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R Benediktsson

Publications and source records attributed to R Benediktsson.

At least 19 recordsLinked to original sources
PubMed2000

Transfer and metabolism of prostaglandin E(2)in the dual perfused human placenta.

Prostaglandins (PGs) are potent paracrine hormones that are important for the control of several functions in the uterus and fetus during pregnancy and parturition. PGs are rapidly metabolized to inactive metabolites by prostaglandin dehydrogenase (PGDH). However, the regulation of transfer and metabolism of PGs across the placenta is not well understood. This study used an in vitro dual perfused human placental cotyledon preparation to examine the production of the potent vasoactive and myometrial stimulants PGE(2)and PGF(2alpha), transfer of PGs from the maternal to the fetal circulation and the metabolism of PGs by PGDH. Secretion of PGE(2)was greater into the fetal compared to the maternal circulation. PGE(2)output was higher than PGF(2alpha)and concentrations of PGE(2)and PGF(2alpha)metabolites (PGEM and PGFM) were greater in both fetal and maternal outputs when compared to the primary prostaglandins. Infusion of PGE(2)into the maternal circulation did not result in increased PGE(2)efflux but PGEM was output was increased, demonstrating a rapid and efficient metabolism by the placenta. There was no significant transfer of PGE(2)across to the fetal circulation, although there was some transfer but in the form of inactivated PGEM. There was no significant interconversion of PGE(2)to PGF(2alpha)by the 9-keto-reductase pathway. Expression of PGDH as detected by immunoblot was high in placenta. This PGDH was localized throughout the syncytiotrophoblast at the fetal-maternal interface and also in extravillous trophoblast cells. The presence of PGDH at this site acts to stabilize output of primary PG from the placenta and also as a barrier preventing transfer to the fetal circulation, resulting in the separation of PG homeostasis in the fetus and mother.

Biological Transport, Active↗
PubMed1998

Management of the unexpected result: compensated hypothyroidism.

The combination of elevated serum thyrotropin and normal serum thyroxine is called compensated or subclinical hypothyroidism. This most commonly represents clinically silent autoimmune thyroiditis. Whether this condition warrants treatment or simply observation is still debated. The risk of developing overt hypothyroidism is high in females with elevated thyrotropin above 10 mU/l and/or positive thyroid microsomal antibodies. Males are also at high risk of progression towards overt hypothyroidism, regardless of antibody status or degree of thyrotropin elevation. We advise routine treatment of only those at high risk of developing overt hypothyroidism.

Disease Progression↗
PubMed1998

Tissue-specific messenger ribonucleic acid expression of 11beta-hydroxysteroid dehydrogenase types 1 and 2 and the glucocorticoid receptor within rat placenta suggests exquisite local control of glucocorticoid action.

Placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) regulates transplacental passage of maternal glucocorticoids to the fetus and is thus a key determinant of fetal glucocorticoid levels. It has also been proposed that placental 11beta-HSD expression may influence local glucocorticoid actions by regulating access of corticosterone to the glucocorticoid receptor (GR) or mineralocorticoid receptor (MR). Therefore, the present study used a rat model to assess whether the GR or MR are coexpressed with the two forms of 11beta-HSD (types 1 and 2) in the placental labyrinth zone, the major site of maternal-fetal transfer, and in the basal zone, the primary site of placental hormone synthesis. In situ hybridization analysis was used to assess messenger RNA (mRNA) expression for the GR, MR, 11beta-HSD-1, and 11beta-HSD-2 in the two placental zones on days 16, 19 and 22 of pregnancy (term = day 23). Whereas expression of the GR appeared relatively unchanged in both zones at these three stages of pregnancy, that of 11beta-HSD-1 clearly increased in the labyrinth zone but fell in basal zone, whereas the opposite pattern of expression was observed for 11beta-HSD-2. MR expression was not detected at any stage. The pattern of placental 11beta-HSD-2 mRNA expression over days 16, 19, and 22 of pregnancy was paralleled by changes in 11beta-HSD-2-specific bioactivity, but despite clear expression of 11beta-HSD-1 mRNA, no bioactivity attributable to this enzyme was measurable in either placental zone. To assess the role of fetal adrenal maturation on these changes in 11beta-HSD, two experimental models, maternal adrenalectomy and fetectomy, were employed. Maternal adrenalectomy on day 13 advanced maturation of the fetal adrenal cortex but had no effect on 11beta-HSD-2 bioactivity in either of the placental zones at day 19. Placental 11beta-HSD-2 bioactivity on day 22 was also unaffected by fetectomy 3 or 6 days earlier. In conclusion, the consistent expression of the GR in the two placental zones late in pregnancy suggests that concomitant and marked changes in 11beta-HSD-1 and 11beta-HSD-2 expression could have a major influence on glucocorticoid action in the placenta at this time. Moreover, the changes in 11beta-HSD expression appear to be unrelated to development of the fetal adrenal cortex and are likely to reduce the placental glucocorticoid barrier near the end of pregnancy.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1997

Placental 11 beta-hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure.

OBJECTIVE: Placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which converts active cortisol to inactive cortisone, has been proposed to be the mechanism guarding the fetus from the growth retarding effects of maternal glucocorticoids; however, other placental enzymes have also been implicated. Placental 11 beta-HSD is unstable in vitro, and enzyme activity thus detected may not be relevant to the proposed barrier role. We have therefore examined placental glucocorticoid metabolism in dually perfused freshly isolated intact human placentas. DESIGN: Placentas were obtained from randomly selected normal term deliveries. The maternal circuit was perfused with physiological concentration of cortisol, the fetal effluent collected and steroid metabolites separated and quantified using silica columns (Sep-pak Plus) and HPLC. RESULTS: Most of the maternally administered cortisol was metabolized to cortisone, and no conversion of cortisone to cortisol was detected. Cortisone was the only product of cortisol metabolism. Inhibition of 11 beta-HSD with glycyrrhetinic acid allowed cortisol to gain direct access to the fetal circulation. CONCLUSION: We conclude that human placental 11 beta-HSD plays a crucial role in controlling glucocorticoid access to the fetus. Other enzymes are not significant contributors at physiologically relevant cortisol concentrations.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

11 beta-Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects.

Recent studies have demonstrated that the interconversion of active and inactive glucocorticoids plays a key role in determining the specificity of the mineralocorticoid receptor and controlling local tissue glucocorticoid receptor activation. Two distinct isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) have been identified. 11 beta-HSD1 is NADPH-dependent and at its major site of action (the liver) is a reductase, converting cortisone to cortisol (11-dehydrocorticosterone to corticosterone in the rat). 11 beta-HSD2 is NAD-dependent, is present in tissues such as the kidney and placenta, and converts cortisol to cortisone (corticosterone to 11-dehydrocorticosterone in the rat). Congenital or acquired deficiency of 11 beta-HSD2 produces the syndrome of apparent mineralocorticoid excess (SAME) in which cortisol gains access to the unprotected nonspecific mineralocorticoid receptor. The congenital deficiency is associated with mutations in the gene encoding the kidney isoform of 11 beta-HSD2; the acquired form results from inhibition of the enzyme by licorice, carbenoxolone, ACTH-dependent steroids in the ectopic ACTH syndrome, and possibly circulating inhibitors of the enzyme. This paper focuses on recent evidence, which suggest that low levels of placental 11 beta-HSD2 result in increased exposure of the fetus to maternal glucocorticoid and low birth weight. In animal studies using the rat we have shown that birth weight is correlated positively and placental weight negatively with the level of placental 11 beta-HSD. Thus animals with low birth weight and large placentae were those likely to be exposed to the highest level of maternal glucocorticoid. In man a similar relationship was found with birth weight being significantly correlated either with placental 11 beta-HSD activity or with the extent of cortisol inactivation by isolated perfused placental cotyledons. Administration of dexamethasone (which is poorly metabolized by placental 11 beta-HSD2) to pregnant rats resulted in decreased birth weight and the development of hypertension in the pups when adult. The same results were obtained when pregnant rats were given carbenoxolone, an inhibitor of placental 11 beta-HSD2. Low protein diet during pregnancy in the rat resulted in low birth weight of the pups, increased placental weight but decreased placental 11 beta-HSD activity, and adult hypertension. Thus increased glucocorticoid exposure of the fetus secondary to a failure of the normal inactivation of maternal glucocorticoid by the placental may be an important mechanism linking changes in the in utero environment and common adult diseases.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

11beta-Hydroxysteroid dehydrogenase type 2 in the rat corpus luteum: induction of messenger ribonucleic acid expression and bioactivity coincident with luteal regression.

The corpus luteum (CL) is the major source of progesterone during rat pregnancy, and its regression precedes and is essential for parturition. Recent studies show that luteal regression in the rat can be blocked by the administration of synthetic glucocorticoids, yet endogenous glucocorticoids are maximal at the time of normal luteal regression in pregnancy. This suggests that endogenous glucocorticoid may be inactivated locally within the CL, presumably via the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2), which is known to regulate glucocorticoid access to receptors in other target tissues. This possibility was examined in the present study by measurement of 11beta-HSD-2 messenger RNA (mRNA) expression and bioactivity in rat CL over the second half of pregnancy, thus covering periods of maximal and minimal progesterone secretion. 11beta-HSD-2 bioactivity was measured in luteal homogenates obtained from rats on days 11, 16, 19, and 22 of pregnancy (term = day 23). Bioactivity was measurable in CL at each stage of pregnancy, with an apparent Km for corticosterone of approximately 100 nM. Enzyme activity was lowest on day 11 (maximum velocity, 1.0 +/- 0.6 pmol/min x mg protein), increased more than 5-fold by day 16 (6.2 +/- 0.5), then increased by an additional 4-fold by day 19 (24.3 +/- 4.3), and this high level of activity was maintained to day 22 (26.5 +/- 5.2). In kidney, the apparent Km for corticosterone was lower than that in CL, but remained unchanged throughout pregnancy (overall mean, 28.9 +/- 1.9 nM) as did the maximum velocity (overall mean, 25.4 +/- 1.3 pmol/min x mg protein). Consistent with the pattern of bioactivity in CL, mRNA for 11beta-HSD-2 was not detectable in CL by Northern analysis on either day 11 or day 16, but was clearly evident on days 19 and 22. In situ hybridization also revealed a substantial up-regulation of 11beta-HSD-2 expression specifically within the CL on days 19 and 22, whereas glucocorticoid receptor mRNA expression was consistent across all stages. In contrast, there was no detectable mRNA expression in CL for either 11beta-HSD-1 or the mineralocorticoid receptor at any stage. These data show that a marked induction of 11beta-HSD-2 mRNA expression and bioactivity occurs within the CL late in rat pregnancy and thus suggest that local inactivation of endogenous glucocorticoids facilitates luteal regression.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

11 beta-Hydroxysteroid dehydrogenases: tissue-specific dictators of glucocorticoid action.

11 beta-HSD catalyses the interconversion of active and inactive corticosteroids and exists as two isoforms with less than 30% amino acid homology. The bi-directional NADP-dependent type 1 enzyme appears to function as a tissue-specific glucocorticoid provider. The uni-directional NAD-dependent type 2 enzyme functions as a tissue-specific glucocorticoid protector. The syndrome of AME is caused by mutations in the gene of 11 beta-HSD2. Placental 11 beta-HSD2 is a barrier to growth-retarding maternal glucocorticoids and may play a key role in prenatal programming of hypertension.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Placental 11 beta-hydroxysteroid dehydrogenase and the programming of hypertension.

Excessive foetal exposure to glucocorticoids retards growth and "programmes" adult hypertension in rats. Placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which catalyses the conversion of corticosterone and cortisol to inert 11 keto-products, normally protects the foetus from excess maternal glucocorticoids. In both rats and humans there is considerable natural variation in placental 11 beta-HSD, and enzyme activity correlates with birth weight. Moreover, inhibition of placental 11 beta-HSD in the rat reduces birth weight and produces hypertensive adult offspring, many months after prenatal treatment with enzyme inhibitors; these effects are dependent upon maternal adrenal products. These data suggest that placental 11 beta-HSD, by regulating foetal exposure to maternal glucocorticoids, crucially determines foeto-placental growth and the programming of hypertension. Maternal protein restriction during pregnancy also produces hypertensive offspring and selectively attenuates placental 11 beta-HSD activity. Thus, deficiency of the placental barrier to maternal glucocorticoids may represent a common pathway between the maternal environment and foeto-placental programming of later disease. These data may, at least in part, explain the human epidemiological observations linking early life events to the risk of subsequent hypertension. The recent characterization, purification and cDNA cloning of a distinct human placental 11 beta-HSD (type 2) will aid the further study of these intriguing findings.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Cellular selectivity of aldosterone action: role of 11 beta-hydroxysteroid dehydrogenase.

Mineralocorticoid receptors in the distal nephron have no intrinsic specificity for mineralocorticoids over glucocorticoids (cortisol in humans; corticosterone in rodents), but are protected from glucocorticoids by the enzyme 11 beta-hydroxysteroid dehydrogenase, which inactivates these steroids to cortisone and 11-dehydrocorticosterone, respectively. Recent work has demonstrated that the enzyme is expressed as multiple tissue-specific isoforms, some of which catalyse the reverse conversion of cortisone to cortisol. These isoforms may allow 11 beta-hydroxysteroid dehydrogenase to modulate access of ligands to glucocorticoid and mineralocorticoid receptors, as well as to amplify and attenuate tissue responses. 11 beta-hydroxysteroid dehydrogenase-mediated protection of mineralocorticoid receptors fails in congenital 11 beta-hydroxysteroid dehydrogenase deficiency and after inhibition of the enzyme by liquorice. In these circumstances, cortisol-dependent mineralocorticoid excess and hypertension ensue. Recent studies suggest that similar deficiencies of 11 beta-dehydrogenase activity may contribute to pathophysiology in common clinical syndromes, illustrating the potential significance of this novel mechanism for development of hypertension.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Fetal osteocalcin levels are related to placental 11 beta-hydroxysteroid dehydrogenase activity in humans.

OBJECTIVE: Overexposure to glucocorticoids in utero reduces birth weight and, in animals, leads to persistent hypertension in the offspring. The fetus is normally protected from maternal glucocorticoids by placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) which catalyses the conversion of cortisol to inert cortisone. In adult humans, osteocalcin is a sensitive marker of glucocorticoid exposure. The aim of this study was to determine whether cord blood osteocalcin levels were related to the ability of placental 11 beta-HSD to inactivate maternal cortisol. DESIGN: Cross-sectional study examining the relation between cord blood levels of osteocalcin and placental glucocorticoid metabolism at term. PATIENTS: Twenty-one women attending for delivery at the Simpson Memorial Maternity Pavilion in Edinburgh had cord venous and arterial blood samples collected at delivery. MEASUREMENTS: Cord plasma levels of osteocalcin, cortisol and cortisone were measured by radioimmunoassay and indices of placental 11 beta-HSD activity were calculated. RESULTS: All indices of placental 11 beta-hydroxysteroid dehydrogenase activity correlated directly and significantly with cord blood osteocalcin levels. For cord blood osteocalcin and the placental 11 beta-HSD Activity Index, Pearson's r was +0.58, r2 = 0.33 and P < 0.02. CONCLUSION: We conclude that term cord blood osteocalcin level reflects the effectiveness of placental glucocorticoid inactivation, and may be a marker for the development of adult hypertension.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Ambulatory blood pressure monitoring: from research to clinical practice.

Evidence from the medical literature is reviewed to indicate that ambulatory monitoring of blood pressure (ABPM) is a better predictor of target organ damage and clinical outcome in the hypertensive patient than clinic measurements of blood pressure (BP). A re-analysis of the documented BPs from the placebo limb of the Medical Research Council's treatment trial of mild hypertension is presented to indicate the difficulties inherent in the advice given by the various published guidelines on the diagnosis and management of hypertension. Finally, it is argued that because ABPM identifies a similar proportion of patients for treatment as a more prolonged follow-up, its use should be considered in the evaluation of all patients with mild hypertension as they can be categorised rapidly with less risk of being 'lost to follow-up'.

Blood Pressure↗
PubMed1994

Apparent mineralocorticoid excess.

In 1979, Ulick and New first coined the term Apparent Mineralocorticoid Excess (AME) for a syndrome of hypertension, hypokalaemia, suppressed renin-angiotensin-aldosterone axis and raised urinary ratio of 11 beta-hydroxy to 11-oxo metabolities of cortisol (suggesting a failure of conversion of cortisol to cortisone). In retrospect, the first case was described in 1974 and since then over 20 children have been reported worldwide but only one adult patient. The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-OHSD) confers aldosterone specificity on intrinsically nonspecific kidney mineralocorticoid receptors by converting the active glucocorticoid cortisol to its inactive 11-oxo form (cortisone). Patients with AME have a deficiency of this enzyme which allows physiological levels of cortisol to flood mineralocorticoid receptors. Dexamethasone, by suppressing adrenal cortisol production, reverts the biochemistry but not usually the BP to normal. Liquorice inhibits 11beta-OHSD by virtue of its active ingredient glycyrrhetinic acid, resulting in an identical clinical picture. Renal 11beta-OHSD is the protagonist in AME but this enzyme is found in many other tissues including liver, placenta and vasculature, and one-third of essential hypertensives have deficient 11beta-OHSD. The placental isoform is thought to be the main barrier to maternal glucocorticoids reaching the fetus. The lowest rat placental 11beta-OHSD activity is found in the largest placentas corresponding to the smallest fetuses (presumably exposed to the highest glucocorticoid levels). This is the group which in humans are most at risk of developing hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Glucocorticoid exposure in utero: new model for adult hypertension.

Hypertension is strongly predicted by the combination of low birthweight and a large placenta. This association could be due to increased fetal exposure to maternal glucocorticoids. Fetal protection is normally effected by placental 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which converts physiological glucocorticoids to inactive products. We found that rat placental 11 beta-OHSD activity correlated positively with term fetal weight and negatively with placental weight. Offspring of rats treated during pregnancy with dexamethasone (which is not metabolised by 11 beta-OHSD) had lower birthweights and higher blood pressure when adult than did offspring of control rats. Increased fetal glucocorticoid exposure secondary to attenuated placental 11 beta-OHSD activity may link low birthweight and high placental weight with hypertension.

Animals↗
PubMed1993

Congenital and acquired syndromes of apparent mineralocorticoid excess.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) interconverts cortisol and cortisone. Congenital deficiency of the renal isoform of the enzyme results in hypertension, hypokalemia and suppression of the renin-angiotensin-aldosterone system--the apparent mineralocorticoid excess syndrome (AME). In these patients cortisol acts as a potent mineralocorticoid. Suppression of plasma cortisol with dexamethasone results in natriuresis, potassium retention and reduction in blood pressure. Ingestion of excess liquorice or taking carbenoxolone produces an acquired form of AME. The active component of liquorice is glycyrrhetinic acid (GE) and carbenoxolone is the hemisuccinate derivative. Both GE and carbenoxolone are potent inhibitors of 11 beta-OHSD. In vitro studies have shown that 11 beta-OHSD is present in aldosterone-selective tissues and acts as an autocrine mechanism which prevents cortisol from gaining access to the non-specific mineralocorticoid receptor (MR). Congenital or acquired absence of this enzyme allows cortisol to bind to MR resulting in AME. 11 beta-OHSD also appears to be important in controlling cortisol access to glucocorticoid receptors. Variable placental 11 beta-OHSD may alter foetal exposure to maternal cortisol and affect growth as indicated by the correlation between foetal weight and placental 11 beta-OHSD. Thus the tissue-specific distribution, ontogeny and modulation of this enzyme allows it to dictate glucocorticoid effects in addition to its key role in ensuring the specificity of the MR.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1992

11 beta-Hydroxysteroid dehydrogenase in the rat ovary: high expression in the oocyte.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the conversion of physiological glucocorticoids to inactive products, thus modifying the access of glucocorticoids to glucocorticoid and mineralocorticoid receptors. Glucocorticoids may affect ovarian function both indirectly and via binding to ovarian receptors. We have demonstrated 11 beta-HSD bioactivity and mRNA expression in rat ovary in vitro. The enzyme was localized to oocytes and luteal bodies immunohistochemically using two antibodies raised against purified rat liver 11 beta-HSD. These data are supported by in-situ hybridization studies, which also localized 11 beta-HSD mRNA expression to oocytes and luteal bodies. The results suggest that 11 beta-HSD may modulate the effects of glucocorticoid on ovarian function.

11-beta-Hydroxysteroid Dehydrogenases↗