Kegg Pathway: C21-Steroid hormone metabolism

PDA J Pharm Sci Technol. 2008 Mar-Apr; 62(2): 111-24
Kapoor DN, Manvi FV, Doijad RC, Dhawan S

Prednisolone-loaded bovine serum albumin (BSA) nanospheres prepared by pH-coacervation were evaluated regarding recovery, drug entrapment efficiency, particle size, shape, surface morphology, in vitro drug release profile, and in vivo distribution. The method of analysis was validated in terms of accuracy, precision, and repeatability. No significant change in the drug's chemical integrity was observed when incorporated in the nanospheres. It was observed that the average particle size and drug entrapment efficiency of the nanospheres increased with the increase in drug loading. All the batches exhibited biphasic drug release with an initial burst effect followed by gradual steady release. The higher the drug loading, the greater was the burst effect. The mechanism of prednisolone release from the nanospheres was found to be due to diffusion and erosion as observed by fitting the release data in different models. The drug's in vivo distribution was found to be highest in the liver followed by the spleen and lungs. Stability studies indicated that nanosphere formulations should be stored at 4 +/- 2 degrees C.

Epigenetics. 2008 Mar-Apr; 3(2): 97-106
Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM

BACKGROUND: In animal models, variations in early maternal care are associated with differences in hypothalamic-pituitary-adrenal(HPA) stress response in the offspring, mediated via changes in the epigenetic regulation of glucocorticoid receptor (GR) gene (Nr3c1) expression. OBJECTIVE: To study this in humans, relationships between prenatal exposure to maternal mood and the methylation status of a CpG-rich region in the promoter and exon 1F of the human GR gene (NR3C1) in newborns and HPA stress reactivity at age three months were examined. RESULTS: Prenatal exposure to increased third trimester maternal depressed/anxious mood was associated with increased methylation of NR3C1 at a predicted NGFI-A binding site. Increased NR3C1 methylation at this site was also associated with increased salivary cortisol stress responses at 3 months, controlling for prenatal SRI exposure, postnatal age and pre and postnatal maternal mood. METHODS: The methylation status of a CpG-rich region of the NR3C1 gene, including exon 1F, in genomic DNA from cord blood mononuclear cells was quantified by bisulfite pyrosequencing in infants of depressed mothers treated with a serotonin reuptake inhibitor antidepressant (SRI) (n = 33), infants of depressed nontreated mothers (n = 13) and infants of non depressed/non treated mothers (n = 36). To study the functional implications of the newborn methylation status of NR3C1 in newborns, HPA function was assessed at three months using salivary cortisol obtained before and following a non noxious stressor and at a late afternoon basal time. CONCLUSIONS: Methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood and may offer a potential epigenetic process that links antenatal maternal mood and altered HPA stress reactivity during infancy.

J Aquat Anim Health. 2008 Mar; 20(1): 63-71
Lepak JM, Kraft CE, Honeyfield DC, Brown SB

No consistent explanation has been found for the variability in the thiaminase activity of alewives Alosa pseudoharengus despite the role of alewife thiaminase in large-scale salmonine mortality in the Laurentian Great Lakes. We conducted experiments to evaluate the effect of two stressors, reduced salt content in the water and food limitation, on alewife thiaminase activity. Alewives were subjected to treatments in replicated tanks in which conductivity was lowered (< 100 microS/cm) for 8 d and feeding was limited for 39 d. Circulating white blood cells, plasma cortisol, plasma glucose, and whole-body thiaminase were measured in individual alewives to assess their response to these experimental treatments. Alewives from the controls had significantly larger numbers of circulating white blood cells than those in the salt-reduced and food-limited treatments (24,000 and 19,000 cells/microL and 11,000 and 9,000 cells/microL for alewives from the two control and salt-reduced treatment tanks, respectively, and 34,000 and 30,000 cells/microL and 21,000 and 16,000 cells/microL for alewives from the two control and food-limited treatment tanks). No significant differences in alewife thiaminase activity were found between treatment fish and their controls. The mean thiaminase activity in the alewives studied increased from 6,900 to 16,000 pmol x g(-1) x min(-1) from the time of their collection in Cayuga Lake to the start of laboratory experiments 1.5-2.5 years later; the latter value was more than twice that of previously reported levels of thiaminase activity from alewives collected in the wild. These data suggest that the variability in alewife thiaminase is not related to stress from salt reduction or food limitation, but laboratory holding conditions significantly increased thiaminase through a mechanism not evaluated by our experimental treatments.

Acta Pol Pharm. 2008 Jan-Feb; 65(1): 159-64
Piwowarska J, Dryll K, Szelenberger W, Pachecka J

The aim of this research was to find out whether increased plasma cortisol levels appear in unipolar or bipolar patients with major depressive disorder (MDD) and whether the effective antidepressant treatment by imipramine and fluoxetine leads to regulation of the cortisol level. Cortisol levels were studied in two groups of patients with major depressive disorder: unipolar and bipolar patients treated with fluoxetine (doses: 20-60 mg/day). This group included 5 patients (age 29-46 yr); unipolar and bipolar subjects treated with imipramine (50-150 mg/day), this group included 5 patients (aged 24-70 yr). Cortisol and fluoxetine or imipramine plasma levels were assessed using HPLC methods: before treatment, after 3, 6 and 24 h of drug administration as well as in the 2nd, 4th, 6th, and 8th week of antidepressant treatment. HPLC methods were previously validated. The research conducted and the clinical data may be useful for proving the essential role of enhanced HPA axis activity for the pathogenesis and depressive disorder proceedings.

Trans Am Clin Climatol Assoc. 2007; 118: 45-56
Kone BC, Wenzhang Z, Zhiyuan Y

Gene transcription is highly regulated to ensure that specific genes are expressed at the appropriate times, places and levels in response to various genetic and environmental stimuli. Activation of some genes occurs by relief of basal repression controls, whereas termination of active transcription can involve feedback inhibition. We describe our characterization of aldosterone-triggered de-repression of the epithelial Na(+) channel-alpha subunit (ENaCalpha) gene in renal collecting duct cells in a process that involves a novel nuclear repressor complex, consisting of a histone H3 K79 methyltransferase and the putative transcription factor AF9, that regulates targeted histone H3 K79 methylation at the ENaCalpha promoter. As an example of feedback inhibition, we describe our work characterizing how the end product, nitric oxide, feedback inhibits inducible nitric oxide synthase (iNOS) gene transcription by S-nitrosylating its transactivator poly(ADP-ribose) polymerase (PARP-1) and, thereby, decreasing its ability to act at the iNOS promoter.

Alzheimer Dis Assoc Disord. 2008 Apr-Jun; 22(2): 181-3
Wahbeh H, Kishiyama SS, Zajdel D, Oken BS

Alterations in the hypothalamic-pituitary-adrenal axis have been noted in people with Alzheimer disease (AD) and in the people caring for them. In a case-control study, we assessed whether the cortisol response at awakening and diurnal cortisol would reflect these changes. AD patients, their caregivers, and healthy senior noncaregivers collected saliva within 5 minutes of waking, 30 minutes after waking, before lunch, 1 hour after lunch, and at 11 pm or when getting ready for bed. They also completed a Perceived Stress Scale. Total cortisol for the day after adjusting for antidepressant use revealed a group effect [F(2,39)=12.49, P<0.0001], with mild AD patients and caregivers having higher cortisol values. Unlike the noncaregivers (t=-1.15, df=14, P>0.27), both cortisol values of the AD caregivers (t=-2.96, df=16, P<0.03) and the AD patients' (t=-2.5, df=14, P<0.01) increased between awakening and 30 minutes afterward. There were also group differences at awakening [F(2,48)=4.6, P=0.012] adjusting for antidepressant use and 30 minutes after waking adjusting for antidepressant use and awakening cortisol [F(2,46)=4.7, P=0.014<0.02). AD patients (r=0.45, P=0.08) and caregivers (r=0.44, P=0.10) with higher cortisol values 30 minutes after waking also showed a trend toward higher perceived stress scores. Salivary cortisol and cortisol response on awakening may enhance future studies relating free cortisol to subjective psychologic and physiologic markers.

N Engl J Med. 2008 Jun 5; 358(23): 2518; author reply 2519-20
Guba M, Jauch KW

Arch Pediatr Adolesc Med. 2008 Jun; 162(6): 521-5
Rachmiel M, Kives S, Atenafu E, Hamilton J

OBJECTIVE: To compare clinical and metabolic features of adolescents having primary amenorrhea (PA) and polycystic ovarian syndrome (PCOS) with those having oligomenorrhea or secondary amenorrhea (OM/SA) and PCOS. DESIGN: Retrospective case-control study. SETTING: Endocrine Gynecology Clinic at The Hospital for Sick Children, Toronto, Ontario, Canada. PATIENTS: Girls and young women aged 14 to 18 years having PA and PCOS (n = 9) seen during a 2(1/2)-year period were compared with control subjects having OM/SA and PCOS (n = 18) randomly selected during the same period. INTERVENTION: Medical record review was performed to assess clinical, biochemical, and ultrasonographic measures, as well as response to a progesterone challenge. MAIN OUTCOME MEASURES: Differences in response to the progesterone challenge, hyperandrogenism, and the presence of features of the metabolic syndrome. RESULTS: Compared with adolescents having OM/SA, adolescents having PA demonstrated older age at pubarche, higher androstenedione levels, greater prevalence of family history of obesity, a tendency toward no withdrawal bleeding in response to the progesterone challenge, and more features associated with the metabolic syndrome (acanthosis nigricans, higher diastolic blood pressure, and lower high-density lipoprotein cholesterol level). No significant correlation was demonstrated between response to the progesterone challenge, metabolic features, and androstenedione levels. CONCLUSION: Adolescents with PA and PCOS exhibit increased features of the metabolic syndrome and higher androstenedione levels and may represent a more severe spectrum of a common condition.

Comp Med. 2008 Apr; 58(2): 180-7
Sadosky PW, Scammell JG

In squirrel monkeys (Saimiri spp.), cortisol circulates at levels much higher than those seen in man and other Old World primates, but squirrel monkeys exhibit no physiologic signs of the mineralocorticoid effects of cortisol. These observations suggest that squirrel monkeys have mechanisms for protection of the mineralocorticoid receptor (MR) from these high levels of cortisol. We previously showed that the serum cortisol to cortisone ratio in these animals is low relative to that in human serum, suggesting that production of the MR protective enzyme, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), is increased in squirrel monkeys. Here, we directly evaluate whether increased production of 11beta-HSD2, which inactivates cortisol to cortisone, is a mechanism for protection of MR. In vitro assays showed that 11beta-HSD2 activity in squirrel monkey kidney microsomes was 3 to 7 times higher than that seen in kidney microsomes from pig or rabbit. 11beta-HSD2 protein detected by Western blot analysis was 4 to 9 times greater in squirrel monkey microsomes than in pig or rabbit microsomes. Comparison of the effect of expression of either human or squirrel monkey 11beta-HSD2 on MR transactivation activity showed similar inhibition of MR response to cortisol by both enzymes, indicating that the intrinsic activities of the human and squirrel monkey enzymes are similar. These findings suggest that one mechanism by which squirrel monkeys protect the MR from activation by high cortisol levels in the kidney is by upregulation of 11beta-HSD2 activity through increased production of the enzyme.

Am J Forensic Med Pathol. 2008 Jun; 29(2): 181-4
Clapper A, Nashelsky M, Dailey M

Normal adrenocortical activity is necessary for electrolyte regulation and the maintenance of cardiovascular function. Although chronic adrenal insufficiency generally presents with the gradual onset of a set of characteristic symptoms and signs, the more sudden loss of adrenal activity can present with acute, rapidly progressive cardiovascular dysfunction that can be fatal if not recognized and treated promptly. We herein describe a patient who had most of his adrenal tissue removed during resection of metastatic renal carcinoma, conventional clear cell type, with much of the remaining adrenal tissue undergoing necrosis during or shortly after surgery. Although the patient appeared to be stable and progressing adequately well, he died suddenly 2 days postoperatively. When the gross autopsy findings suggested the possibility of adrenal insufficiency, clinical laboratory assessment of adrenocortical activity was sought. Analysis of stored antemortem serum samples and of blood obtained at autopsy demonstrated a progressive decrease in cortisol levels which, in this stressed postsurgical patient, proved fatal. The use of both antemortem and postmortem blood in the demonstration of acute adrenal insufficiency at autopsy is discussed.

Pediatr Res. 2008 Jun; 63(6): 686-90
Masumoto K, Kusuda S, Aoyagi H, Tamura Y, Obonai T, Yamasaki C, Sakuma I, Uchiyama A, Nishida H, Oda S, Fukumura K, Tagawa N, Kobayashi Y

A recent survey found that approximately 4% of very low birth weight infants in Japan were treated with glucocorticoids postnatally for circulatory collapse thought to be caused by late-onset adrenal insufficiency. We identified 11 preterm infants with clinical signs compatible with this diagnosis (hypotension, oliguria, hyponatremia, lung edema, and increased demand for oxygen treatment) and matched them for gestational age with 11 infants without such signs. Blood samples were obtained for cortisol and its precursors from the patient group before the administration of hydrocortisone, and from the control group during the same postnatal week. All samples were analyzed using a gas chromatography-mass spectrometry system. Cortisol concentrations did not differ between the two groups (6.6 +/- 4.5 vs 3.4 +/- 2.7 microg/dL); however, the total concentration of precursors in the pathway to cortisol production was significantly higher in the patient group (72.2 +/- 50.3 vs 25.0 +/- 28.5 microg/dL; p < 0.05). We conclude that the clinical picture of late-onset adrenal insufficiency in preterm infants is not a result of an absolute deficiency of cortisol production, but may be a result of a limited ability to synthesize sufficient cortisol for the degree of clinical stress.