH were seen: (a) normal testosterone and normal LH (12 cases); (b) normal testosterone and high LH (13 cases), consistent with early primary hypogonadism; (c) low testosterone and high LH (10 cases), consistent with frank primary hypogonadism; (d) low testosterone and normal or low LH (9 cases), consistent with secondary hypogonadism. Significantly decreased ideal body weight was found in the group with low testosterone and low or normal LH level. We conclude that decreased gonadal hormone secretion is frequently seen in adult males with advanced cancer and malnutrition even prior to chemotherapy treatment.

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.

20-epi-vitamin D3 analogues: a novel class of potent inhibitors of proliferation and inducers of differentiation of human breast cancer cell lines.

We have studied the in vitro biological activities and mechanism of action of 1,25-dihydroxyvitamin D3 (1,25D3) and four potent 1,25D3 analogues [20-epi-22oxa-24a,26a,27a-tri-homo-1,25(OH)2D3 (KH 1060); 20-epi-1,25(OH)2D3; 1,25(OH)2-16ene-D3; and 1,25(OH)2-16ene-23yne-D3] on proliferation and differentiation of estrogen receptor-negative (MDA-MB-436, BT-20, SK-BR-3, and MDA-MB-231), estrogen receptor-weakly positive (BT474), and estrogen receptor-positive (MCF-7) breast cancer cell lines. Dose-response studies showed that KH 1060 was the most potent analogue, because it was able to induce differentiation in all seven breast cancer cell lines (measured by lipid staining) and to suppress more than 50% clonal proliferation (ED50) at 10(-10) M in all cell lines, except MDA-MB-436 and BT-20. To explore how these compounds mediated antiproliferative actions, their effects on the cell cycle, on expression of bcl-2 and p53, and on apoptosis were assessed. Five of six cell lines have a mutant p53 gene, whereas MCF-7 has wild-type p53. Immunohistochemical staining showed that the p53 protein was predominantly localized in the nucleus in each of the breast cancer cell lines except for MCF-7, which expressed the protein predominantly in the cytoplasm. After incubation with KH 1060 (3 days; 10(-7) M), expression of bcl-2 protein as determined by immunohistochemical localization was markedly decreased in BT-474, MCF-7, and MDA-MB-231; these same cells were profoundly inhibited in their clonal proliferation and arrested in the G0/G1 phase of the cell cycle when cultured with KH 1060. In contrast, BT-20 and MDA-MB-436 cells that were refractory to the antiproliferative effect of KH 1060 (ED50 < 10(-6) M) had no down-regulation of their bcl-2 expression and no cell cycle changes after exposure to KH 1060. MCF-7 showed morphological changes and DNA fragmentation, indicative of apoptosis after 48 h incubation with KH 1060 (10(-6) M), during which time p53 protein accumulated in the nucleus and decreased in the cytoplasm. In contrast, no apoptosis was detected in three other breast lines (MDA-MB-231, SK-BR-3, and BT-474) that had a mutated p53. In conclusion, the data indicate that KH 1060 is an extremely potent 1,25D3 analogue inducing differentiation of all six breast cancer lines and potently inhibiting clonal growth of four of them with concomitant decreased bcl-2 and cell cycle arrest at G0/G1.(ABSTRACT TRUNCATED AT 400 WORDS)

Phytoestrogens induce differential estrogen receptor alpha- or Beta-mediated responses in transfected breast cancer cells.

Increased intake of phytoestrogens may be associated with a lower risk of cancer in the breast and several other sites, although there is controversy surrounding this activity. One of the mechanisms proposed to explain the activity of phytoestrogens is their ability to bind and activate human estrogen receptor alpha (ERalpha) and human estrogen receptor beta (ERbeta). Nine phytoestrogens were tested for their ability to transactivate ERalpha or ERbeta at a range of doses. Mammary adenocarcinoma (MCF-7) cells were co-transfected with either ERalpha or ERbeta, and an estrogen-response element was linked to a luciferase reporter gene. Dose-dependent responses were compared with the endogenous ligand 17beta-estradiol. Purified genistein, daidzein, apigenin, and coumestrol showed differential and robust transactivation of ERalpha- and ERbeta-induced transcription, with an up to 100-fold stronger activation of ERbeta. Equol, naringenin, and kaempferol were weaker agonists. When activity was evaluated against a background of 0.5 nM 17beta-estradiol, the addition of genistein, daidzein, and resveratrol superstimulated the system, while kaempferol and quercetin were antagonists at the highest doses. This transfection assay provides an excellent model to evaluate the activation of ERalpha and ERbeta by different phytoestrogens in a breast cancer context and can be used as a screening bioassay tool to evaluate the estrogenic activity of extracts of herbs and foods.

Long-term efficacy of soy-based meal replacements vs an individualized diet plan in obese type II DM patients: relative effects on weight loss, metabolic parameters, and C-reactive protein.

BACKGROUND: Achieving significant weight loss and glycemic control in diabetic patients remains a challenging task. OBJECTIVE: This study compared the effects of a soy-based meal replacement (MR) plan vs an individualized diet plan (IDP; as recommended by the American Diabetes Association) on weight loss and metabolic profile. DESIGN/SUBJECTS: A total of 104 subjects were randomized prospectively to the two treatments for a total of 12 months. RESULTS: In all, 77 of the 104 subjects completed the study. Percentage weight loss in MR group (4.57+/-0.81%) was significantly greater (P<0.05) than in IDP group (2.25+/-0.72%). Fasting plasma glucose was significantly reduced in MR group (126.4+/-4.9 mg/dl) compared with IDP group (152.5+/-6.6 mg/dl, P<0.0001) at 6 months but not at 12 months. Controlling for baseline levels, hemoglobin Alc level improved by 0.49+/-0.22% for those receiving MR when compared to IDP group (P<0.05). A greater number of subjects in MR group reduced their use of sulfonylureas (P<0.0001) and metformin (P<0.05) as compared to IDP group. High-sensitivity C-reactive protein (hs-CRP) decreased -26.3% (P = 0.019) in MR group compared to -7.06% (P = 0.338) in IDP group at 6 months. Similar changes were observed at 12 months with MR groups, with hs-CRP decreasing by -25.0% (P = 0.019) compared to -18.7% (P = 0.179) in IDP group. CONCLUSION: This study demonstrates that MR is a viable strategy for weight reduction in diabetic patients, resulting in beneficial changes in measures of glycemic control and reduction of medications.

Low-dose continuous insulin therapy for diabetic ketoacidosis. Prospective comparison with "conventional" insulin therapy.

Low-dose insulin infusion has recently been used to treat ketoacidosis. We have prospectively compared patients with ketoacidosis either treated with insulin infusion at the rate of 6 units per hour or with high-dose, intermittent subcutaneously administered insulin, with emphasis placed on the hormonal responses. Basal glucagon, cortisol, and growth hormone levels were elevated in both groups. Cortisol and growth hormone levels did not fall with therapy in either group but glucagon levels fell in parallel with glucose levels in both groups. There was no difference in the time taken for glucose levels to fall below 250 mg/100 ml between groups. Whereas both methods of therapy appeared to be equally effective, low-dose infusion had the advantages of ease of administration, a predictable, relatively linear rate of fall of glucose levels, and ability to be stopped abruptly in the event of hypoglycemia.

A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer.

BACKGROUND: The primary objective of this study was to compare the effects of pomegranate juice on PSA doubling times (PSADT) in subjects with rising PSA levels after primary therapy for prostate cancer. METHODS: Double-blind, placebo-controlled multi-institutional study, evaluated the effects of pomegranate liquid extract on serum PSA levels. The primary end point of this study was change in serum PSADT. Additional secondary and exploratory objectives were to evaluate the safety of pomegranate juice and to determine the interaction of manganese superoxide dismutase (MnSOD) AA genotype and pomegranate treatment on PSADT. RESULTS: One-hundred eighty-three eligible subjects were randomly assigned to the active and placebo groups with a ratio of 2:1 (extract N=102; placebo N=64; juice N=17). The majority of adverse events were of moderate or mild grade. Median PSADT increased from 11.1 months at baseline to 15.6 months in the placebo group (P<0.001) compared with an increase from 12.9 months at baseline to 14.5 months in the extract group (P=0.13) and an increase from 12.7 at baseline to 20.3 in the juice group (P=0.004). However, none of these changes were statistically significant between the three groups (P>0.05). Placebo AA patients experienced a 1.8 month change in median PSADT from 10.9 months at baseline to 12.7 months (P=0.22), while extract patients experienced a 12 month change in median PSADT from 13.6 at baseline to 25.6 months (P=0.03). CONCLUSIONS: Compared with placebo, pomegranate extract did not significantly prolong PSADT in prostate cancer patients with rising PSA after primary therapy. A significant prolongation in PSADT was observed in both the treatment and placebo arms. Men with the MnSOD AA genotype may represent a group that is more sensitive to the antiproliferative effects of pomegranate on PSADT; however, this finding requires prospective hypothesis testing and validation.

Gonadotropin-releasing hormone analog and testosterone synergistically inhibit spermatogenesis.

We recently demonstrated that superactive gonadotropin-releasing hormone (GnRH) analogs and testosterone synergistically suppress gonadotropin secretion in castrate rats. We proposed that these two classes of agents used in combination would lead to enhanced suppression of spermatogenesis by synergistically inhibiting gonadotropin secretion. This hypothesis was tested in the present study in which synergistic inhibition of spermatogenesis was produced by combined analog and testosterone treatment. The mechanism of the synergistic action observed differed from that hypothesized in that the analog had both primary inhibitory actions directly on the testis and effects at a pituitary level. The addition of testosterone to the regimen further inhibited spermatogenesis by decreasing the secretion of gonadotropins thereby attenuating the compensatory rise in LH and FSH secretion expected with direct analog inhibition of the testis. These studies demonstrate the potential of combined GnRH analog and testosterone administration as a male contraceptive agent and indicate the complexity of their synergistic interactions.

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.

Down-regulation of pituitary gonadotropin secretion in postmenopausal females by continuous gonadotropin-releasing hormone administration.

Four normal postmenopausal females were infused with synthetic gonadotropin-releasing hormone (GnRH) iv at a rate of 1 microgram/min for 72 h. Serum LH, FSH, and estradiol were measured every 4 h. LH and FSH levels increased from basal values of 23 +/- 3 and 94 +/- 27 mIU/ml, respectively, to peak values of 50 +/- 5 and 145 +/- 9 mIU/ml at 12 h. Serum LH then fell progressively toward basal levels during the continued iv administration of GnRH. Serum FSH fell below basal levels and remained suppressed between 36-72 h of the study period. Serum estradiol remained at levels less than 25 pg/ml throughout the GnRH infusion. Studies of LH and FSH secretion during the continuous administration of GnRH may be a useful model with which to study paradoxical down-regulation of pituitary gonadotropin secretion.

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.

Metabolic effects of triiodothyronine replacement during fasting in obese subjects.

The adaptation to fasting reduces muscle protein breakdown by switching from a carbohydrate to fat fuel economy in normal man. With the discovery of T3 and the observation that its formation from T4 was reduced significantly during starvation, it was proposed that T3 mediated many of these changes. To examine this possibility, otherwise healthy, obese subjects were fasted for 10 days and supplemented with T3 the last 3 days of the fast to bring circulating T3 levels within normal prefasting (weight maintenance) levels. The effects of the same dose of T3 for 3 days were tested during the last 3 days of a 10-day weight maintenance diet for comparison. Both metabolic rate and CO2 production decreased as expected with fasting and did not increase after T3 supplementation. Hepatic glucose appearance rates fell with fasting and increased significantly during T4 supplementation, but not to prefasting levels. Urinary urea nitrogen excretion decreased significantly with fasting and decreased further with T3 supplementation. Lysine appearance did not change during fasting or T3 supplementation, but leucine appearance decreased with T3 supplementation during fasting. These observations suggest that the fall in serum T3 during fasting may not mediate the observed decreases in protein breakdown that occur during fasting and prolonged starvation, but may instead initiate the fall in hepatic glucose appearance.

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.