Placental 11β-hydroxysteroid dehydrogenase (11β-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 11β-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 11β-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, 11β-HSD-1, and
11β-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 11β-HSD-1 clearly increased in the labyrinth zone but fell in
basal zone, whereas the opposite pattern of expression was observed for
11β-HSD-2. MR expression was not detected at any stage. The pattern
of placental 11β-HSD-2 mRNA expression over days 16, 19, and 22 of
pregnancy was paralleled by changes in 11β-HSD-2-specific
bioactivity, but despite clear expression of 11β-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 11β-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 11β-HSD-2
bioactivity in either of the placental zones at day 19. Placental
11β-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 11β-HSD-1 and 11β-HSD-2 expression could have a
major influence on glucocorticoid action in the placenta at this time.
Moreover, the changes in 11β-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.
Recent epidemiological data have implicated prenatal events in the development of cardiovascular disorders. Thus low birth weight strongly predicts the later occurrence of hypertension, type II ...diabetes mellitus, syndrome X and deaths from ischaemic heart disease. The mechanism linking prenatal events and later disease is not clear, although maternal malnutrition has been advocated. We have advanced the hypothesis that glucocorticoids might be important as they retard foetal growth and programme offspring hypertension in rats. The foetus has been thought to be protected from the 2-10 times higher maternal glucocorticoid levels by the placental enzyme 11B-hydroxysteroid dehydrogenase (11B-HSD), which is present in many tissues and in humans catalyses the conversion of the active glucocorticoid cortisol to inert cortisone (corticosterone to 11-dehydrocorticosterone in rats). The precise role of 11B-HSD as a barrier to maternal glucocorticoids during prenatal life has not been fully characterised. The role of 11B-HSD in controlling prenatal glucocorticoid exposure in humans and animals has thus been examined. Two isoforms of 11B-HSD exist, type 1, a widespread NADP dependent reversible enzyme and type 2, a high affinity NAD dependent dehydrogenase found mainly in placenta and kidney. 11B-HSD was found in abundance in the ovary and placenta. The main site of immunohistochemical staining and expression of mRNA (11B-HSD-1) in the rat ovary was in the oocyte. 11B-HSD was oxidative, inactivating corticosterone. In both rat placenta in-vitro (11B-HSD-2), and human placenta in-vitro and ex-vivo (11B-HSD-2) the bioactivity was also predominantly oxidative. The lowest placental enzyme activity at term (and hence the greatest foetal glucocorticoid exposure) was found in the smallest rats with the largest placentas, i.e. those in human studies who would be predicted to develop the highest adult blood pressures (birth weight vs. placental 11B-HSD activity: n = 56; r = 0.46; p < 0.0005). A method to examine 11B-HSD function in fresh intact human placentas was developed (ex-vivo dual circuit cotyledon perfusion) which allows close approximation to the in-vivo situation. The majority of cortisol, from low to high nanomolar concentrations, infused through the maternal circulation was metabolised to inert cortisone by the time it reached the foetal circulation, although considerable individual variation was observed. 118-HSD was the only significant contributor to placental cortisol metabolism at physiological maternal concentrations and inhibition of 118-HSD with either the liquorice constituent glycyrrhetinic acid or its hemi-succinate, carbenoxolone, resulted in abolition of the glucocorticoid barrier, allowing maternally administered cortisol to pass unmetabolised through the placenta. In a prospective study, on 16 normal primiparous women whose placentas were studied with this technique, a positive and significant correlation was found between the effectiveness of 118-HSD and offspring birth weight (r = 0. 67; p < 0. 005). The relationship between placental 118-HSD effectiveness in-vivo and term cord blood osteocalcin (a sensitive marker of glucocorticoid exposure) was prospectively examined in 19 women. Cord blood levels of the bone specific protein osteocalcin were determined with radioimmunoassay. The lowest cord blood osteocalcin levels were found in the foetuses whose placental 118-HSD barrier function was poorest (r = 0.58; p < 0.02), (and had presumably had the greatest glucocorticoid exposure), suggesting that term cord blood osteocalcin levels might be a useful predictor of hypertension, ischaemic heart disease and possibly metabolic bone disease. The findings presented in this thesis represent direct evidence that 118-HSD is the barrier to maternal glucocorticoids, its effectiveness correlating with foetal growth in rats (in-vitro), in humans (ex-vivo), and in-vivo with human cord blood osteocalcin levels (osteocalcin may be a marker of glucocorticoid exposure). In the light of studies on pregnant rats in which administration of exogenous glucocorticoids or 118-HSD inhibitors reduces birth weight and programmes hypertension in the offspring, it is reasonable to propose that increased foetal glucocorticoid exposure consequent upon attenuated placental 118-HSD function may play a role in intrauterine programming of later hypertension.
Recent epidemiological data have implicated prenatal events in the development of cardiovascular disorders. Thus low birth weight strongly predicts the later occurrence of hypertension, type II ...diabetes mellitus, syndrome X and deaths from ischaemic heart disease. The mechanism linking prenatal events and later disease is not clear, although maternal malnutrition has been advocated. We have advanced the hypothesis that glucocorticoids might be important as they retard foetal growth and programme offspring hypertension in rats. The foetus has been thought to be protected from the 2-10 times higher maternal glucocorticoid levels by the placental enzyme 11B-hydroxysteroid dehydrogenase (11B-HSD), which is present in many tissues and in humans catalyses the conversion of the active glucocorticoid cortisol to inert cortisone (corticosterone to 11-dehydrocorticosterone in rats). The precise role of 11B-HSD as a barrier to maternal glucocorticoids during prenatal life has not been fully characterised. The role of 11B-HSD in controlling prenatal glucocorticoid exposure in humans and animals has thus been examined. Two isoforms of 11B-HSD exist, type 1, a widespread NADP dependent reversible enzyme and type 2, a high affinity NAD dependent dehydrogenase found mainly in placenta and kidney. 11B-HSD was found in abundance in the ovary and placenta. The main site of immunohistochemical staining and expression of mRNA (11B-HSD-1) in the rat ovary was in the oocyte. 11B-HSD was oxidative, inactivating corticosterone. In both rat placenta in-vitro (11B-HSD-2), and human placenta in-vitro and ex-vivo (11B-HSD-2) the bioactivity was also predominantly oxidative. The lowest placental enzyme activity at term (and hence the greatest foetal glucocorticoid exposure) was found in the smallest rats with the largest placentas, i.e. those in human studies who would be predicted to develop the highest adult blood pressures (birth weight vs. placental 11B-HSD activity: n = 56; r = 0.46; p < 0.0005). A method to examine 11B-HSD function in fresh intact human placentas was developed (ex-vivo dual circuit cotyledon perfusion) which allows close approximation to the in-vivo situation. The majority of cortisol, from low to high nanomolar concentrations, infused through the maternal circulation was metabolised to inert cortisone by the time it reached the foetal circulation, although considerable individual variation was observed. 118-HSD was the only significant contributor to placental cortisol metabolism at physiological maternal concentrations and inhibition of 118-HSD with either the liquorice constituent glycyrrhetinic acid or its hemi-succinate, carbenoxolone, resulted in abolition of the glucocorticoid barrier, allowing maternally administered cortisol to pass unmetabolised through the placenta. In a prospective study, on 16 normal primiparous women whose placentas were studied with this technique, a positive and significant correlation was found between the effectiveness of 118-HSD and offspring birth weight (r = 0. 67; p < 0. 005). The relationship between placental 118-HSD effectiveness in-vivo and term cord blood osteocalcin (a sensitive marker of glucocorticoid exposure) was prospectively examined in 19 women. Cord blood levels of the bone specific protein osteocalcin were determined with radioimmunoassay. The lowest cord blood osteocalcin levels were found in the foetuses whose placental 118-HSD barrier function was poorest (r = 0.58; p < 0.02), (and had presumably had the greatest glucocorticoid exposure), suggesting that term cord blood osteocalcin levels might be a useful predictor of hypertension, ischaemic heart disease and possibly metabolic bone disease. The findings presented in this thesis represent direct evidence that 118-HSD is the barrier to maternal glucocorticoids, its effectiveness correlating with foetal growth in rats (in-vitro), in humans (ex-vivo), and in-vivo with human cord blood osteocalcin levels (osteocalcin may be a marker of glucocorticoid exposure). In the light of studies on pregnant rats in which administration of exogenous glucocorticoids or 118-HSD inhibitors reduces birth weight and programmes hypertension in the offspring, it is reasonable to propose that increased foetal glucocorticoid exposure consequent upon attenuated placental 118-HSD function may play a role in intrauterine programming of later hypertension.
Low birth weight in combination with a large placenta predicts human hypertension. The pathophysiological link remains unclear, but glucocorticoid excess impairs fetal growth and leads to offspring ...hypertension. A key controller of fetal glucocorticoid exposure and local tissue availability is 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). The activity of placental 11β-HSD2 correlates with fetal growth in animals and humans. Ethanol abuse and smoking are known to retard fetal growth which may relate to altered glucocorticoid action or dynamics. This study has examined whether nicotine or ethanol modulate glucocorticoid action in the placenta or fetus by inhibiting 11β-HSD2, using clonal cell cultures, freshly isolated dually perfused intact human placentas and placentas from
in vivo treated rats. No significant effect on the activity of 11β-HSD2 by pathophysiologically relevant nicotine or ethanol concentrations was observed. The mechanism of action of nicotine and ethanol relevant to reduced fetal growth requires further study.
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.
Cross-sectional study examining the relation between cord blood levels of osteocalcin and placental glucocorticoid metabolism at term.
Twenty-one women attending for delivery at the Simpson Memorial Maternity Pavilion in Edinburgh had cord venous and arterial blood samples collected at delivery.
Cord plasma levels of osteocalcin, cortisol and cortisone were measured by radioimmunoassay and indices of placental 11 beta-HSD activity were calculated.
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.
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.
In order to evaluate the morbidity and mortality of chronic left ventricular aneurysm a population based cohort study was carried out. All cardiac catheterizations performed in Iceland during the ...years 1983-1985 were examined (n = 1261). Sixty seven patients with left ventricular aneurysm defined as: (1) normal diastolic contour with segmental dyskinesis (n = 6), (2) abnormal diastolic contour with (a) akinetic (n = 36) or (b) dyskinetic (n = 25) segments in systole, were included. Sixty seven patients with normal diastolic contour and akinetic segments in systole served as controls. The groups had similar mean age, sex ratio, number of diseased vessels and left ventricular end diastolic pressure. Mean ejection fraction was significantly lower in the aneurysm group (46 vs 56%, p = 0.00005). Collaterals were detected significantly more often in controls (88 vs 72%, p = 0.03). At follow up in 1989, 19 in the aneurysm group had died as compared to 12 in the control group. Life table analysis revealed significant differences between survival curves. The relative risk ratio was 2.18 with 95% confidence interval of 1.00-4.74 (p less than 0.05). However, when the amount of myocardial damage was taken into account the differences in survival were no longer statistically significant (relative risk ratio 1.77 with 95% confidence interval of 0.79-3.99). We conclude that the reduced survival probability of patients with chronic left ventricular aneurysm in comparison to controls with akinetic scars is accounted for by the more extensive myocardial damage and not by the presence of aneurysm per se.
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.
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