Rise In Serum Concentrations Research Articles

Stimulation of release of growth hormone from the anterior pituitary by alpha-melanocyte-stimulating hormone: a possible mechanism for induction of pseudopregnancy in the rat.

In hypophysectomized rats on day 1 of dioestrus, as well as on day 4 of pseudopregnancy, alpha-MSH (continuous infusion of 1 microgram/h) failed to maintain serum concentrations of progesterone. On the other hand, alpha-MSH did not modify the increase induced by ACTH (1 microgram/microliter as an infusion plus two additional daily injections of 30 micrograms/microliter), prolactin (200 micrograms/0.2 ml at 12-h intervals) or GH (300 micrograms/0.2 ml twice daily) on serum concentrations of progesterone in such rats. However, in intact rats alpha-MSH caused a significant rise in serum concentrations of GH on day 1 and day 2 of dioestrus. Continuous infusion of alpha-MSH produced an increase in serum concentrations of GH at 12.00 and 14.00 h on day 1 of dioestrus and at 07.00 h on day 2. It is therefore suggested that alpha-MSH may exert its effect by facilitating the secretion of GH, which in turn may induce the release of progesterone.

An implant of a gonadotropin releasing hormone agonist (buserelin) which suppresses ovarian function in the macaque for 3-5 months.

Four adult female stumptailed macaque monkeys with regular menstrual cycles and one with irregular cycles and dysfunctional uterine bleeding were treated with a single implant containing 2.6 mg of the GnRH agonist buserelin in a matrix of polylactide/glycolide copolymer (75:25). The implant was used as a cylindrical rod of 0.8 X 0.12 cm and implanted sc in the abdominal wall. The insertion of the implant was followed by a modest rise in serum concentrations of LH and FSH lasting 3-4 days before falling to basal values. The release profile of buserelin from the implant was measured in urine by a radioimmunoassay detecting the intact molecule and its major metabolites. Immunoreactive buserelin in urine was high between days 1-3 after implant after which there was a rapid decline to form a plateau between days 15-70 followed by a further gradual decline. This prolonged release of buserelin suppressed ovulation for a mean of 148 days (range 105-182 days) as indicated by absence of serum progesterone rises. Serum FSH concentrations were low for at least 75 days and during this time serum oestradiol concentrations were uniformly suppressed in all monkeys. Once the buserelin release from the implant declined serum FSH concentrations began to rise. There was a variable delay of 7-60 days before this rise in FSH was associated with stimulation of ovarian oestradiol secretion followed by rises in serum progesterone concentrations indicative of ovulation. Apart from the first menses after insertion of implant, 4 of the monkeys became amenorrhoeic for the period of anovulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in thyroid function tests and sex hormone binding globulin associated with treatment by gonadotropin

Increasing levels of E2 in gonadotropin-treated women stimulated hepatic synthesis of SHBG and TBG, and consequently increases in T4 concentration. Nevertheless, unchanged FTI and TSH suggested that a euthyroid state was maintained. The temporal patterns for the rise in serum concentrations of TBG and SHBG during gonadotropin therapy suggest that the synthesis of these proteins by the liver has different sensitivities to E2.

Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses.

The pharmacokinetics of ciprofloxacin were evaluated after increasing single oral doses of 100, 250, 500 and 1000 mg, and an intravenous dose of 100 mg given to each of 12 healthy volunteers (6 females and 6 males). Concentrations in serum and urine were determined by microbiological assay. The rise in peak serum concentrations and the values of the total area under the serum concentration curve were proportional to the increase in the oral doses. As the oral dose increased a slight increase was observed in the apparent time lag before absorption from 0.34 h after 100 mg to 0.53 h after 1000 mg. The serum half-life after the intravenous dose was 3.2 h. After the oral doses shorter apparent half-life values were observed. The intravenous dose showed an elimination phase distribution volume of 2.76 l/kg and total body clearance of 40.7 l/h. The total urinary excretion was 42.2 +/- 15.6% of the dose after the intravenous dose; the figure was lower after the oral doses. The bioavailability of the 100 mg oral dose was 83.7% as calculated from the value of the total area under the serum curve after the same oral and intravenous dose in all 12 subjects. Ciprofloxacin thus demonstrates normal linear pharmacokinetics, the rise in serum concentrations being proportional to the dose.

Circulating corticosterone in the infant rat: the mechanism of age and thyroxine effects.

Infant rats exhibit a marked rise in serum concentrations of corticosterone between postnatal days 12 and 24. As this rise appears to be cued by L-thyroxine, the aim of the current study was to determine the physiological bases of the effects of both age and thyroid status on serum corticosterone. The in vivo response to either adrenocorticotropic hormone (60 mU/g body weight) or dibutyryl 3',5'-cyclic adenylate (0.3 mg/g body weight) increased between 10 and 16 days and was advanced and delayed by hyper- and hypothyroidism, respectively. In contrast, in vitro studies with adrenals from rats aged 10 and 16 days showed no effect of age on either basal or adrenocorticotropic hormone-stimulated production of corticosterone. Chronic administration of exogenous corticosterone to hyperthyroid animals resulted in significantly higher concentrations of serum corticosterone than did an identical administration to hypothyroid animals. As hyperthyroidism was associated with marked elevations in the concentration of corticosteroid-binding globulin and in the extent of binding of corticosterone, these results suggest that the effects of both age and thyroid status on serum concentrations of corticosterone may reflect changes in the metabolic clearance of the hormone.

Suppression of follicular maturation by infusion of a luteinizing hormone-releasing hormone agonist starting during the late luteal phase in the stumptailed macaque monkey.

The effect of continuous administration of an LHRH agonist for 14 days on follicular estradiol secretion was studied in adult female stumptailed macaque monkeys. The infusion was started either during the early follicular phase or during the late luteal phase. Both treatments resulted in a rise in serum concentrations of LH and FSH for 2-3 days, after which time values returned to basal levels. Infusion during the early follicular phase induced a rapid rise in serum concentrations of estradiol, which declined after 7-10 days. The normal rise in serum progesterone after midcycle failed to occur, indicating that ovulation had been inhibited. Infusion during the late luteal phase of the cycle prevented the normal rise in serum concentrations of FSH and estradiol at the end of the luteal phase, and there was no indication of follicular estradiol production during the subsequent infusion period. Removal of the minipumps after 14 days was followed promptly by normal cycles, regardless of when the infusion had been started. In a second experiment, infusion of LHRH agonist was started during the luteal phase and extended for 90 days. This resulted in marked and sustained suppression of estradiol secretion and total absence of progesterone rises. These findings show that in the monkey, a rapid and sustained suppression of estradiol production can be obtained if a long term infusion of LHRH agonist is started during the luteal phase of the cycle. Such an approach in women using infusion pumps or sustained delivery preparations may be the most effective way of achieving a medical ovariectomy for the treatment of endometriosis, leiomyomata, and other estrogen-dependent pathological conditions.

Evidence of direct thyroid-stimulating action of thyrotropin-releasing hormone by perifusion of rat thyroid fragments.

The possibility that TRH has a direct thyroid-stimulating action has never been reported. A number of studies have shown a rise in serum concentrations of thyroid hormone after stimulation with TRH, without a rise in TSH secretion. This has led us to test TRH with rat thyroid fragment perifusion. Significant T4 release was observed for TRH concentrations as low as 1.7 X 10(-11) M. A dose-response curve was determined. The response was immediate, reaching a peak after the sixth minute and continuing for 15 min after the stimulation had ceased. This kinetic pattern is different from the one observed with TSH and with theophylline and suggests that a different mechanism may be involved. TRH seems to be capable of directly stimulating both the secretion of the pituitary hormone (TSH) and the corresponding peripheral gland, like LHRH, which also acts directly on the Leydig cells of the testis.

Ciprofloxacin distribution in prostatic tissue and fluid following oral administration.

The penetration of ciprofloxacin into prostatic tissue was studied following oral administration of 500 mg either once or repeatedly in 12-hourly intervals. Following single administration ciprofloxacin was rapidly absorbed from the gastrointestinal tract peaking 1-2 h after administration. Elimination from serum was slow, the half life being 4.3 h. No significant rise in serum concentrations was noticed following repeated administration. Ciprofloxacin was concentrated in the prostatic tissue, levels being on average twice as high as the corresponding serum concentrations. The ratios between prostate and serum levels following single and repeated administration were 227 and 214%, respectively. Intraindividual analysis of prostate concentrations in different areas of the prostatic gland revealed a homogeneous distribution within the prostate. Penetration of ciprofloxacin into prostatic fluid was studied in 11 patients 2-4.5 h after administration. At these points ratios between prostatic fluid and serum ranged between 1.5 and 450%.

The diurnal variations of serum prolactin levels before and during pregnancy in normal and hyperprolactinemic patients

The pattern of 24-hour secretion of prolactin was evaluated in three normal pregnant subjects at the tenth, twenty-fourth, and thirty-sixth gestational week. A similar study was performed in three hyperprolactinemic subjects throughout the course of their gestations. The findings confirm the progressive rise in serum concentrations of prolactin throughout pregnancy in normal subjects, with a tendency to blunting of the ratio of the nighttime mean to the daytime mean (XsXa) as pregnancy progresses. One hyperprolactinemic subject (nontumoral) followed this pattern but demonstrated blunting initially and throughout pregnancy. The other two hyperprolactinemic subjects (one tumoral and one nontumoral) demonstrated an unexpected response in that they remained unresponsive to the increasing concentrations of estradiol throughout pregnancy.

Further studies on adrenarche in nonhuman primates.

Serum concentrations of dehydroepiandrosterone (DHA), DHA sulfate, and cortisol were measured in 52 chimpanzees (aged 0.5--10 yr), 76 Macaca mulatta (aged 0.25--5 yr), and 80 Macaca nemestrina (aged 0.5--9 yr). Sexual maturation was assessed by age and by the presence of menarche or the appearance of perineal turgescence in the females and by measurement of serum testosterone in the males. In an additional group of 10 young adult female M. mulatta, four repeated determinations of these same steroids at 30-min intervals demonstrated that the stress of capture and venipuncture caused a significant rise in serum levels of not only cortisol but also of DHA and DHA sulfate. The chimpanzees demonstrated an age-related rise in serum concentrations of DHA and DHA sulfate relative to cortisol which began before the onset of puberty and thus closely resembled human adrenarche. In M. mulatta, serum DHA levels showed no change with age, while DHA sulfate values decreased progressively both before and during puberty. The pattern in M. nemestrina was similar, with stable DHA and declining DHA sulfate levels before and during puberty. However, in the oldest group (aged 6--9 yr) of mature M. nemestrina, there was a significant postpubertal rise of both DHA and DHA sulfate with no change in serum cortisol. These data suggest that monkeys, just as higher primates, may show increasing adrenal secretion of C19 steroids at around 6--9 yr. This adrenarchal process appears to be completely independent of sexual maturation and probably merely reflects the influence of progressive adrenal growth and the resulting impact of changing intraadrenal steroid concentrations upon steroidogenesis in the zona reticularis.

Seasonal fluctuations in serum concentrations of vitamin D metabolites in normal subjects.

Serum concentrations of 25-hydroxycholecalciferol (25-OHD), 24,25-dihydroxycholecalciferol (24,25-(OH)2D), and 1,25-dihydroxycholecalciferol (1,25-(OH)2D) were measured at monthly intervals throughout the year in eight normal subjects. 25-OHD was measured by competitive protein-binding assay after Sephadex LH 20 chromatography, 24,25-(OH)2D by competitive protein-binding assay after Sephadex LH 20 and high-pressure chromatography, and 1,25-(OH)2D by radioimmunoassay after the same separation procedure as for 24,25-(OH)2D. A seasonal variation, apparently dependent on exposure to ultraviolet light, was found for all three metabolites. A study in six other normal subjects showed that there was no diurnal rhythm in any of the metabolites. Oral administration of 2 microgram 1,25-(OH)2D caused a sharp rise in serum concentrations of 1,25-(OH)2D and no change in the concentrations of the two other metabolites, but by 12 hours the 1,25-(OH)2D concentration had returned to the basal value. The concentrations of all three metabolites studied vary according to the season. Thus to interpret these concentrations in any subject the normal range for the particular season must be referred to.

Variable sensitivity of prepubertal male rats to inhibin-like activity of bull seminal plasma and to testosterone propionate.

Bull seminal plasma (bSP) contains inhibin-like activity that can suppress the rise of serum concentrations of follicle stimulating hormone (FSH) and luteinizing hormone (LH) that otherwise occurs 24 h after castration in the male rat. The sensitivity of prepubertal rats to the, activity in bSP extract varied with the time of the year. In intact rats of the same age, bSP extract could always suppress serum FSH levels, but only sometimes did it affect serum LII; LH suppression occurred during times of greater sensitivity on the part of the acutely castrated rats. These variations in the response of 5-week-old rats to bSP extract may arise from seasonal changes that were observed in the sensitivity of acutely castrated rats to testosterone propionate. The concomitant changes in serum concentrations of LH and testosterone in intact animals indicated that the age of puberty did vary in our colony of rats. Despite the marked changes in the sensitivity of acutely castrated rats to bSP extract and testosterone propionate, serum concentrations of FSH and LH in intact rats showed little change throughout the year.

Pathologic versus physiologic cholestasis: Elevated serum concentration of a secondary bile acid in the presence of hepatobiliary disease

Serum levels of the primary bile acids cholic and chenodeoxycholic acid are transiently elevated in normal neonates and infants; this represents a state of "physiologic cholestasis." In this study we determined, using specific radioimmunoassay, the concentration of a secondary bile acid, sulfated lithocholate, in serum obtained from healthy infants and from those with various hepatobiliary diseases. The serum levels of sulfated lithocholate were low in 69 neonates (less than 5 days of age: mean +/- SEM = 0.45 +/- 0.05 mumoles/L) and in 78 normal infants (less than one year of age: 0.49 +/- 0.02); there was no postprandial rise. These values were similar to those seen in 95 older children (0.56 +/- 0.03) and in maternal (0.49 +/- 0.04) and cord blood (0.44 +/- 0.03) of the neonates. In contrast, in patients with neonatal cholestasis of any nature there was a consistent marked rise in serum concentrations of sulfated lithocholate (mean = 4.46 +/- 0.39, P less than 0.001). In infants monitored during the course of parenteral nutrition, elevated values of sulfated lithocholate often occurred in the presence of normal results of other liver function tests. Serum sulfated lithocholate concentration is an accurate index of neonatal hepatobiliary disease; the sensitivity and specificity of this test remain to be further defined.

Pharmacokinetics of mezlocillin in healthy volunteers.

Mezlocillin in doses of 1.0, 2.0, and 5.0 g and carbenicillin in doses of 2.0 g were given as bolus injections intravenously to 10 healthy volunteers. For mezlocillin, dose-dependent pharmacokinetics was detected. This is reflected by a more than proportional rise in serum concentrations and a decreased total body clearance as doses were increased. Per dose unit, the areas under serum concentration curves to infinity were 33.5 mug.h/ml for the 1.0-g dose, 47.2 mug.h/ml for the 2.0-g dose, and 54.8 mug.h/ml for the 5.0-g dose. The body clearance fell from 31.2 liters/h with the 1.0-g dose to 17.0 liters/h with the 5.0-g dose. This can be explained mainly by a marked depression of nonrenal clearance, which fell from 12.2 to 3.8 liters/h, compared with a parallel change in renal clearance from 19.0 to 13.2 liters/h. Contributing to the non-linearity may be biotransformation, evacuation via bile, or another process. With dose increments, rising amounts are recovered unchanged in the urine-61% after a 1.0-g dose compared with 69% after a 5.0-g dose. This clearly defines metabolism as a major factor of elimination. Carbenicillin, for which the first-order, two-compartment open model was applicable here as in previous studies, had a longer serum half-life than did mezlocillin. For the 2.0-g doses, the former had a half-life of 1.4 h, compared with 0.8 h for the latter (calculated as if the two-compartment model were fully valid). The relative area under the curve (see above) was 76.1 mug.h/ml after the 2.0-g dose.

Urea compounds that increase the biosynthesis of prostaglandins in vivo-in vitro

Various phenylurea analogues, when given orally to rats, increase serum concentrations of PGF2α- and PGE2-like prostaglandins (determined by SnCl2 diversion of the PG-synthetase toward PGF2α for purposes of radio-immunoassay). Of the active phenylureas, some of the most potent have been selected for further evaluation with the following findings: The stimulatory effects are somewhat specific since various chemical fragments of the entire molecule are unable to elicit the effects. Additionally, many members of other pharmacologic classes have been assessed for this function and found not to possess it. With the active phenylureas, prostaglandin stimulatory effects are dose and time-related; they are produced in intact as well as adrenalectomized rats. Chronic administration of active drugs gives no greater increments in PG serum concentrations than acute. The effects occur only in serum, not in plasmas. Platelet-rich plasma (PRP) can only be made to reveal these increases by addition of other appropriate substances like phospholipase A, arachidonic acid and others—substances that ‘trigger’ prostaglandin synthesis and/or make appropriate substrates available. Non-steroidal anti-inflammatory drugs (NSAIFD), given orally, prevent the rise in serum concentrations of PGs in response to the phenylureas. These latter effects are all reproduced, also, by direct additions of the phenylureas and NSAIFD to isolated platelets. All of these stimulatory-inhibitory effects require intact platelets. — lysates and sonicates and/or platelet-free plasmas do not reveal similar effects upon the addition of drugs. The stimulatory effects of phenylureas on prostaglandin synthesis occur without evidence of damage or leakage of the platelet cell membranes. Mechanism(s) and sites of action of the phenylureas of these various systems are unknown. And, although ascorbic acid can be shown to stimulate prostaglandin synthesis at higher concentrations than the phenylureas when added directly to platelets, it fails to do so when given orally — at higher dosages than shown for the substituted phenylureas (2000 mg/kg of ascorbic acid vs. 15–100 mg/kg for the substituted phenylureas).

Hepatic structure and function after modified jejunoileal bypass surgery for obesity.

The most serious adverse effect of standard intestinal bypass for obesity is the high incidence of hepatic dysfunction and death from hepatic failure. We therefore examined the long-term effects of a modified form of jejunoileal bypass (in which a greater continuous length of ileum is retained), on liver function in 120 patients. Substantial weight loss (119-0+/-SD 23-3 kg to 82-3+/-18-8 kg) occurred during the first nine months after surgery, accompanied by a significant rise in serum concentrations of bilirubin, alanine transferase, and alkaline phosphatase, and a significant reduction in albumin concentrations. Biochemical changes were unrelated to weight loss or halothane anaesthesia. After weight stabilisation liver function reverted to normal, and four years after bypass sulphobromophthalein retention and hepatic histology did not differ from those in obese controls. There were two postoperative deaths. Three other patients died during the period of rapid weight loss with severe hepatic steatosis. While transient mild impairment of liver function is common after modified jejunoileal bypass, clinically significant hepatic dysfunction is a rare and unexplained early complication.

Secretion of the adrenal androgen, dehydroepiandrosterone sulfate, during normal infancy, childhood, and adolescence, in sick infants, and in children with endocrinologic abnormalities

Serum concentrations of the adrenal androgen, dehydroepiandrosterone sulfate, were measured by radioimmunoassay in normal infants and children, in sick premature and full-term newborn infants, and in patients undergoing evaluation of the hypothalamic-pituitary-gonadal and -adrenal systems. Premature infants had significantly greater (p less than 0.001) levels of DHAS (263 +/- 40)[SE]migrong/dl) than did full-term infants (58.9 +/- 5.2) during the first ten days of life; further increments occurred in stressed "sick" infants. A gradual age- and maturity-related rise in serum concentrations of DHAS was observed during childhood with the earliest increase occurring prior to the onset of pubertal production of gonadal steroids. Serum levels of DHAS rose following administration of ACTH and were increased in patients with congenital adrenal hyperplasia, in whom rapid decrements followed treatment with dexamethasone. hCG or LH-RH treatment did not alter DHAS concentrations. These data suggest that direct secretion of DHAS by the adrenal gland and/or peripheral sulfation of DHA, rather than gonadal secretion, accounts for the majority of DHAS production. The involvement of adrenal androgens in the pubertal maturation of the reproductive endocrine system thus may be evaluated by quantitation of serum DHAS.

Effect of synthetic 15-methyl analog of PGE2 on gastric acid and serum gastrin response to peptone meal, pentagastrin, and histamine in duodenal ulcer patients.

The effect of 15(S)-15-methyl PGE2, methyl ester (15-ME-PGE2), used intravenously in a standard dose of 0.5 mug/kg-hr on gastric secretion and serum gastrin level was studied in 6 duodenal ulcer patients. 15-Me-PGE2 caused an immediate and almost complete inhibition of basal gastric acid and pepsin secretion. Acid secretion induced by a peptone meal and determined by intragastric titration technique was almost as high as the maximal response to histamine and accompanied by a significant rise in serum concentration of immunoassayable gastrin. 15-Me-PGE2 caused a sudden and complete inhibition of gastric acid response to a peptone meal. 15-Me-PGE2 did not significantly affect serum gastrin levels both under basal conditions and in response to a peptone meal. Gastric acid and pepsin output induced by maximal stimulation with pentagastrin (4 mug/kg-hr) was inhibited by 15-Me-PGE2 by about 70% and that induced by histamine by about 45%. After the withdrawal of 15-Me-PGE2 infusion, gastric secretion remained reduced for the remainder of the test. We conclude that 15-Me-PGE2 is a very strong inhibitor of gastric acid and pepsin secretion induced by various secretory stimuli, particularly under basal conditions and in response to a meal. In view of prolonged inhibitory activity, 15-Me-PGE2 may have clinical potential in the treatment of peptic ulcer disease.

Selective Actions of Prolactin on Catecholamine Turnover in the Hypothalamus and on Serum LH and FSH

The effects of prolactin (PRL) administration on catecholamine turnover in various brain regions of ovariectomized rats were determined by observing the decline of dopamine and norepinephrine concentrations after alpha-methyltyrosine (alphaMT) administration. PRL had no effect on the steady state concentration of dopamine in the median eminence, anterior hypothalamus and corpus striatum or on the norepinephrine concentration in the anterior hypothalamus. However, PRL selectively enhanced dopamine turnover in the median eminence and anterior hypothalamus after a latent period of 10-26 h. In addition, PRL administration significantly decreased serum concentrations of LH and FSH. These results suggest that the PRL-induced increase in activity of dopaminergic neurons in the median eminence or anterior hypothalamus may be responsible for the reduction of the post-castration rise in serum concentrations of LH and FSH.

Studies of GH secretion in mice by a homologous radioimmunoassay for mouse GH.

A sensitive homologous radioimmunoassay for mouse GH capable of measuring concentrations of GH as low as 1 ng/ml of mouse serum has been developed. This assay has been used to study GH secretion in C3H mice under several physiological conditions. Newborn mice possessed very high concentration of GH in serum which persisted for two weeks. Adult male mice had more GH in their pituitary (66.9 μg/mg) and serum (12.0 ng/ml) than comparable females (48.9 μg/mg; 3.4 ng/ml). Ovariectomy in female mice increased pituitary and serum concentrations of GH to male levels whereas stilbestrol administration decreased it. Orchiectomy or stilbestrol treatment of male mice resulted in decreased GH levels. During the estrous cycle, maximum levels of GH were attained during proestrus. Insulininduced hypoglycemia or treatment with L—dopa failed to induce rise in serum concentrations of GH in mice.(Endocrinology 91: 784, 1972)