Effect of estrogens on renal responsiveness to parathyroid hormone in elderly female subjects

The effect of estrogens on the renal responsiveness to parathyroid hormone (PTH) was examined by PTH loading tests with synthetic human-PTH (1-34) in 8 normal elderly females (mean +/- SD age, 81.0 +/- 7.1 yr) before and after administration of estrogen (Premarin 1.25 mg/day for 4 weeks). Basal urinary adenosine cyclic 3', 5'-monophosphate (cAMP) excretion showed a tendency to increase after estrogen administration (5.47 +/- 1.68 vs 6.60 +/- 2.67 nmol/100 ml GFR) and the theoretical renal phosphorous threshold showed a tendency to decrease from 3.22 +/- 0.98 to 2.73 +/- 0.56 mg/dl. The blood ionized calcium concentration did not change after estrogen administration (4.44 +/- 0.16 vs 4.32 +/- 0.20 mg/dl) and serum phosphorous (P) decreased significantly (3.65 +/- 0.47 vs 3.01 +/- 0.42 mg/dl, p less than 0.05). There was no increase in mean serum immunoreactive PTH (0.34 +/- 0.10 vs 0.34 +/- 0.05 ngeq/ml). The urinary excretions of cAMP in response to PTH loading [100 U of human-PTH (1-34), intravenously] significantly (p less than 0.05) increased (94.8 +/- 57.0 vs 196.7 +/- 118.3 nmol/100 ml GFR/h) after estrogen administration. Moreover the changes in urinary excretion of cAMP (r = 0.698, p less than 0.01) and P (r = 0.555, p less than 0.05) induced by the PTH loading were positively correlated with serum estradiol in elderly females, assessed as groups before and after estrogen administration. These results suggest that estrogens may enhance the renal responsiveness to exogenous PTH administration.     

Effects of aging on responses to furosemide

Furosemide causes both diuretic and non-diuretic changes in renal function. We compared responses to intravenous furosemide 0.5 mg.kg-1 in 38 subjects (30 males, 8 females) aged 18 to 30 with those in 14 subjects (9 males, 5 females) aged 50 and over. There were no consistent differences attributable to gender. Older persons showed greater natriuresis (47 percent in males and 26 percent in females) but their increment in plasma renin activity was markedly reduced. The urinary excretion of thromboxane B2 was elevated in older subjects (58 +/- 10 vs. 30 +/- 4 ng/4 h, p less than 0.05 for males; 48 +/- 7 vs. 29 +/- 4 ng/4 hr, p less than 0.05 for females) while that of 6-keto prostaglandin F1 alpha was not different. While differences in the diuretic response to furosemide may be due to pharmacokinetic differences, the non-diuretic response differences may reflect age related changes in renal prostaglandin synthesis.     

Sex differences due to dehydroepiandrosterone (DHEA) feeding affecting dehydroepiandrosterone sulfate secretion in golden Syrian hamsters.

The metabolism of orally administered dehydroepiandrosterone (DHEA) by male and female golden Syrian hamsters was examined by quantification of DHEA and dehydroepiandrosterone sulfate (DHEAS) in gallbladder bile, urine and feces using high-performance liquid chromatography (HPLC). Plasma levels of DHEA and DHEAS were also determined by radioimmunoassay (RIA). After 5 days of oral DHEA administration (100 mg/kg body weight twice a day), RIA showed that plasma levels of DHEA and DHEAS were increased approximately 3-6 and 4-5 times, respectively, compared to controls. More than 95 % of circulating DHEA (S) in the peripheral blood was DHEAS. There was no significant sex difference in DHEAS plasma levels between male and female animals in the DHEA-supplemented group. However, 0.2 - 0.3 % of ingested DHEA was conjugated to DHEAS and excreted in urine by females, whereas less than 0.002 % was excreted in urine by males (p < 0.005). DHEAS was excreted in bile by males after DHEA supplementation, and the sex differences in DHEAS levels observed in bile were statistically significant (male, 18.7 +/- 7.5 vs. female, 5.6 +/- 3.1 micromol/l) (p < 0.005). Small amounts of ingested DHEA were excreted in an unchanged state in feces, and no sex difference was observed. These results suggest that there is a considerable sex difference in the conjugation and excretion of orally administered DHEA in the hamster.     

Long term 'marine diet' in Eskimos is not associated with altered urinary excretion of total tetranor prostaglandin metabolites

The total urinary excretion of tetranor prostaglandin metabolites, measured as tetranorprostanedioic acid (TPD), was quantified in traditionally living Greenland Eskimos (E) and compared with that in Caucasian Danes (D). TPD excretion (microgram/24h) was not significantly different between both groups, neither for males (331 +/- 62.4 (E) vs. 331 +/- 25.7 (D), mean +/- SEM, n = 9 and 10) nor for females (190 +/- 31.7 (E) vs. 264 +/- 27.4 (D), n = 11 and 10, P2 greater than 0.05). Since urinary prostaglandin metabolites are thought to reflect the total prostaglandin turnover in vivo, these results suggest that a long-term intake of relatively large amounts of polyunsaturated fatty acids of the (n-3) family does not alter total prostaglandin turnover in vivo. This is in contrast to stimulated prostanoid formation in vitro, and thus suggests a different regulatory role of dietary and tissue fatty acids for 'stimulated' and 'basal' prostaglandin production.     

Mechanism of enhanced bioavailability and diuretic effect of azosemide by ascorbic acid in rats

To increase the extent of comparative oral bioavailability (F) value and the diuretic and natriuretic effects of orally administered azosemide, ascorbic acid was coadministered to rats. The rationales for this study are that ascorbic acid might inhibit intestinal first-pass effect of azosemide and might increase the unionized fraction of azosemide at the receptor sites. After oral administration of azosemide (20 mg/kg) with 100 mg of ascorbic acid, the F value (138% vs. 100%), 8-h urinary excretion of azosemide (5.18% vs. 1.32% of oral dose), 8-h urine output (41.3 vs. 23.0 ml), and 8-h urinary excretion of sodium (24.6 vs. 15.3 mmol/kg) were greater than controls (without ascorbic acid). The amount of spiked azosemide remaining after 30 min incubation of 50 mug of azosemide with the 9000 g supernatant fraction of rat small intestine was significantly greater by 100 microg of ascorbic acid (45.3 vs. 40.9 microg) than controls (without ascorbic acid). After oral administration of azosemide with NH4Cl, the urine pH decreased by 0.5 U, and 8-h urine output (25.8 vs. 11.0 ml) and 8-h urinary excretion of sodium (13.3 vs. 6.89 mmol/kg) were significantly greater than controls (without NH4Cl). The increase in F value and diuretic and natriuretic effects of azosemide with coadministration of ascorbic acid seemed to be due to reduced intestinal first-pass metabolism of azosemide, increased urinary excretion of azosemide, and increased unionized fraction of azosemide at the renal tubular receptor sites.     

Effect of trilostan on steroid excretion in man: compensated inhibition of 3 beta-hydroxysteroid dehydrogenase

Trilostan (240, 360 and 480 mg/day administered p.o. to healthy men) induced an increase (P less than 0.05) in the urinary excretion rates of DHEA, androstenediol and pregnenolone but failed to influence the excretion rates of cortisol, aldosterone, and of the four glucocorticoid metabolites, THF, allo-THF, THE and allo-THE. A rise in plasma renin concentrations was seen in the initial phase of the trial. Administration of dexamethasone in addition to trilostan suppressed plasma and urinary concentrations of cortisol and the excretion rates of all estimated steroid metabolites but did not modify the relative abundance in the excretion rates of DHEA, androstenediol and pregnenolone. These results confirm that trilostan interferes with the activity of 3 beta-hydroxysteroid dehydrogenase in man. However, under physiological conditions production of cortisol and aldosterone is kept at a constant level, most likely by compensatory stimulation of the secretion of ACTH and renin.     

Increase in plasma 5 alpha-androstane-3 alpha,17 beta-diol glucuronide as a marker of peripheral androgen action in hirsutism: a side-effect induced by cyclosporine A

Dose-dependent hypertrichosis is a common dermatological side-effect affecting the majority of patients treated with cyclosporine A (CSA). Previous studies have not demonstrated the influence of CSA on specific sex hormone levels. The aim of this study is to investigate whether CSA increases the activity of 5 alpha-reductase, an enzyme which transforms androgens into dihydrotestosterone in peripheral tissues. The metabolite which best reflects this activity is 5 alpha-androstane-3 alpha,17 beta-diol glucuronide (Adiol G). The study was carried out on 49 insulin-dependent diabetes patients participating in the double-blind "Cyclosporine-Diabète-France" clinical trial, of which 28 were treated with CSA (16 males and 12 females), and 21 received only placebo (10 males and 11 females). All patients underwent extensive clinical and laboratory evaluations prior to and during the present study. In addition to Adiol G, testosterone (T), dehydroepiandrosterone sulfate (DHEA S) and sex hormone-binding globulin (SHBG) were assayed. Levels of Adiol G increased significantly in CSA-treated groups: males, 11.86 +/- 2.58 vs 7.83 +/- 2.30 nmol/l; females, 4.48 +/- 2.70 vs 2.10 +/- 1.22 nmol/l; P less than 0.02 (comparison of means). There were no significant differences in this parameter before and during treatment in either the male or female placebo groups (paired t-test). During the treatment period, T, DHEA S, SHBG and the T/SHBG ratio did not significantly change with respect to their baseline values in any of the groups studied (comparison of means). Comparison (using paired t-test) showed a significant increase of DHEA S in CSA-treated groups: males, delta = 3.08 +/- 3.33 nmol/l, P less than 0.01; females, delta = 0.98 +/- 1.13 nmol/l, P less than 0.05. In conclusion, it is possible that CSA induces hypertrichosis or hirsutism by increasing 5 alpha-reductase activity in peripheral tissues. Nevertheless the role of increased DHEA S as a possible Adiol G precursor cannot be excluded.     

The source of urinary epidermal growth factor in humans

To clarify the source of human urine EGF, we studied EGF renal clearance in 20 healthy, young adult subjects. Immunoreactive EGF was measured hourly in EDTA plasma, heparin plasma, serum and urine of 12 males and 8 females during a 3 h study period. Plasma and urine creatinine and creatinine clearance were measured and calculated hourly. Mean (and SEM) creatinine clearance was similar in males and females (118 +/- 12 vs 105 +/- 6 ml/min). EGF was not detectable in plasma, whereas relatively high levels were measured in serum (2.5 +/- 0.25 vs 1.5 +/- 0.18 ng/ml in males and females respectively p less than 0.05). Urine EGF excretion averaged 1641 +/- 233 ng/h in males and 1507 +/- 191 ng/h in females (p greater than 0.05). A significant correlation was observed between urine creatinine and urine EGF concentrations in both male (r = 0.98, p less than 0.01) and female (r = 0.94, p less than 0.01) subjects. EGF immunoreactivity in urine and serum eluted from G-75 sephadex columns similarly to recombinant 6000 Mr hEGF. Urine excretion of EGF approximated 1.5 micrograms/h or 25 ng/mg creatine. The high concentrations of EGF found in urine in the face of non-detectable levels of EGF in plasma favor the hypothesis that EGF in urine is derived from kidney synthesis and secretion. The significant positive correlation between urine creatinine and urine EGF suggests a functional correlation between glomerular filtration and the process of tubular EGF excretion.     

Urinary excretion of free progestins, androgens, and estradiol after injection of (1-24)ACTH in the Mongolian gerbil

Injection of a "long-acting" synthetic adrenocorticotrophin [(1-24)ACTH, 20 IU/animal] into Mongolian gerbils resulted in a 3.1 fold increase of urinary free testosterone excretion over 2 days. It was accompanied by an elevation of urinary free progesterone (2.1 fold), 17-hydroxyprogesterone (2.5 fold), DHEA (2.8 fold) and androstenedione (3.0 fold) excretion. Similarly, administration of human chorionic gonadotrophin (HCG, 100 IU/animal) increased urinary excretion of free testosterone (2.3 fold), progesterone (4.1 fold), 17-hydroxyprogesterone (2.9 fold), DHEA (4.6 fold), androstenedione (5.4 fold) and of estradiol (2.9 fold). Data presented in this work show that the measurement of urinary free steroid excretion represents a reliable index for the secretory activity of the adrenal-gonadal-axis, and that it may in some aspects be more practicable than the measurement of steroid plasma levels, especially in small laboratory animals, enabling us to monitor the excretion of various steroids over longer time periods without stressing the animals by handling/or blood sampling.     

Reference intervals of urinary steroid metabolites using gas chromatography-mass spectrometry in Chinese adults

BACKGROUND: Urinary steroid profiling by GC or GC-MS are established clinical tools to complement other biochemical tests in the diagnosis and investigation of a wide range of adrenocortical disorders, but normative data on adults using the more specific GC-MS are lacking. Our objective was to set up the reference intervals of commonly detected urinary steroid metabolites as well as marker metabolites seen in disease states. METHOD: Apparently healthy adult Chinese males and females were recruited by completing health questionnaires. A 24-h urine specimen was collected from all the participants for urinary steroid profiling by GC-MS in cyclic scan mode. The analyzer was calibrated by using authentic steroid standards. Statistical methods recommended by the National Committee for Clinical Laboratory Standards were followed for setting up the reference intervals of various steroid metabolites. After outliers were excluded, the data were tested for the necessity to partition into sex-, menopausal status- and age-specific reference intervals. RESULTS: 83 males and 89 females were recruited for the study. Necessity to partition into sex-specific reference intervals was demonstrated for almost all steroid metabolites. Menopausal status and age also had a significant impact on steroid metabolite excretion, making separate reference intervals necessary. CONCLUSIONS: We have set up the normative data on the levels of urinary steroid metabolite excretion in Chinese adults for future reference in patient management and research in steroid metabolism.     

A novel radioimmunoassay of 7-oxo-DHEA and its physiological levels

A novel radioimmunoassay (RIA) of unconjugated 7-oxo-dehydroepiandrosterone (7-oxo-DHEA) in human serum was developed for the first time. This steroid is an intermediate in the biosynthesis of immunomodulatory 7-hydroxylated DHEA metabolites, and has been shown to possess thermogenic properties. The method employs polyclonal rabbit antiserum to (19E)-3beta-hydroxy-7,17,19-trione-19-O-(carboxymethyloxime):BSA conjugate and a homologous radioiodinated derivative with tyrosine methyl ester. The cross reactivity of the antiserum with structurally closest 7-hydroxyepimers of DHEA was lower than 1.7%, with DHEA 0.4%, with all other related steroid less than 0.4%. The method includes ether extraction of serum (0.5 ml), followed by RIA. Its detection limit was 0.06 pmol (18 pg)/tube, the average intra- and inter-assay coefficients of variation were 4.1% and 8.3%, respectively. Mean recovery of serum spiked with 7-oxo-DHEA varied between 78.8% and 112%. Its levels in three serum pools were compared with a low-resolution gas chromatography-mass spectrometry method with satisfactory results. The method has been used for determination of 7-oxo-DHEA in serum samples of 215 subjects (91 males and 124 females) without overt endocrine disorders, aged 5-71 years. The over-all mean+/-S.D. was 0.280+/-0.227, the median 0.239 nmol/l. No significant sex differences were recorded. The only group which differed significantly from all other ones were males below 10 years, significantly lower values than in other age groups were found also in the first two age groups of females.     

Intrauterine position affects sex-accessory biochemistry in adult female mice

Female mouse fetuses that develop in utero implanted between two male fetuses (2M females) are shown as adults to have significantly elevated (P less than 0.01) levels of beta-glucuronidase activity in their preputial glands compared to that of OM females, females that had not been contiguous to males in utero, and 1M females, females contiguous in utero to only one male (mean +/- SEM, 2M females = 23,9 +/- 2.1, 1M females = 13.3 +/- 5.2, and OM females = 7.8 +/- 2.5 Modified Sigma Units/mg frozen weight). It is hypothesized that the increased enzymatic activity in the preputial glands of 2M females could be important in releasing steroid metabolites from voided urine. These metabolites could then act as pheromones and thus explain some of the described differences in sexual behavior correlated with intrauterine position.     

Effect of oral DHEA on serum testosterone and adaptations to resistance training in young men.

This study examined the effects of acute dehydroepiandrosterone (DHEA) ingestion on serum steroid hormones and the effect of chronic DHEA intake on the adaptations to resistance training. In 10 young men (23 +/- 4 yr old), ingestion of 50 mg of DHEA increased serum androstenedione concentrations 150% within 60 min (P < 0.05) but did not affect serum testosterone and estrogen concentrations. An additional 19 men (23 +/- 1 yr old) participated in an 8-wk whole body resistance-training program and ingested DHEA (150 mg/day, n = 9) or placebo (n = 10) during weeks 1, 2, 4, 5, 7, and 8. Serum androstenedione concentrations were significantly (P < 0.05) increased in the DHEA-treated group after 2 and 5 wk. Serum concentrations of free and total testosterone, estrone, estradiol, estriol, lipids, and liver transaminases were unaffected by supplementation and training, while strength and lean body mass increased significantly and similarly (P < 0.05) in the men treated with placebo and DHEA. These results suggest that DHEA ingestion does not enhance serum testosterone concentrations or adaptations associated with resistance training in young men.     

Sexual dimorphism in the renin-angiotensin system in aging spontaneously hypertensive rats

In young adult spontaneously hypertensive rats (SHR), mean arterial pressure (MAP) is higher in males than in females and inhibition of the renin-angiotensin system (RAS) eliminates this sex difference. After cessation of estrous cycling in female SHR, MAP is similar to that in male SHR. The purpose of this study was to determine the role of the RAS in maintenance of hypertension in aging male and female SHR. At 16 mo of age, MAP was similar in male and female SHR (183+/-5 vs. 193+/-8 mmHg), and chronic losartan (40 mg.kg-1.day-1 po for 3 wk) reduced MAP by 52% (to 90+/-8 mmHg, P<0.05 vs. control) in males and 37% (to 123+/-11 mmHg, P<0.05 vs. control) in females (P<0.05, females vs. males). The effect of losartan on angiotensin type 1 (AT1) receptor blockade was similar: MAP responses to acute doses of ANG II (62.5-250 ng/kg) were blocked to a similar extent in losartan-treated males and females. F2-isoprostane excretion was reduced with losartan more in males than in females. There were no sex differences in plasma renin activity, plasma angiotensinogen or ANG II, or renal expression of AT1 receptors, angiotensin-converting enzyme, or renin. However, renal angiotensinogen mRNA and protein expression was higher in old males than females, whereas renal ANG II was higher in old females than males. The data show that, in aging SHR, when blood pressures are similar, there remains a sexual dimorphism in the response to AT1 receptor antagonism, and the differences may involve sex differences in mechanisms responsible for oxidative stress with aging.     

Assessment of urine and fecal testosterone metabolite excretion in Chinchilla lanigera males

Endemic chinchilla (Chinchilla spp.) populations are nearly extinct in the wild (South America). In captive animals (Chinchilla lanigera and C. brevicaudata), reproduction is characterized by poor fertility and limited by seasonal breeding patterns. Techniques applied for studying male reproductive physiology in these species are often invasive and stressful (i.e. repeated blood sampling for sexual steroids analysis). To evaluate endocrine testicular function, the present experiments were designed to (a) determine the main route of testosterone excretion (14C-testosterone infusion in four males); (b) validate urine and fecal testosterone metabolite measurements (HPLC was used to separate metabolites and immunoreactivity was assessed in all metabolites using a commercial testosterone radioimmunoassay, and parallelism, accuracy and precision tests were conducted to validate the immunoassay); and (c) investigate the biological relevance of the techniques applied (quantification of testosterone metabolite excretion into urine and feces from five males injected with hCG and comparison between 10 males and 10 females). Radiolabelled metabolites of 14C-testosterone were excreted, 84.7+/-4.2 % in urine and 15.2+/-3.9 % in feces. A total of 82.7+/-4.2% of urinary and 45.7+/-13.6% of fecal radioactivity was excreted over the first 24 h period post-infusion (metabolite concentration peaked at 8.2+/-2.5 h and 22.0+/-7.0 h, respectively). Several urinary and fecal androgen metabolites were separated by HPLC but only fecal metabolites were associated with native testosterone; however, there was immunoreactivity in more than one metabolite derived from 14C-testosterone. After hCG administration, an increase in androgen metabolite excretion was observed (p<0.05). Males excreted greater amounts daily of urinary androgen metabolites as compared with females (p<0.05); this difference was not evident in feces. Results of the present study indicate that the procedure used is a reliable and non-invasive method to repeatedly monitor variations in testicular endocrine activity in this species. It can be a useful tool that would help ensure the survival of the wild populations as well as to provide the basis for a more efficient use by the fur industry.     

Comparative effects of dehydroepiandrosterone sulfate on ventricular diastolic function with young and aged female mice

The adrenal steroid hormone dehydroepiandrosterone (DHEA) and its sulfated derivative [DHEA(S)] have been extensively studied for their potential anti-aging effects. Associated with aging, DHEA levels decline in humans, whereas other adrenal hormones remain unchanged, suggesting that DHEA may be important in the aging process. However, the effect of DHEA(S) supplementation on cardiac function in the aged has not been investigated. Therefore, we administered to young and old female mice a 60-day treatment with exogenous DHEA(S) at a dose of 0.1 mg/ml in the drinking water and compared the effects on left ventricular diastolic function and the myocardial extracellular matrix composition. The left ventricular stiffness (beta) was 0.30 +/- 0.06 mmHg/mul in the older control mice compared with 0.17 +/- 0.02 mmHg/mul in young control mice. Treatment with DHEA(S) decreased left ventricular stiffness to 0.12 +/- 0.03 mmHg/mul in the older mice and increased left ventricular stiffness to 0.27 +/- 0.04 mmHg/mul in young mice. The mechanism for the DHEA(S)-induced changes in diastolic function appeared to be associated with altered matrix metalloproteinase activity and the percentage of collagen cross-linking. We conclude that exogenous DHEA(S) supplementation is capable of reversing the left ventricular stiffness and fibrosis that accompanies aging, with a paradoxical increased ventricular stiffness in young mice.     

Reduced urinary aldosterone excretion rates with normal plasma concentrations of aldosterone in the very elderly

Although aldosterone production declines with age, so does the aldosterone metabolic clearance rate (MCR), and the net effect of age on the circulating level of aldosterone may be less than can be predicted from production rates alone. The effect of age on aldosterone production and plasma levels was studied in a group of elderly individuals at a very advanced age when susceptibility to the impacts of age might be particularly pronounced. Seventeen nursing home patients, ages 75-99 (mean age 86 years), had aldosterone production assessed from the urinary excretion rate of the acid hydrolyzable 18-glucuronide conjugate of aldosterone. Aldosterone excretion was low in the elderly when compared to a group of healthy, young to middle-aged subjects: 123 +/- 19 (SEM) vs. 234 +/- 18 ng/h (P less than 0.001). However, plasma aldosterone concentrations in the elderly were well within a range observed in much younger and fully ambulatory subjects: 14.1 +/- 1.3 in the elderly vs. 15.9 +/- 1.8 ng/dL in the young. The plasma aldosterone concentration was apparently maintained at a normal level by a coincident decrease in both the metabolic clearance rate and the aldosterone production rate. In conclusion, an aldosterone deficiency state resulting from an age-correlated reduction in aldosterone production is probably uncommon in the elderly.     

Urinary analysis of 16(5alpha)-androsten-3alpha-ol by gas chromatography/combustion/isotope ratio mass spectrometry: implications in anti-doping analysis

We present a method for the analysis of urinary 16(5alpha)-androsten-3alpha-ol together with 5beta-pregnane-3alpha,20alpha-diol and four testosterone metabolites: androsterone (Andro), etiocholanolone (Etio), 5alpha-androstane-3alpha,17beta-diol (5alphaA), 5beta-androstane-3alpha,17beta-diol (5betaA) by means of gas chromatography/combustion/isotopic ratio mass spectrometry (GC/C/IRMS). The within-assay and between-assay precision S.D.s of the investigated steroids were lower than 0.3 and 0.6 per thousand, respectively. A comparative study on a population composed of 20 subjects has shown that the differences of the intra-individual delta(13)C-values for 16(5alpha)-androsten-3alpha-ol and 5beta-pregnane-3alpha,20alpha-diol are less than 0.9 per thousand. Thereafter, the method has been applied in the frame of an excretion study following oral ingestion of 50 mg DHEA initially and oral ingestion of 50mg pregnenolone 48 h later. Our findings show that administration of DHEA does not affect the isotopic ratio values of 16(5alpha)-androsten-3alpha-ol and 5beta-pregnane-3alpha,20alpha-diol, whereas the isotopic ratio values of 5beta-pregnane-3alpha,20alpha-diol vary by more 5 per thousand upon ingestion of pregnenolone. We have observed delta(13)C-value changes lower than 1 per thousand for 16(5alpha)-androsten-3alpha-ol, though pregnenolone is a precursor of the 16-ene steroids. In contrast to 5beta-pregnane-3alpha,20alpha-diol, the 16-ene steroid may be used as an endogenous reference compound when pregnenolone is administered.     

Postabsorption antidotal effects of N-acetylcysteine on acetaminophen-induced hepatotoxicity in the mouse

Male Swiss Webster mice, treated with N-acetylcysteine (NAC, 500 mg/kg po) 1 h following acetaminophen (NAPA, 350 mg/kg po) administration, had control levels of transaminases indicating that NAC protects against NAPA-induced hepatotoxicity by postabsorption antidotal mechanism(s). Hepatic congestion induced by NAPA was reduced by NAC. Significantly higher elimination rate constants (K) for indocyanine green (500 micrograms/kg, iv) in mice treated with NAPA and NAC (K = 0.676 +/- 0.062) than in animals receiving NAPA alone (0.341 +/- 0.105) suggested NAC improved or preserved the hepatic circulation of the compromised liver. This NAC-induced improvement and (or) preservation of hepatic circulation was reflected in biliary and urinary excretion of acetaminophen and its metabolites by a general increase in elimination during the first 6 h (70.2 +/- 2.6 vs. 32.6 +/- 7.1%), and in the repletion of glutathione (GSH) in the liver by a return to control levels more quickly (3 vs. greater than 5 h) following depletion by NAPA. The metabolic consequences of the postabsorption antidotal effect of NAC in the compromised liver was a preferential excretion of sulphydryl-derived metabolites in the 1-4 h bile (GSH conjugate 11.30 +/- 1.25 vs. 7.25 +/- 0.39%) which was subsequently observed in the urine by preferential excretion of glutathione degradation products.     

Effect of low birth weight on adrenal steroids and carbohydrate metabolism in early adulthood

AIM: Data are inconsistent whether hyperinsulinemia might be associated with adrenal hyperandrogenism in young adults born with low birth weight (LBW). METHOD: We investigated the insulin and adrenal steroid production of 70 young LBW adults [33 women (birth weight: 1,795 +/- 435 g) and 37 men (birth weight: 1,832 +/- 337 g)]. Their results were compared to those of 30 controls (14 men, 16 women), born with normal weight. RESULTS: In LBW women, we measured higher basal DHEA (33.5 +/- 13.1 vs. 23.6 +/- 8.7 nmol/l, p < 0.05), DHEAS (8.0 +/- 2.3 vs. 6.3 +/- 2.1 micromol/l, p < 0.05), androstenedione (8.3 +/- 2.8 vs. 6.0 +/- 2.2 nmol/l, p < 0.05) and cortisol (0.25 +/- 0.07 vs. 0.20 +/- 0.07 micromol/l, p < 0.05) levels and higher insulin response during oral glucose tolerance test (log.AUCins: 2.62 +/- 0.06 vs. 2.57 +/- 0.03, p < 0.05). DHEA levels correlated with fasting insulin levels (r = 0.45, p < 0.01) and insulin response (r = 0.33, p < 0.05). In LBW men, higher cortisol (0.27 +/- 0.06 vs. 0.22 +/- 0.06 micromol/l, p < 0.01) and SHBG (18.4 +/- 10.4 vs. 12.7 +/- 5.9 nmol/l, p < 0.05) levels were found. CONCLUSIONS: Our results suggest that modest hypercortisolism is present in young LBW adults. While the endocrine sequel of hypercortisolism raised insulin response and hyperandrogenism is detectable in apparently healthy young LBW women, it is absent in young LBW men. This suggests that gender-dependent mechanisms might play a role in the development of insulin resistance in LBW adults.