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N S Panesar

Publications and source records attributed to N S Panesar.

At least 19 recordsLinked to original sources
PubMed2006

Evidence for nitrite reductase activity in intact mouse Leydig tumor cells.

Nitric oxide (NO) supposedly derived via L-arginine-NO synthase (NOS) pathway has been implicated in inhibiting steroidogenesis by binding the heme moiety of steroidogenic enzymes. Previously, nitrite, and to a lesser extent nitrate ions inhibited steroidogenesis via NO by hitherto unknown reduction mechanism. Recently, a putative mammalian nitrite reductase activity ascribed to complex III of mitochondrial respiratory chain complexes (MRCC) has been reported, where MRCC inhibitors reduced NO production from nitrite variably. We thus studied the effects of MRCC inhibitors on testosterone production in mouse Leydig tumor cells (MLTC-1) without (basal) or with human chorionic gonadotropin (hCG) stimulation. In stimulated MLTC-1, MRCC inhibitors decreased testosterone production, order being: complex III (antimycin A and myxothiazol) > complex I (rotenone) > complex II (thenoyltrifluoroacetone), while cAMP production increased inversely. In unstimulated MLTC-1, MRCC inhibitors in same order, increased basal testosterone production, which correlated inversely with the percentage inhibition of NO production, with one exception; while antimycin A did not inhibit NO production in the nitrite reductase study mentioned above, it increased basal testosterone production in the present study. While MLTC-1 expressed mRNA for endothelial and neuronal, but not inducible NOS, various stimulators and inhibitors of L-arginine-NOS pathway had no effect on basal testosterone production in MLTC-1 or fresh Balb/c Leydig cells. Moreover, hCG increased nitrate uptake into MLTC-1, which suggests the gonadotropin aids nitrite and nitrate ions in their steroidogenesis inhibitory activity. In conclusion, this study supports the existence of a surrogate mammalian nitrite reductase and the dormancy of L-arginine-NOS pathway in MLTC-1.

Animals↗
PubMed2006

Status of anti-thyroid peroxidase during normal pregnancy and in patients with hyperemesis gravidarum.

Autoimmune thyroid diseases (AITD) comprising Hashimoto's thyroiditis, primary myxedema, and Graves' disease are associated with autoantibodies directed against thyroglobulin and thyroid peroxidase (anti-TPO). Anti-TPO occur in 10% of pregnant women, half of whom reportedly develop postpartum thyroid dysfunction. We recently published data on the thyroid function reference ranges in pregnant Chinese but the AITD status of our cohort was unknown. In view of this missing information we have measured anti-TPO in specimens from our cohort stored at -80 degrees C, and compared these to those of patients with hyperemesis gravidarum (HG) and nonpregnant controls. After eliminating 3 outliers from 47 nonpregnant controls, the anti-TPO concentration range was 2.2-14.7 kIU/L (n = 44). In 282 pregnant control subjects, the anti-TPO levels were less than 14.7 kIU/L (upper limit of nonpregnant controls) in 189 (67%); between 14.7-55 kIU/L in 82 (29.1%); and greater than 55 kIU/L in 11 (3.9%). The percentage of women with anti-TPO greater than 14.7 kIU/L during the first, second, and third trimesters were 47% (30/64), 39% (49/126), and 16% (15/92), respectively. Anti-TPO level was significantly higher in pregnant controls compared to nonpregnant controls and patients with HG. With reference to other studies in which anti-TPO levels greater than 60 kIU/L were considered pathologic, we conclude that more than 96% of our pregnant controls were without AITD and the data on thyroid function reference ranges we previously reported remain valid.

Adult↗
PubMed2005

Blocking BRE expression in Leydig cells inhibits steroidogenesis by down-regulating 3beta-hydroxysteroid dehydrogenase.

Conversion of cholesterol to biologically active steroids is a multi-step enzymatic process. Along with some important enzymes, like cholesterol side-chain cleavage enzyme (P450scc) and 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD), several proteins play key role in steroidogenesis. The role of steroidogenic acute regulatory (StAR) protein is well established. A novel protein, BRE, found mainly in brain, adrenals and gonads, was highly expressed in hyperplastic rat adrenals with impaired steroidogenesis, suggesting its regulation by pituitary hormones. To further elucidate its role in steroidogenic tissues, mouse Leydig tumor cells (mLTC-1) were transfected with BRE antisense probes. Morphologically the BRE antisense cells exhibited large cytoplasmic lipid droplets and failed to shrink in response to human chorionic gonadotropin. Although cAMP production, along with StAR and P450scc mRNA expression, was unaffected in BRE antisense clones, progesterone and testosterone yields were significantly decreased, while pregnenolone was increased in response to human chorionic gonadotropin stimulation or in the presence of 22(R)OH-cholesterol. Furthermore, whereas exogenous progesterone was readily converted to testosterone, pregnenolone was not, suggesting impairment of pregnenolone-to-progesterone conversion, a step metabolized by 3beta-HSD. That steroidogenesis was compromised at the 3beta-HSD step was further confirmed by the reduced expression of 3beta-HSD type I (3ss-HSDI) mRNA in BRE antisense cells compared with controls. Our results suggest that BRE influences steroidogenesis through its effects on 3beta-HSD action, probably affecting its transcription.

3-Hydroxysteroid Dehydrogenases↗
PubMed2004

Low temperature blocks the stimulatory effect of human chorionic gonadotropin on steroidogenic acute regulatory protein mRNA and testosterone production but not cyclic adenosine monophosphate in mouse Leydig tumor cells.

Low temperatures slow down metabolism, partly because the kinetic energy of molecules is reduced and enzymes may be structurally impaired. We now report that relative to its maximal activity at 37 degrees C, adenylate cyclase (AC) still retained 25% functionality (determined as cyclic adenosine monophosphate [cAMP] production) at 4 degrees C in mouse Leydig tumor cells (MLTC-1) in response to 50 IU/L human chorionic gonadotropin (hCG), whereas steroidogenic acute regulatory (StAR) protein mRNA and testosterone production were completely impaired. The incubation of MLTC-1 with the phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine; IBMX) resulted in significantly increased intracellular cAMP concentration at all 3 temperatures, but this had no impact on testosterone production. AC, cAMP, and phosphodiesterase form an important intracellular second-messenger mechanism in many organisms, some that inhabit very low temperature niches. The cold-resistance of AC and phosphodiesterase may thus have evolved to cope with adverse conditions. Although hibernation may lead to decreased steroid hormone production, it is also likely that cold-mediated decreased steroid hormone production induces hibernation.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Differential expression of a stress-modulating gene, BRE, in the adrenal gland, in adrenal neoplasia, and in abnormal adrenal tissues.

Genes that modulate the action of hormones and cytokines play a critical role in stress response, survival, and in growth and differentiation of cells. Many of these biological response modifiers are responsible for various pathological conditions, including inflammation, infection, cachexia, aging, genetic disorders, and cancer. We have previously identified a new gene, BRE, that is responsive to DNA damage and retinoic acid. Using multiple-tissue dot-blotting and Northern blotting, BRE was recently found to be strongly expressed in adrenal cortex and medulla, in testis, and in pancreas, whereas low expression was found in the thyroid, thymus, small intestine and stomach. In situ hybridization and immunohistochemical staining indicated that BRE was strongly expressed in the zona glomerulosa of the adrenal cortex, which synthesizes and secretes the mineralocorticoid hormones. It is also highly expressed in the glial and neuronal cells of the brain and in the round spermatids, Sertoli cells, and Leydig cells of the testis, all of which are associated with steroid hormones and/or TNF synthesis. However, BRE expression was downregulated in human adrenal adenoma and pheochromocytoma, whereas its expression was enhanced in abnormal adrenal tissues of rats chronically treated with nitrate or nitrite. These data, taken together, indicate that the expression of BRE is apparently associated with steroids and/or TNF production and the regulation of endocrine functions. BRE may play an important role in the endocrine and immune system, such as the cytokine-endocrine interaction of the adrenal gland.

Adrenal Gland Neoplasms↗
PubMed2001

Reference intervals for thyroid hormones in pregnant Chinese women.

OBJECTIVE: To establish gestation-related reference intervals for thyroid hormones in a Chinese population. MATERIALS AND METHODS: A prospective study with 343 healthy pregnant women (5-41 weeks) and 63 non-pregnant controls. Thyroid stimulating hormone (TSH), free thyroxine (T4) and tri-iodothyronine (T3) (and human chorionic gonadotrophin) were measured by immunoassays. The median, 2.5th and 97.5th percentiles at 4-week intervals were calculated. Data were also analysed for significant trends using ANOVA. RESULTS: Free T3 decreased during pregnancy, whereas free T4 initially increased, peaking between 9-13 weeks and then decreased, the decline becoming significant by week 21. TSH mirrored changes in free T4. CONCLUSION: The gestation-related reference intervals for thyroid hormones should alleviate the misinterpretation of thyroid function in pregnancy.

Adult↗
PubMed2001

Are thyroid hormones or hCG responsible for hyperemesis gravidarum? A matched paired study in pregnant Chinese women.

OBJECTIVE: To determine the relative importance of thyroid hormones and human chorionic gonadotropin in the etiology of hyperemesis gravidarum. DESIGN: A prospective study comparing the hormonal status in women with hyperemesis gravidarum (5-18 weeks), with healthy pregnant controls, matched for gestational age. Sensitive thyroid stimulating hormone, free thyroxine, free triiodothyronine and total beta human chorionic gonadotropin were measured by immunoassays. The hormone results for hyperemesis gravidarum group (n=58) were compared with pregnant control women (n=58) using the Mann Whitney test. Stepwise logistic regression analysis was performed to determine which variables were significantly associated with hyperemesis gravidarum and to estimate the probability of each woman having hyperemesis gravidarum. The strength of the resulting association was tested by generating a receiver operating characteristic curve for predicting hyperemesis gravidarum using these probabilities. RESULTS: Maternal age and all hormones were significantly different between the hyperemetic and control groups. However, logistic regression analysis demonstrated that only maternal age, free thyroxine and thyroid stimulating hormone were significant independent variables. The area beneath the receiver operating characteristic curve for prediction of hyperemesis gravidarum was 0.84. CONCLUSION: Human chorionic gonadotropin is not independently involved in the etiology of hyperemesis gravidarum but may be indirectly involved by its ability to stimulate the thyroid. Differences in maternal age and thyroid function are highly discriminatory with regard to hyperemesis gravidarum.

Adult↗
PubMed2000

Decreased steroid hormone synthesis from inorganic nitrite and nitrate: studies in vitro and in vivo.

Nitrites and nitrates are consumed nonchalantly in diet. Organic nitrates are also used as vasodilators in angina pectoris, but the therapy is associated with tolerance whose mechanism remains elusive. Previously, we found inorganic nitrate inhibited steroidogenesis in vitro. Because adrenocorticoids regulate water and electrolyte metabolism, tolerance may ensue from steroid deficiency. We have studied the effects of nitrite and nitrate on in vitro synthesis and in vivo blood levels of steroid hormones. In vitro, nitrite was more potent than nitrate in inhibiting human chorionic gonadotropin (hCG)-stimulated androgen synthesis by Mouse Leydig Tumor cells. At concentrations above 42 mM, nitrite completely inhibited androgen synthesis, and, unlike nitrate, the inhibition was irreversible by increasing hCG concentration. The cAMP production remained intact but reduced with both ions. The nitric oxide (NO) scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (c-PTIO) significantly increased hCG- or cAMP-stimulated androgen synthesis in all buffers, suggesting that NO is a chemical species directly involved in the nitrite/nitrate-induced inhibition. This is further supported by c-PTIO countering the inhibitory action of methylene blue on androgen synthesis. Rats given distilled water containing 50 mg/L NaNO(2) or NaNO(3) for 4 weeks drank significantly less daily. At the end, their blood corticosterone and testosterone levels were significantly decreased. The adrenocortical histology showed bigger lipid droplets, which are pathogonomic of impaired steroidogenesis. Nitrite and nitrate are metabolized to NO, which binds heme in cytochrome P450 enzymes, thereby inhibiting steroidogenesis. Therapeutic nitrates likewise may decrease adrenal (and gonadal) steroidogenesis. Cortisol deficiency would impair water excretion causing volume expansion, and aldosterone deficiency would cause sodium loss and raised renin. Paradoxically, volume expansion without sodium retention and raised renin has all been reported in tolerance.

Androgens↗
PubMed2000

Is steroid deficiency the cause of tolerance in nitrate therapy?

The award of the Nobel Prize in Physiology and Medicine for 1998 bears witness to the 'explosive' field of nitric oxide (NO), and who would have thought the explosive nitroglycerin owed its therapeutic effectiveness to this little molecule? NO is also involved in causing penile erection, which has brought sildenafil to the aid of patients with erectile dysfunction. However, emerging evidence in animals and in vitro studies indicates that NO also inhibits steroidogenesis, which may have repercussions in humans. The decrease in androgen secretion may impact on secondary sexual characteristics, including penile size. The tolerance to the nitrate therapy in angina, characterized by volume expansion and not due to sodium retention, may also be related to steroid hormone deficiency. Decreased cortisol secretion may impair water excretion, resulting in volume expansion. Impaired aldosterone secretion would cause hyponatraemia with resultant raised renin. I hypothesize that continuous therapy with nitrates and sildenafil will result in diminished levels of steroid hormones with predicted sequelae.

Angina Pectoris↗
PubMed1999

The effect of percutaneous oestradiol on atheroma formation in ovariectomized cholesterol-fed rabbits.

OBJECTIVE: The aim of this study was to examine the effect of percutaneous oestradiol on the lipid profile and on atheroma formation using an animal model. METHODS: The study was of 12 weeks duration. Fifty sexually mature female New Zealand White rabbits were divided into five groups of equal size. Two groups acted as controls and received normal rabbit chow. Rabbits in one of these groups were ovariectomized. The remaining three groups were ovariectomized but received 1% cholesterol enriched rabbit chow. One of these cholesterol-fed groups received 0.3 mg/kg percutaneous oestradiol daily whilst another received 0.1 mg/kg oral oestradiol daily. Measurements of concentrations of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were made at the beginning and end of the study. Aortic atheroma formation was measured using computerized image analysis of uptake of Sudan III staining. RESULTS: After 12 weeks there were significant increases in the mean concentrations of TC in the three cholesterol-fed groups compared with controls (P < 0.001). Changes in HDL-C and TG concentrations were less consistent. The mean area of aortic atheroma formation was significantly less in both the percutaneous oestradiol group (4.9%) and the oral oestradiol group (8.6%) compared with the non-oestrogen-treated cholesterol-fed group (19.5%) (P < 0.001, < 0.01 respectively). CONCLUSION: These results suggest that percutaneous oestradiol has a direct protective effect on atheroma formation independent of serum concentrations of total cholesterol.

Administration, Oral↗
PubMed1999

Role of chloride and inhibitory action of inorganic nitrate on gonadotropin-stimulated steroidogenesis in mouse Leydig tumor cells.

The involvement of adenylate cyclase-cyclic adenosine monophosphate (AC-cAMP) in gonadotropin-stimulated testicular steroidogenesis is well known. Little is known about the role of guanylate cyclase-cyclic guanosine monophosphate (GC-cGMP) or early chloride conductance stimulated by gonadotropins in steroidogenesis. Human chorionic gonadotropin (hCG) 1 IU/L caused significant androgen secretion without a discernible effect on cAMP production. Despite negligible intracellular cAMP, the protein kinase A inhibitor H89 blocked basal and hCG-stimulated steroidogenesis. The GC inhibitors methylene blue (MB) and LY83583 decreased androgen secretion, but hCG did not stimulate cGMP production and there was not a steroidogenic response to exogenous cGMP. A chloride-channel inhibitor, diphenylamine-2-carboxylate (DPC), at concentrations up to 0.6 mmol/L stimulated basal steroid secretion and hCG 10 IU/L stimulated cAMP production, but higher concentrations had an inhibitory effect. Substitution of chloride by gluconate enhanced basal steroid secretion, but nitrate completely abolished the effect of 1 IU/L hCG on androgen secretion, which could be partially overcome by increasing the gonadotropin concentration. In conclusion, chloride, perhaps by activating AC-cAMP, mediates the steroidogenic action of gonadotropins in mouse Leydig tumor cells (MLTC-1). Inorganic nitrate probably inhibited steroidogenesis via conversion to nitric oxide (NO) without involving the GC-cGMP pathway. Nevertheless, the results obtained with GC inhibitors suggest a role for the GC-cGMP pathway in Leydig cell steroidogenesis.

Aminoquinolines↗
PubMed1999

Human chorionic gonadotropin: a secretory hormone.

There are several physiological and pathophysiological situations where there is an apparent fluid flux across plasma membranes at the time when human chorionic gonadotropin (hCG) levels are high. These fluxes may take the form of a fluid loss from gastrointestinal tract (e.g. emesis/hyperemesis gravidarum) or accumulations in enclosures (e.g. amniotic fluid or hydatidiform mole). What is not obvious though is whether hCG is the cause of these fluid fluxes. Although glycoprotein hormones like hCG are mainly hormonogenic, their action in the latter process involves the efflux or conductance of halide ions. Since the basis of fluid secretion is an active efflux of ions such as chloride stimulated by a humoral agent, accompanied by a passive diffusion of water across a cell wall, I hypothesize that hCG is also a secretory hormone and responsible for fluid fluxes in the above and other clinical situations.

Chorionic Gonadotropin↗
PubMed1999

Could growth retardation in cystic fibrosis be partly due to deficient steroid and thyroid hormonogenesis?

Cystic fibrosis (CF) mainly affects Caucasians of northwestern-European ancestry with severe morbidity. The individuals are malnourished and growth retarded. The latter is thought to be the consequence of delayed maturation of the hypothalamic-pituitary-gonadal axis due to malnourishment. However, there is evidence that steroid and thyroid hormone syntheses may be impaired in CF. Thyrotropin stimulates the uptake and efflux of iodide before the halide is incorporated into thyroid hormones and it is becoming apparent that gonadotropins likewise mobilise chloride ions in Leydig cells prior to steroidogenesis. Since the primary defect causing CF is the mutated cystic fibrosis transmembrane conductance regulator (CFTR)--a chloride channel residing on the apical membrane of wet epithelia, the growth retardation in CF may in part be due to deficient hormone syntheses. The latter may involve CFTR or may be the halide channel activated by glycoprotein hormones prior to hormonogenesis.

Cystic Fibrosis↗
PubMed1998

Histochemical, clinical, and in vitro beta cell responses in a neonate with persistent hyperinsulinaemic hypoglycaemia of infancy.

When treatment with diazoxide and somatostatin for persistent hyperinsulinaemic hypoglycaemia of infancy failed, subtotal pancreatectomy was performed on a neonate on day 41. The pancreatic tissue was saved and used for immunohistochemical and cell culture studies. The initial immunohistochemistry of beta cells for insulin was negative, using a 1 in 200 dilution of insulin antiserum, but positive results were obtained with an increased concentration of the antiserum. The insulin to somatostatin cell ratio in islets of Langerhans was about 1:1, with no somatostatin cells outside the islets. Glucose stimulated insulin secretion in a concentration dependent manner in vitro. Isobutyl methyl xanthine doubled insulin secretion, but lithium had no effect. The glucose stimulated insulin secretion was inhibited by somatostatin, epinephrine, and in the absence of Ca2+. In view of the normal in vitro responses of beta cells to various secretory analogues, the lack of responsiveness to somatostatin analogue before pancreatectomy may not have been due to deficiency or resistance to somatostatin, but to beta cell hyperplasia overwhelming the paracrine regulatory mechanism(s).

1-Methyl-3-isobutylxanthine↗
PubMed1998

hCG: its pancreatic and duodenal receptors and in vivo electrolyte secretion in female rats.

A state of fluid flux probably resulting from ion movement across the plasma membrane occurs during early pregnancy or trophoblastic disease, manifesting as emesis or hyperemesis gravidarum or hydatidiform moles. In emesis or hyperemesis gravidarum, excessive secretion induced by a humoral agent may trigger vomiting by distending and activating the gastrointestinal (GI) tract mechanoreceptors. This agent may be human chorionic gonadotropin (hCG). High-affinity hCG binding sites similar to those in the ovary were found in the duodenum and pancreas of female rats, with dissociation constant values of 0.11 +/- 0.02, 1.9 +/- 0.6, and 4.7 +/- 3.5 nM, respectively. The isoelectric point for duodenal and ovarian proteins was 5.5. With the use of two antisera directed against amino acid residues 24-33 and 239-249 of the lutropin receptor, positive immunohistochemical staining was seen in smooth muscle, Brunner's glands, parasympathetic ganglia, crypt cells, and blood vessels of the duodenum, in zymogen granules of acini, and in intralobular ducts and blood vessels of the pancreas. Under nonreducing conditions, 150- and 170-kDa proteins were seen, through Western blot analysis, in the pancreas, duodenum, and ovary. Administration of hCG to female rats in vivo caused a significant increase in HCO-3 and K+ secretion from the duodenum and pancreas. We hypothesize that during pregnancy hCG stimulates excessive secretion of electrolytes (and fluid) into the upper GI tract, which culminates in the vomiting during pregnancy.

Animals↗
PubMed1996

Urinary excretion of testosterone and estradiol in Chinese men and relationships with serum lipoprotein concentrations.

Urinary excretion of total and free testosterone and estradiol was measured in 46 healthy Chinese men, along with serum concentrations of total testosterone and estradiol and the calculated free (unbound) concentrations. Associations with serum concentrations of total, low-density lipoprotein (LDL), high-density lipoprotein-2 (HDL2), and HDL3 cholesterol, apolipoproteins (apos) A-I and B, lipoprotein(a) [Lp(a)] were studied. Serum total and free testosterone concentrations were positively correlated with HDL and HDL2 cholesterol and apo A-I. Serum total and free estradiol levels showed borderline-significant negative associations with total and LDL cholesterol levels. Among urinary variables, total estradiol excretion was negatively associated with apo B levels and showed borderline-significant associations with total and LDL cholesterol. Adjustment for potential confounders, including age, body mass index (BMI), and waist to hip ratio (WHR), strengthened the associations between urinary total estradiol and serum total cholesterol, LDL cholesterol, and apo B. Urinary free estradiol showed a significant correlation with HDL3 cholesterol. Urinary excretion of total testosterone was significantly negatively associated with serum cholesterol and LDL cholesterol levels only after controlling for confounding variables. There were no significant associations between hormone variables and Lp(a) values. This study suggests that variation in sex hormone production accounts for some of the variation in serum lipid levels.

Adult↗