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At least 631 records · Page 35Linked to original sources

PubMed1986

Fetal growth of beef calves. I. Effect of prepartum dietary crude protein on birth weight, blood metabolites and steroid hormone concentrations.

Fifty-nine crossbred heifers (427 kg) bred to one Hereford sire were randomly assigned at 75 d prepartum to two diets. Heifers were individually fed, and diets were isocaloric but contained either a low (LP = 81% NRC, .56 kg/d) or high (HP = 141% NRC, .98 kg/d) level of crude protein. Jugular vein cannulae were inserted into 16 LP and 16 HP heifers at 10 prepartum. Daily preprandial blood samples that were collected until parturition were analyzed for serum estradiol-17 beta (E2), progesterone (P4), glucose (G) and urea nitrogen (UN). Heifers fed LP gained slower than HP-fed heifers before calving (.73 vs 1.02 kg/d; P less than .01); immediate post-calving weights and condition scores were 418 vs 444 kg (P less than .01) and 5.4 vs 6.1 (P less than .01; LP vs HP, respectively). Calf birth weights (35.3 vs 36.1 kg), average calving difficulty score (1.6 vs 1.6) and percent assisted births (35.5 vs 35.7%) did not differ (P greater than .10; LP vs HP, respectively). Prepartum concentrations of UN (6.2 vs 13.5 mg/dl) and G (52.9 vs 58.2 mg/dl) were lower (P less than .05) and P4 (5.94 vs 4.26 ng/ml) was higher (P approximately equal to .07) in LP heifers. Prepartum concentration profiles were related to calving difficulty score (CD, 1 = no assistance to 3 = hard pull) for E2 (CD1 vs CD2 + CD3, P less than .01; CD2 vs CD3, P approximately equal to .01), P4 (CD1 vs CD2 + CD3, P less than .05), G (CD1 vs CD2 + CD3, P less than .05) and UN (CD2 vs CD3, P less than .05). After calving, all dams were maintained together on pasture and supplemented with alfalfa hay and grain mix until adequate range forage was available to maintain weight gains. Dams that were fed LP prepartum gained faster than HP dams during this period (.49 vs .15 kg/d; P less than .01). Prebreeding weights (443 vs 453 kg; LP vs HP) and condition scores (5.1 vs 5.1) did not differ, nor was the postpartum interval affected (44 vs 40 d; LP vs HP). There was no effect of dietary protein on dystocia or postpartum interval, although there were diet-induced differences in body weight and condition of the dams at calving. Results indicate that differences in prepartum profiles of serum steroid hormones and metabolites may be related to dystocia, in addition to relative fetal oversize.

Animals↗

PubMedDate not supplied

Clinical pharmacokinetics of the newer intravenous anaesthetic agents.

In the last 15 years the role of opioids in anaesthesia management has undergone dramatic change. Initially used as premedicants, or adjuvants to inhalation anaesthetic agents or as analgesics for postoperative pain relief, narcotics have now evolved into primary anaesthetic agents, primarily because of their ability to maintain cardiovascular stability especially in patients with compromised myocardial function. Sufentanil, alfentanil, and lofentanil are 3 new synthetic congeners of fentanyl. Sufentanil and alfentanil afford not only the haemodynamic stability but also the desirable anaesthetic properties of analgesia, and unconsciousness. Their major advantage lies in their pharmacokinetic behaviour; a rapid onset of action and short elimination half-life, allowing for greater flexibility in anaesthetic management. Sufentanil's pharmacokinetic profile is consistent with a 2-compartment model. Its elimination half-life is 149 minutes and its clearance is 11.3 ml/min/kg. Alfentanil's pharmacokinetic profile has been described by both 2- and 3-compartment models. Its distribution and redistribution are rapid, with an elimination half-life of 83 to 137 minutes and a clearance of 4.37 to 6.47 ml/min/kg in adult patients. Lofentanil, however, is an extremely long-acting narcotic analgesic. Presently, its use is justified only when prolonged mechanical ventilation is anticipated. Etomidate, a carboxylated imidazole, is rapidly distributed within a central compartment and then to peripheral compartments; its slow distribution and terminal elimination half-lives are 28 and 273 to 330 minutes, respectively, and its clearance (11.6 to 25 ml/min/kg) is equal to its hepatic plasma flow. Its ability to maintain cardiovascular stability in patients with compromised myocardial function make it a useful induction agent. However, reports of increased mortality and inhibition of steroidogenesis in patients receiving either single injections or constant infusions have created controversies regarding its use. Minaxolone is a water-soluble steroid whose pharmacokinetic profile is consistent with a 2-compartment model. Distribution is rapid with a mean half-life of 2.1 minutes and an elimination half-life of 47 minutes. There do not appear to be any cumulative effects. Plasma levels on recovery were similar in those patients receiving single bolus or continuous infusions. Midazolam and flunitrazepam are two new benzodiazepines. As a class of drugs, benzodiazepines provide the pharmacological properties of anxiolysis, sedation, hypnosis, muscle relaxation, amnesia and anticonvulsant activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex↗

PubMed2004

Glucocorticoid receptor subunit expression in adenotonsillar tissue of children with obstructive sleep apnea.

Tonsillectomy and adenoidectomy (T&A) is a frequent surgical procedure in children with obstructive sleep apnea (OSA). Many symptomatic children who do not fulfill the currently recommended criteria for T&A may benefit from topical intranasal steroid therapy. However, the expression of glucocorticoid receptor (GCR) expression in adenoid and tonsillar tissue is currently unknown. The objective of this study was to assess and compare expression patterns of the human GCR in children who undergo T&A for either recurrent throat infections (RI) or OSA. Adenotonsillar tissues from 36 children with OSA or RI were subjected to quantitative PCR using specific primers for GCR-alpha and GCR-beta and to immunohistochemistry and Western blotting for protein expression of GCR isoforms. mRNA encoding for expression of both GCR-alpha and GCR-beta was detected in the tonsils and adenoids of all children, with markedly higher relative abundance of the GCR-alpha. Furthermore, GCR-alpha mRNA expression was increased in OSA-derived adenoid and tonsil tissues compared with RI, whereas no differences emerged for GCR-beta. Immunoblots confirmed these findings for the protein transcripts of these genes, and immunohistochemistry showed a specific topographic pattern of distribution for both receptors in tonsillar tissue. GCR-alpha and GCR-beta are expressed in pediatric adenotonsillar tissue, are more abundant in OSA patients, and demonstrate a specific topographic pattern of expression. These findings along with the high GCR-alpha:GCR-beta ratio suggest a favorable profile for topical steroid therapy in snoring children with adenotonsillar hypertrophy.

Adenoids↗

PubMed2000

Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: comparison with diazepam and valproate.

A high-affinity positive modulator of the GABA(A) receptor complex, ganaxolone, is a 3beta-methylated analog of the naturally occurring neuroactive steroid allopregnanolone. In the present study, ganaxolone was tested for its ability to (1) suppress seizures (clonic and tonic) and lethality induced by pentylenetetrazol (PTZ) in PTZ-kindled mice (anticonvulsive effect) and (2) to attenuate the development of sensitization to the convulsive and lethal effects of PTZ in kindled mice (anti-epileptogenic effect) when given as a pretreatment prior to each PTZ injection during kindling acquisition. Two classical antiepileptic drugs, diazepam and valproate, were tested for comparison. All three drugs dose-dependently suppressed tonic seizures and lethality induced by PTZ in kindled mice; only ganaxolone was effective against clonic seizures. Ganaxolone showed anti-epileptogenic properties as it reduced the sensitivity of kindled mice to the convulsive (clonic and tonic seizures) and lethal effects of PTZ. Diazepam showed anti-epileptogenic effects against tonic seizures and lethality, but not clonic seizures; valproate was ineffective in preventing development of any of these effects. Sensitivity to PTZ-induced seizures and lethality was not affected in mice with a history of repeated treatment with ganaxolone, diazepam, or valproate. The drugs had effects on ambulatory activity that ranged from no effect (ganaxolone) through moderate impairment (diazepam) to marked disruption (valproate). Taken together, the results of the present study add to accumulating evidence of the unique anticonvulsive/behavioral profile of neuroactive steroids.

Animals↗

PubMed1992

Lipid and apolipoprotein abnormalities in hirsute women. I. The association with insulin resistance.

OBJECTIVE: We attempted to evaluate apolipoprotein lipid levels in hirsute hyperandrogenic women and to clarify the influence of insulin resistance versus endogenous sex steroids on these profiles. STUDY DESIGN: Forty-seven women seen for evaluation of hirsutism in the Reproductive Endocrine Clinic were contrasted with 15 normal women. Thirty-one patients were treated with the gonadotropin-releasing hormone analog, leuprolide acetate, 7.5 mg intramuscularly monthly for 3 months. Insulin resistance was assessed before and after GnRH analog administration. Mean concentrations were compared with the Student t test and analysis of variance. RESULTS: Hirsute women were heavier and had higher systolic and diastolic blood pressures, more menstrual irregularities (all p less than 0.01), and higher waist/hip ratios (p less than 0.05). They had higher triglyceride, very-low-density lipoprotein C-III levels and lower high-density lipoprotein cholesterol concentrations (all p less than 0.01). They had lower apolipoprotein A-I/A-II ratios (p less than 0.01). After administration of GnRH analog, androgen and estrogens were suppressed and insulin resistance was unaltered. Insulin correlated with apolipoprotein lipid abnormalities. CONCLUSION: Lipid and apolipoprotein abnormalities in these hirsute women seem to be associated more with insulin resistance than with endogenous androgens or estrogens.

Adult↗

PubMed2005

Nongenotropic, anti-apoptotic signaling of 1alpha,25(OH)2-vitamin D3 and analogs through the ligand binding domain of the vitamin D receptor in osteoblasts and osteocytes. Mediation by Src, phosphatidylinositol 3-, and JNK kinases.

Because sex steroids regulate the life span of bone cells by modulating cytoplasmic kinase activity via a nongenotropic action of their classical receptors, we have explored the possibility that the vitamin D nuclear receptor (VDR) might exhibit similar nongenotropic actions. We report that the conformationally flexible full VDR agonist, 1alpha,25(OH)2-vitamin D3 (1alpha,25(OH)2D3), and the 6-s-cis-locked 1alpha,25(OH)2-lumisterol3 (JN) analog, also acting through the VDR but with poor transcriptional activity, protected murine osteoblastic or osteocytic cells from apoptosis. This effect was reproduced in HeLa cells transiently transfected with either wild type VDR or a mutant consisting of only the VDR ligand binding domain. The VDR ligand binding domain bound [3H]1alpha,25(OH)2D3 as effectively as wild type VDR but did not induce vitamin D response element-mediated transcription. The anti-apoptotic effects of 1alpha,25(OH)2D3 and the 6-s-cis-locked 1alpha,25(OH)2-lumisterol3 analog in calvaria cells were blocked by three cytoplasmic kinase inhibitors: Src kinase inhibitor 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), phosphatidylinositol 3 kinase inhibitor Wortmannin, and the JNK kinase inhibitor SP600125. However, inhibition of p38 with SB203580 or ERK with either U0126 or a transfected dominant negative MEK did not interfere with these anti-apoptotic actions. Further, 1alpha,25(OH)2D3 induced rapid (5 min) association of VDR with Src kinase in OB-6 cells. Finally, actinomycin D or cycloheximide prevented the anti-apoptotic effect of 1alpha,25(OH)2D3, indicating that transcriptional events are also required. These findings suggest that nongenotropic modulation of kinase activity is also a general property of the VDR and that ligands that activate nongenotropic signals, but lack transcriptional activity, display different biological profiles from the steroid hormone 1alpha,25(OH)2D3.

Animals↗

PubMed2004

Chirality effect of C-20 on metabolism of methyl 11beta,17alpha,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate derivatives.

Epimers at C-20 of methyl 11beta,17alpha,20-trihydroxy-3-oxo-1,4-pregnadien-21-oates, their 9alpha-fluoro analogs, their carbonate derivatives, and their acetonide derivatives were subjected to metabolism study in rat plasma and rat liver homogenate. These steroids were synthesized based on the antedrug concept. In rat plasma, the carboxy ester bonds of 20beta-triols and their acetonides were hydrolyzed with half-lives (T(1/2)) of between 5.7 and 7.7 min, while their corresponding alpha-epimers had longer half-lives of more than 2.5 h. A more profound difference was observed between the alpha- and beta-epimers of the carbonates, with the latter showing a T(1/2) less than 1 min (0.3 and 0.43 min for P20beta- and PF20beta-carbonate, respectively), while that of the former about 3 h (165 min for P20alpha-carbonate and 191 min for PF20alpha-carbonate). In rat liver homogenate, the triol and acetonide derivatives showed greater stability than they did in rat plasma, with T(1/2) for the beta-group in the range of 54-108 min, and T(1/2) for the alpha-group over 7 h. A significant difference in hydrolysis of the carbonate derivatives was also observed in rat liver homogenate. The half-lives of P20beta- and PF20beta-carbonate were 0.67 and 0.66 min, respectively, and the alpha-isomers showed the similar metabolic rate with other alpha-isomers. An esterase inhibitor effectively blocked the hydrolysis of the ester bond, indicating that this metabolism is an enzymatic reaction. Molecular modeling studies show that steric hindrance around the ester group of the alpha-epimers is much greater than that of their beta-counterparts, affording one explanation for the large difference in the metabolic hydrolysis rate; i.e. the carboxy ester bond of beta-isomer which is less hindered sterically than their counter alpha-isomers is hydrolyzed faster than that of alpha-isomers. In conclusion, this study confirms that chirality at C-20 had profound effects on metabolism and pharmacological profile of the steroid acid ester derivatives.

Animals↗

PubMed1998

A longitudinal study of maternal serum inhibin-A, inhibin-B, activin-A, activin-AB, pro-alphaC and follistatin during pregnancy.

Maternal serum concentrations of inhibin-A, inhibin-B, activin-A, activin-AB, pro-alphaC-related inhibin forms, total follistatin, steroids and gonadotrophins were measured longitudinally in six normal singleton pregnancies. Maternal venous blood was collected randomly during a spontaneous follicular phase prior to donor insemination, at 5, 7, 9, 11, 16, 20, 24, 28, 32 and 36 weeks after the first missed menses and in the early puerperium. Steroid and gonadotrophin profiles conformed to previous reports. While at week 5 of gestation inhibin-A, activin-A and follistatin concentrations were similar to those at the follicular phase, all three increased progressively (P < 0.001) to maximal concentrations in week 36: approximately 48-fold (3740 +/- 1349 ng inhibin-A/ml), approximately 22-fold (6109 +/- 1443 ng activin-A/ml) and approximately 10-fold (3563 +/- 418 ng follistatin/ml) higher. Pro-alphaC concentrations reached a maximum in weeks 5 (approximately 5-fold, P < 0.001) and 36 (1027 +/- 174 pg/ml, P < 0.01). Inhibin-B (71 +/- 23 pg/ml prior to pregnancy) was undetectable (<12 pg/ml) between week 5-16 of gestation but increased slightly in the third trimester (26 +/- 7 pg/ml in week 36). Activin-AB was undetectable throughout pregnancy. Post-partum concentrations of inhibin-A (41 +/- 12 ng/ml), inhibin-B (<12 pg/ml), activin-A (950 +/- 149 pg/ml), pro-alphaC (128 +/- 22 pg/ml) and follistatin (990 +/- 79 ng/ml) were substantially lower than at week 36 of gestation. The activin-A:follistatin ratio increased from 0.5 in week 5 to 1.8 in week 36, suggesting that more free activin-A is available in the maternal circulation during late pregnancy.

Activins↗

PubMed2003

Determination of faecal pollutants in Torrens and Patawalonga catchment waters in South Australia using faecal sterols.

This research investigated faecal pollution by sterol profiling in two Adelaide metropolitan catchments in winter 2000 and summer 2001. Water was sampled from five sites on the River Torrens and two sites on Patawalonga river catchment. The steroids detected were coprostanol, epicoprostanol, cholesterol, cholestanol, stigmasterol, betasitosterol, and stigmastanol. The concentrations range from 5 ng/L (of coprostanol) to 34 microg/L (of stigmasterol), with cholesterol detected more frequently at relatively high concentrations (approximately 2 microg/L). Sterol profiling suggested two sites on two occasions may have been impacted by human faecal contamination. Other steroid profiles suggested that sources of pollution consistently included dogs and birds. The steroid concentrations in the Torrens catchment were higher in winter, however, this was not observed in the Patawalonga catchment.

Animals↗

PubMed1987

Determination of methylprednisolone metabolites in human urine by gas chromatography-mass spectrometry.

Methylprednisolone and its metabolites were studied as their methoxyamine-trimethylsilyl derivatives by means of capillary gas chromatography-mass spectrometry. The expected unchanged drug and 11-keto and 20-hydroxy metabolites were found in human urine. The typical metabolites are 6,7-dehydro analogues of the above-mentioned compounds. Characteristic gas chromatographic profiles of urine steroids were obtained. Retention indices and m/z values are presented for methylprednisolone and its main metabolites.

Biotransformation↗

PubMed2004

Characterization of a new class of selective nonsteroidal progesterone receptor agonists.

The identification of a new series of selective nonsteroidal progesterone receptor (PR) agonists is reported. Using a high-throughput screening assay based on the measurement of transactivation of a mouse mammary tumor virus promoter-driven luciferase reporter (MMTV-Luc) in human breast cancer T47D cells, a benzimidazole-2-thione analog was identified. Compound 1 showed an apparent EC50 of 53 nM and efficacy of 93% with respect to progesterone. It binds to PR with high affinity (Ki nM), but had no or very low affinity for other steroid hormone receptors. Structure-activity relationship studies of a series of benzimidazole-2-thione analogs revealed critical positions for high PR binding affinity and transactivation potency as well as receptor selectivity, as exemplified by 25. Compound 25 binds to human PR with high affinity (Ki nM) and had at least > 1000-fold selectivity for PR versus other steroid receptors. Molecular modeling studies suggested that these agonists overlap favorably with progesterone in the ligand-binding domain of PR. In T47D cells, compound 25 acted as a full agonist in the MMTV-Luc reporter assay, as well as in the induction of endogenous alkaline phosphatase activity with apparent EC50 values of 4 and 9 nM, respectively. In the immature rat model, compound 25 provided a significant suppression of estrogen-induced endometrium hypertrophy as measured by luminal epithelial height. In contrast, compound 25 was inactive in the luteinizing hormone release assay in young ovariectomized rats. These benzimidazole-2-thione analogs constitute a new series of nonsteroidal PR agonists with an excellent steroid receptor selectivity profile. The differential activities observed in the in vivo progestogenic assays in rat models suggest that these analogs can act as selective PR modulators.

Animals↗

PubMed1999

Reproductive hormones, aging, and sleep.

Insomnia, disturbed sleep, and fatigue are among the most frequent health complaints of perimenopausal women. Estrogen replacement therapy (ERT) usually improves sleep, most likely by alleviating vasomotor symptoms. However, sleep difficulties are not restricted to the perimenopausal period. Older postmenopausal women typically experience longer latencies to sleep onset, increased nocturnal waking, increased fragmentation of sleep, and less slow wave (deep) sleep. These sleep changes in older women may be partially related to the postmenopausal profile of sex steroid hormones. Estrogen has powerful effects on several biological factors that directly influence sleep, including body temperature regulation, circadian rhythms, and stress reactivity. The link between sleep disturbance in older women and these CNS effects of estrogen is largely speculative at present. This article reviews what is known, what remains to be addressed, and some clinical implications.

Aged↗

PubMed2005

In utero and lactational exposure to TCDD; steroidogenic outcomes differ in male and female rat pups.

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) has a potency to induce decreased fertility and structural reproductive anomalies in male and female mammals. While the activity profile of sex steroid hormone production distinctly differs in developing males and females, we wanted to analyze sex-specific effects of TCDD introduced in utero and via lactation on gonadal steroidogenesis and gonadotropin levels in male and female rat infant pups. One oral dose of TCDD (0, 0.04, 0.2, or 1.0 microg/kg) was given to dams on gestational day (GD) 13. Plasma testosterone, estradiol, progesterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), and gonadal mRNA levels for steroid acute regulatory protein (StAR), cytochrome P-450 cholesterol side-chain cleavage (P450scc), 3beta-hydroxy-steroid-dehydrogenase/Delta(5)-Delta(4) isomerase type I (3beta-HSD1), P-450 17alpha-hydroxylase/17,20-lyase (P450-17alpha), and cytochrome P-450 aromatase (P450arom) were determined on postnatal days (PND) 10-16. TCDD 1.0 mug/kg reduced body weights but did not affect relative testis weight or alter testicular and ovarian histology. Plasma estradiol levels in dams and female pups were reduced on PND 14 and 16. Progesterone levels remained unaltered, and FSH levels were increased in female pups. In males, testosterone levels were elevated on PND 10. Gonadal mRNA levels for StAR and steroidogenic enzymes increased during the postnatal growth. TCDD caused no changes in relatively low testicular mRNA levels. However, significant reductions in StAR and P450arom mRNA levels were seen in PND 14 ovaries, and P450arom activity was decreased in isolated ovarian follicles. We conclude that developing testis and male gonadotropin secretion are resistant to TCDD-induced toxicity. In female pups, reduced estradiol, ovarian P450arom expression and enzyme activity levels, and elevated FSH levels may have a role in the development of ovarian dysfunction reported in TCDD-exposed females.

Abnormalities, Drug-Induced↗

PubMed2001

A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients.

BACKGROUND: Corticosteroids have been a mainstay of rejection prophylaxis for several decades, despite the multiple adverse effects of long-term use, including weight gain, hyperlipidemia, diabetes, hypertension, and bone disease. The detrimental effect of steroids on the metabolic profile begins in the early posttransplantation period, and the complete avoidance of steroids in transplantation would therefore be optimal. We hypothesized that the addition of mycophenolate mofetil (MMF) and a humanized monoclonal anti-CD25 antibody (daclizumab) to a cyclosporine (CsA microemulsion)-based immunosuppression protocol would permit transplantation without steroids. METHODS: Steroid-free renal transplantation was attempted in 57 patients treated with daclizumab, MMF, and CsA. Twenty-eight patients received kidneys from living donors; the remaining 29 received cadaveric grafts. RESULTS: At 1 year, patient and graft survival were 95% and 89%, respectively. Fourteen patients (25%) experienced rejections, of which 13 were readily reversed with steroids; 1 patient required OKT3. Mean serum creatinine at 12 months for patients not experiencing rejection was 149+/-58 micromol/L, compared with 158+/-102 micromol/L for those experiencing rejection. Five patients required hospitalization for infection; no patients developed lymphoproliferative disease. At baseline, 17 patients required 3 or more antihypertensive medications, compared with 2 patients at 1 year. Three of 43 nondiabetic patients developed diabetes during the study. There was no significant reduction in lumbar or femoral bone density. CONCLUSIONS: On the basis of these positive results, we believe steroid avoidance with this immunosuppressive regimen merits further study.

Acute Disease↗

PubMed1995

Response of cynomolgus macaques to immunization against a synthetic peptide from the human zona pellucida.

This study tested immunogenicity of a synthetic peptide hZP3(327-341) from a human zona pellucida (ZP) glycoprotein. After antibody response to various peptide-carrier conjugates was assessed in mice, two female cynomolgus macaques were immunized with the peptide conjugated to keyhole limpet hemocyanin (KLH). A control macaque was immunized with KLH. The peptide was immunogenic in both species, and included both B and T cell epitopes since low to moderate titers of peptide-specific antibodies and a T cell proliferative response were measured. Profiles of ovarian steroid metabolites indicated unchanged ovarian function in the macaques, but only the control conceived when bred. Ovarian histology was normal except that immunoglobulin was bound to ZP in follicles of the peptide-immune macaques. ZP from these females bound sperm and induced acrosome reactions at rates equal to those of an untreated control. The results support the feasibility of an immunocontraceptive vaccine based on autologous ZP peptides.

Amino Acid Sequence↗

PubMed1995

17 alpha-hydroxyprogesterone, 4-androstenedione, and testosterone profiled by routine stable isotope dilution/gas chromatography-mass spectrometry in plasma of children.

Using stable isotope dilution/gas chromatography-mass spectrometry (ID/GC-MS), a physicochemical method, we have profiled the plasma steroids 17 alpha-hydroxyprogesterone, 4-androstenedione, and testosterone in normal children of various age groups. Comparison of our values with those obtained by direct immunologic assays and those using an extraction or purification step showed that immunoassays in general overestimate steroid concentrations. This was especially true for plasma samples in the neonatal period and was most expressed for the concentrations of 17 alpha-hydroxyprogesterone. Our study demonstrated the applicability of ID/GC-MS to routine clinical steroid analysis. The application of ID/GC-MS is recommended whenever problems from matrix effects or cross-reactivity are likely to arise or suspicious results by immunoassays need to be rechecked.

17-alpha-Hydroxyprogesterone↗

PubMed2003

Suppression of a pituitary-ovarian axis by chronic oral administration of a novel nonpeptide gonadotropin-releasing hormone antagonist, TAK-013, in cynomolgus monkeys.

TAK-013 is a novel nonpeptide and orally active GnRH antagonist. We first examined the effect of TAK-013 on GnRH-stimulated LH release using primary-cultured pituitary cells of cynomolgus monkeys. TAK-013 suppressed LH release to below basal levels at concentrations higher than 100 nM with the IC(50) value of 36 nM. Next, we examined the effect of chronic oral administration of TAK-013 on serum hormone levels in regularly cycling female cynomolgus monkeys. TAK-013 administered at 90 mg/kg x d (30 mg/kg 3 times daily) for approximately 80 d continued to suppress LH, estradiol, and progesterone, but not FSH. The suppressive effect was reversible, in that normal profiles of sex steroids were observed immediately after discontinuation of the TAK-013 treatment. Interestingly, the suppressive effect of TAK-013 was not observed in marmoset monkeys. In summary, TAK-013 by oral administration suppresses a pituitary-ovarian axis continuously and reversibly in cynomolgus monkeys. Considering that TAK-013 has more potent antagonistic properties for human GnRH receptor than for monkey receptor, our data suggest that TAK-013 would be effective for reproductive disorders such as endometriosis and uterine leiomyoma and useful for assisted reproductive technology procedures.

Animals↗

PubMed2000

Gender differences in the urinary excretion rates of cortisol and androgen metabolites.

Animal studies show significant differences in steroid metabolism between male and female subjects. Similar studies in human subjects are still needed. The aim of this study was to evaluate differences in 24-h urinary excretion of cortisol and androgen metabolites between healthy male and female volunteers to estimate if such differences were significant. Urinary metabolite measurements were performed by gas chromatography. The median urinary excretion of total cortisol metabolites was 6965 microg/day for men and 4595 microg/day for women (P = 0.0005). Urinary excretion of 11beta-hydroxyandrosterone, tetrahydrocortisone, tetrahydrocortisol (5beta), allotetrahydrocortisol (5alpha), alpha-cortolone, beta-cortolone + beta-cortol and alpha-cortol were also significantly different in men compared with women. Total androgen metabolites in men (2660 microg/day) were also higher than in women (1850 microg/day) (P<0.0003). Similarly, urinary excretion of androsterone (5alpha), aetiocholanolone (5beta) and dehydroepiandrosterone were also significantly greater (all P=0.01). This confirms significant differences in the steroid metabolite excretion profiles between men and women. Laboratories should consider adopting gender-related reference ranges for cortisol and androgen metabolite excretion in 24-h urine samples.

Adult↗