Effects of the Booroola gene FecBB on somatic and germ cells of the fetal testis

The present study was conducted to compare in homozygous FecBBFecBB(BB) Booroola and ++ male fetuses, the body and the testicular growths and the tissular and cellular compositions of the testis between 60 and 140 days of gestation. To eliminate differences in growth due to uterine environment, single embryos have been transferred in recipient Mérinos d' Arles ewes. At 60 and 100 days of gestation, the body masses of BB fetuses were significantly lower than those of ++ foetuses (11 and 13%; P = 0.05); but their testis masses of their total contents of somatic (Leydig or Sertoli) cells did not differ significantly whatever the fetal age. At 100 and 140 days of gestation, testis and body masses were significantly correlated without difference between BB and ++ genotypes. In conclusion, the presence or absence of homozygous gene FecBB does not induce significant differences in somatic or germ cell composition of the testis between 60 and 140 days of gestation.     

Evidence that elevated plasma corticosterone levels are the cause of reduced hypothalamic corticotrophin-releasing hormone gene expression in diabetes

Uncontrolled diabetes mellitus causes both a sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis and reduced expression of corticotrophin-releasing hormone (CRH) mRNA in the hypothalamic paraventricular nucleus (PVN). To investigate the role of glucocorticoids in the regulation of CRH mRNA expression in the PVN of diabetic rats, we studied surgically adrenalectomized (ADX) and sham-operated male Sprague-Dawley rats 4 days after i.v. injection of streptozotocin (STZ; 65 mg/kg i.v.) or vehicle. Among sham-operated animals, AM plasma corticosterone levels were significantly increased in diabetic as compared to nondiabetic animals (1.46+/-0.54 vs. 0.22+/-0.05 microg/dl; P <0.05), and were positively correlated to both plasma ACTH levels (r = 0.74; P = 0.015) and adrenal gland weight (r = 0.70; P = 0.025). In contrast, CRH mRNA levels measured in the PVN by in situ hybridization were inversely related to the plasma corticosterone level (r = -0.68; P = 0.045). In a second experiment, both diabetic and nondiabetic ADX rats received a continuous subcutaneous infusion of either corticosterone at one of two doses or its vehicle for 4 days. Among vehicle-treated ADX animals, STZ diabetes raised hypothalamic CRH mRNA levels, in contrast to the tendency for diabetes to lower CRH mRNA in intact rats in the first experiment. Corticosterone administration lowered CRH mRNA comparably in both diabetic and nondiabetic ADX rats. In contrast, diabetes reduced arginine vasopressin (AVP) mRNA levels in the PVN of ADX rats and blunted the inhibitory effect of glucocorticoids on AVP mRNA levels in this setting. We conclude (1) glucocorticoids are necessary for the effect of diabetes to reduce hypothalamic CRH gene expression, since diabetes causes a paradoxical increase in CRH mRNA levels in adrenalectomized animals; (2) glucocorticoid inhibition of hypothalamic CRH gene expression is intact in diabetic rats; and (3) the activation of the HPA axis by diabetes is associated with a proportionate decrease in PVN CRH gene expression. These findings support a model in which hypothalamic factors additional to CRH activate the HPA axis in uncontrolled diabetes, and inhibit CRH gene expression indirectly by negative glucocorticoid feedback.     

Pituitary growth hormone release and gene expression in cafeteria-diet-induced obese rats

PURPOSE: To determine prospectively the feasibility and accuracy of combined gadolinium-enhanced magnetic resonance (MR) angiography, MR urography, and MR nephrography in the presurgical evaluation of potential renal transplant donors. MATERIALS AND METHODS: Twenty-two potential donors for renal transplantation were evaluated with 1.5-T MR imaging. MR angiograms were evaluated for the number of renal arteries, presence of early arterial branches, and renal artery stenoses. The renal collecting system and ureters were evaluated on the MR urograms. Renal parenchyma was assessed on the MR nephrogram. Prospective interpretation of MR images was compared with that of conventional angiograms and excretory urograms and with surgical findings. RESULTS: Gadolinium-enhanced MR angiography enabled correct identification of the arterial supply to all 44 native kidneys (44 single or dominant renal arteries and nine accessory renal arteries), four of five early arterial branches arising in the proximal 2 cm of the renal artery, a mild truncal stenosis in one renal artery, and two anomalies of the draining renal veins. The MR urogram accurately depicted a duplicated collecting system and mild unilateral pelvicalicectasis. The MR nephrogram showed renal size and a solitary cyst in one kidney, confirmed with sonography. CONCLUSION: Combined gadolinium-enhanced MR angiography, MR urography, and MR nephrography can accurately depict the arterial supply, collecting system, and renal parenchyma of donor kidneys.     

Stature in Ecuadorians heterozygous for growth hormone receptor gene E180 splice mutation does not differ from that of homozygous normal relatives

Heterozygosity for certain mutations of the GH receptor (GHR) gene has been proposed as the cause of partial resistance to GH, and there has been a recent demonstration of a dominant-negative effect of such a mutation in a mother and child. To examine the effect of heterozygosity in a large genetically homogeneous population with GHR deficiency, in which a substantial number of heterozygous (carrier) subjects and homozygous normal individuals can be compared, we studied a population in Ecuador in which 70 individuals with GHR deficiency were homozygous for the E180 splice mutation. We found that 58 heterozygous relatives of probands were not significantly shorter than 37 homozygous normal relatives [SD score (SDS) for height -1.85 +/- 1.04 (SD) vs. -1.55 +/- 0.96, P > 0.10]. When only those families with both homozygous normals and carriers were compared, the 33 heterozygous and 29 normal relatives did not differ significantly in height SDS (-1.98 +/- 1.07 vs. -1.77 +/- 0.91, P > 0.3). If heterozygosity for the E180 splice mutation were to influence stature, heights of heterozygous parents of probands would be expected to correlate with those of probands and of carriers who are their offspring and not with heights of their homozygous normal children. Parental height SDS did not correlate with height SDS of affected offspring (r = 0.24). For unaffected siblings as a group or analyzed separately as normals or carriers, there was a strong correlation between parental and offspring SDS for height (P < 0.01 for all comparisons). Thus, the effect of homozygosity for the GHR mutation was so profound as to abolish parental influence on height, and there was no difference in the influence of parental stature between carrier and noncarrier offspring. These findings demonstrate no meaningful effect on stature of heterozygosity for the E180 splice mutation of the GHR, which is a functional null mutation and, in the homozygous state, results in profound short stature from severe insulin-like growth factor-I deficiency.     

A homozygous nonsense mutation of the human growth hormone receptor gene in a Sardinian boy with Laron-type dwarfism

Patients with idiopathic intracranial hypertension may occasionally present with coexisting lower motor neuron facial weakness. This study reviews a 6-year experience at Mayo Clinic. The aim of this study was to determine the possible association of idiopathic intracranial hypertension and facial paresis. Two cases were identified. Both fulfilled the modified Dandy's diagnostic criteria for idiopathic intracranial hypertension. Treatment consisted of steroids in one, and emergent optic nerve sheath fenestration in the other. The cranial nerve palsies resolved in both cases.     

Decreased dietary protein or energy intake and plasma growth hormone levels of the pregnant pig, its fetuses and developing progeny

The effects of low protein diets on plasma growth hormone were studied in pregnant pigs, fetuses and the developing progeny. Pregnant pigs were fed 18%, 3% or 0.5% protein diet throughout the gestation period. At 10, 13 and 15 week of gestation, fetuses were removed from the uterus after the dam had been bled to death. Plasma samples were used for growth hormone determinations. In a second experiment, 2-day old pigs from another set of pregnant pigs fed the diet containing 18%, 3% or 0.5% protein during gestation were cross-fostered to control nursing dams and weaned at 4 weeks of age to a standard diet. Plasma obtained at regular intervals was used for growth hormone determination. Plasma growth hormone was significantly higher in dams fed 0.5% protein after week 13 of gestation. High growth hormone (ten times the dam GH level) was observed in all fetuses irrespective of maternal dietary manipulation. Offspring of severely protein deprived pits (0.5% protein) had significantly elevated growth hormone levels up to 12 weeks of age in spite of cross fostering to a control dam after birth. The data suggest that there is little or no effect of maternal protein restriction on fetal growth hormone levels but the persistent high growth hormone levels in the progeny of severely malnourished pigs indicate a possible impairment of the production, release or catabolism of growth hormone and/or its releasing factor.     

Plasma insulin and growth hormone concentrations in pregnant sheep II: post-absorptive levels in mid- and late pregnancy

1. The incorporation of L-[U-14C]leucine, L[U-14C]histidine and L-[U-14C]phenylalanine into casein secreted during perfusion of isolated guinea-pig mammary glands was demonstrated. 2. The extent of incorporation of label into casein residues was consistent with their being derived from free amino acids of the perfusate plasma. 3. The mean transit time of the amino acids from perfusate into secreted casein was approx. 100 min. 4. Whereas radioactive histidine and phenylalanine were incorporated solely into milk protein, radioactivity from [U-14C]valine was also transferred to CO2 and to an unidentified plasma component, and from [U-14C]leucine to plasma glutamic acid. 5. Evidence from experiments with [U-14C]phenylalanine suggests that, as in rats, but in contrast with ruminant species, guinea-pig mammary tissue does not possess phenyl alanine hydroxylase activity. 6. The results are discussed in relation to the possible role of essential amino acid catabolism in the control of milk-protein synthesis.     

Immunoreactive growth hormone levels in pigs fed protein or energy restricted diets during the postweaning period

Developmental changes in growth hormone levels during protein or energy malnutrition was studied in weaned pigs. Three or 4 weeks old pigs from control dams were fed a control diet (18% protein), an energy-restricted diet (18% protein) or a low protein diet (6% protein) for 8 weeks. Energy restriction was achieved by feeding the control diet in amounts that allowed very little growth. After the restriction period, all pigs were fed the control diet ad libitum for another 8 weeks. Blood samples were collected at intervals throughout the experiment and the plasma was analyzed for growth hormone by radioimmunoassay. Post weaning protein deprivation resulted in higher growth hormone levels during the restriction period as compared to control pigs or pigs with a restricted energy intake.     

Effects of oral glucose administration on plasma growth hormone levels in women with polycystic ovary syndrome

OBJECTIVE: To evaluate the sensitivity of GH secretion to the suppressive effect of oral glucose administration in women with polycystic ovary syndrome (PCOS). DESIGN: Comparison of the GH response to an oral glucose load in women with PCOS and in weight-matched normally menstruating women (controls). SETTING: Reproductive endocrinology unit. PATIENT(S): Eighteen obese and 11 nonobese patients and 10 obese and 10 nonobese controls. INTERVENTION(S): After an overnight fast, each woman underwent a 75-g, 3-hour oral glucose tolerance test (OGTT). MEAN OUTCOME MEASURE(S): Growth hormone, glucose, and insulin responses to OGTT. RESULT(S): No significant differences in the glycemic and insulinemic responses were found between the patients and the weight-matched controls. No decrease in plasma GH was observed in both obese and nonobese patients and in obese controls during the OGTT, whereas a significant GH decrease occurred in nonobese controls 60 and 120 minutes after glucose intake. CONCLUSION(S): Oral glucose administration was unable to suppress GH levels in nonobese as well as in obese women with PCOS and in obese control women. These data suggest that both PCOS and obesity are associated with a reduced sensitivity of GH secretion to glucose suppression.     

Changes in plasma levels of the two prolactins and growth hormone during adaptation to different salinities in the euryhaline tilapia, Oreochromis mossambicus

Studies were undertaken to determine whether the adaptation of the tilapia, Oreochromis mossambicus, to different salinities was accompanied by changes in plasma levels of growth hormone (GH) and its two prolactins (tPRL177 and tPRL188). Transfer from fresh water to 70% seawater (22 ppt) produced significant increases in plasma GH levels in males, but not in females. Both tPRLs decreased by the first sampling interval (6 hr) after transfer to seawater in both sexes. A second group of tilapia were adapted gradually to seawater (32 ppt) and were maintained in seawater for an additional 2 weeks. The fish were then transferred from seawater to fresh water. The transfer to fresh water induced a significant decline in plasma GH levels in both males and females. Both tPRLs increased within 6 hr after transfer to fresh water in both sexes. Then, plasma tPRL177 levels decreased gradually. By contrast, tPRL188 continued to increase and attained its highest levels 3 days after transfer to fresh water. These findings show that blood levels of the two tPRLs change rapidly during freshwater and seawater adaptation. The fact that tPRL177 and tPRL188 levels followed distinctly dissimilar patterns as freshwater acclimation proceeded suggests that the secretion and/or metabolic clearance of the two PRLs may be differentially regulated. The changes in GH which occurred when tilapia were moved between fresh water and seawater are compatible with the idea proposed by others for salmonids that GH may have an important role for seawater adaptation.     

Growth hormone, insulin, prolactin and total thyroxine in the plasma of sheep implanted with the anabolic steroid trenbolone acetate alone or with oestradiol

The mode of action of the anabolic steroid trenbolone acetate (19-norandrost-4,9,11-trien-3-one-17-acetate) was studied through the endogenous hormonal response of castrated male sheep to subcutaneous implantation of 140 mg of trenbolone acetate and 20 mg of oestradiol both separately and in combination. Radioimmunoassay of delta-4,9,11-trienic steroids and oestradiol-17 beta in plasma confirmed that simultaneous administration of trenbolone acetate with oestradiol led to a significantly greater persistence of oestradiol-17 beta residues in plasma (P less than 0.05) than with implantation of oestradiol alone. Oestradiol treatment increased concentrations of growth hormone and insulin (P less than 0.05; P less than 0.001 respectively) in plasma samples collected weekly. Trenbolone acetate by itself had no significant effect and the oestrogenic response was blocked on the simultaneous implantation of trenbolone acetate and oestradiol (despite higher plasma levels of oestradiol-17 beta with this treatment). Plasma total thyroxine was markedly depressed to 45 per cent of its basal level by trenbolone acetate, alone or with oestradiol (P less than 0.001) and depressed to 80 per cent of basal by oestradiol treatment alone (P less than 0.001). Plasma prolactin was unaltered by the above treatments.     

An investigation on plasma progesterone levels during pregnancy and at parturition in the Ivesi sheep

We have investigated the toxicity of dose-escalation of BCNU, etoposide and melphalan ('BEM') chemotherapy with autologous stem cell transplantation in patients with haematological malignancies. Seventy-two patients with haematological malignancies were treated with BCNU (600 mg/m2, 450 mg/m2 or 300 mg/m2), etoposide 2 g/m2 and melphalan 140 mg/m2 followed by autologous bone marrow transplantation (ABMT), n = 51, or autologous peripheral blood progenitor cell transplantation (APBPCT), n = 21. Liver and pulmonary function was monitored pretransplant and at regular intervals post-transplant. Mucositis was graded daily during in-patient stay. There was a significantly higher incidence of symptomatic pulmonary toxicity in the patients who received BCNU at 600 mg/m2 than in the other two groups, and there was a significant increase in the incidence of asymptomatic decrease in carbon monoxide (KCO) in the patients who received BCNU 450 mg/m2. There was no significant difference between the three groups in the incidence and severity of mucositis or in the incidence of transiently abnormal liver function. We conclude that etoposide at 2 g/m2 can be used without unacceptable mucositis. BCNU at 600 mg/m2 is associated with an unacceptably high incidence of lung toxicity, but at 450 mg/m2 there is minimal symptomatic lung toxicity.     

Increased pulsatile, but not basal, growth hormone secretion rates and plasma insulin-like growth factor I levels during the periovulatory interval in normal women

The secretion of GH changes during the menstrual cycle, exhibiting high levels during the periovulatory phase (PO). Previous studies have not investigated whether this difference in GH status is due to increased secretion or reduced clearance of pituitary GH and amplified pulsatile vs. basal GH secretion. It is also unclear whether the PO phase is accompanied by changes in circulating insulin-like growth factor I (IGF-I). In this study we investigated the 24-h GH release patterns in the early follicular (EF) vs. the periovulatory menstrual phase in the same individuals. Ten young (aged 24-34 yr) healthy women with regular menses were studied with deconvolution analysis of GH profiles obtained by blood sampling every 20 min for 24 h, followed by an arginine stimulation test. A high sensitivity immunofluorometric GH assay was used. All women were studied in both the EF and PO phases in random order. There were no differences in the basal GH secretion rate or GH half-life during the two phases. The number of GH secretory bursts identified during the 24-h sampling period was significantly increased during the PO (13.3 +/- 0.5) compared to the EF (10.3 +/- 0.6) phase (P = 0.002); conversely, the mean interburst interval was shorter in the PO (107 +/- 5 min) than in the EF (134 +/- 8 min) phase (P = 0.004). There was no difference in GH pulse mass (P = 0.13) or amplitude (P = 0.21) between the two phases. The pulsatile GH production rate (milligrams per L/24 h) was significantly elevated during the PO (61 +/- 6) compared to that during the EF (37 +/- 8; P = 0.004). Increased total GH pulse area was confirmed by Cluster analysis (P = 0.027). Furthermore, the 24-h mean serum GH concentration was significantly increased in the PO (1.4 +/- 0.1 mg/L) vs. that in the EF (0.9 +/- 0.1 mg/L; P = 0.002). There was a positive correlation between estradiol (E2) and GH secretory pulse amplitude, frequency, and mean 24-h serum GH concentration in the PO cycle phase, indicating E2 to be a major statistical determinant of GH secretion. Serum GH increased significantly after arginine infusion in both phases (P < 0.001), whereas there was no difference between the two cycle phases (P = 0.20). Serum IGF-I levels were increased during the PO phase (253 +/- 20 mg/L) compared to those during the EF phase (210 +/- 16 mg/L; P = 0.03), whereas serum IGF-binding protein-3, IGF-II, and GH-binding protein were similar during the two phases. This study unequivocally documents elevated GH levels during the PO phase of the menstrual cycle, mediated by increased GH production rate and burst frequency. The concomitant increase in serum IGF-I suggests a central stimulation of the GH-IGF-I axis, which may be mediated by endogenous E2 levels.     

The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency

Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.