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C. J. Edmonds and J. Mackenzie


The cellular sodium transport pool and sodium transepithelial fluxes were investigated in vivo in rat distal colon in relation to sodium loading by intravenous infusion (3·5 h), and to short (4 h) and prolonged (72 h) i.v. administration of aldosterone. Considerable natriuresis and increase in body sodium content were produced by the sodium load but there was no significant effect on the transcellular sodium flux (active absorption from lumen to plasma) or on the sodium transport pool. Both short and prolonged aldosteronism produced similar increases in the transport pool and in the transcellular sodium flux, but the transepithelial electrical potential difference (p.d.) was significantly greater in rats given the prolonged infusion. Addition of amiloride to the solution in the lumen of the colon almost completely abolished the p.d., the transport pool and the transcellular sodium flux of the rats receiving prolonged infusion, but had much less effect in those given the short infusion. The time-course of recovery of p.d. following prolonged aldosteronism was similar to that described for the turnover rate of rat colonic epithelial cells.

Lithium within the lumen had no significant effect in untreated rats but after prolonged aldosterone infusion lithium reduced the p.d. and the transcellular sodium flux although the transport pool was not reduced. These findings are consistent with the hypothesis that aldosteronism renders the apical membranes of the epithelial cells permeable to lithium and that intracellular accumulation of lithium depresses active sodium transfer.

The observations are interpreted in terms of an epithelial model in which aldosterone induces amiloride-sensitive pathways (diffusion channels permeable to sodium and lithium) in the apical membrane which totally replace the amiloride-insensitive pathways when aldosteronism is prolonged; the resulting expansion of the sodium transport pool is the stimulus for increased active sodium transport across the basolateral membranes.

J. Endocr. (1987) 112, 247–252

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M. G. Metcalf and J. A. Mackenzie


It is claimed that the exposure of women to oestrogens unopposed by progesterone increases the risk of breast cancer. Despite indirect evidence in support of this claim, the impracticability of monitoring oestrogen and progesterone levels in large numbers of women for prolonged periods of time has meant that no direct demonstration of the effect has been made. A possible technique is suggested.

The ratio (R) of oestrogens to pregnanediol in urine has been used as an index of oestrogen exposure relative to progesterone. Samples were collected at weekly intervals on 700 occasions from 30 perimenopausal women, and on 519 occasions from 66 women with a history of regular menstrual cyclicity. Unusually prolonged episodes of unopposed high oestrogen excretion (R ≥ 100 for ≥ 2 successive weeks) were observed on 30 occasions in 15 of the perimenopausal women and on four occasions in the other women. In the perimenopausal group, these episodes occurred in 46·9% of the 32 menstrual cycles which were longer than 50 days compared with 6·9% of the 72 cycles which were shorter than 35 days (P < 0·001). The association of prolonged episodes of unopposed high oestrogen excretion with long menstrual cycles suggests the possibility of using menstrual cycle length as an index of oestrogen exposure during the menopausal transition.

J. Endocr. (1985) 104, 137–141

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M. G. Metcalf, J. J. Evans and J. A. Mackenzie


An increased daily excretion of pregnanediol, relative to that early in the menstrual cycle, is often taken to be evidence that a woman has ovulated. This paper assesses the value of alternative procedures for this purpose. Urine, plasma and saliva samples were collected during a 24-h period from 20 women during the follicular phase and from 20 women during the luteal phase. The 24-h excretion of pregnanediol was compared with (1) the concentration of progesterone in plasma, (2) the concentration of progesterone in saliva, (3) the concentration of pregnanediol in small urine samples, (4) the rate of excretion of pregnanediol and (5) the ratio of pregnanediol to creatinine in small urine samples. Each analyte increased substantially during the luteal phase. The median increases (ratio of luteal to follicular phase values) were 14·8, 3·2, 10·6, 11·9 and 11·1 respectively. By comparison, the median increase in 24-h pregnanediol output was 9·2. When the other analytes were used instead of the 24-h excretion of pregnanediol to assess the possibility of ovulation, the incidence of misclassifications (follicular samples classed as luteal and luteal samples classed as follicular) was 0, 12·8, 5·9, 2·0 and 1·0% respectively. It was concluded that the most satisfactory alternative to the measurement of 24-h pregnanediol output for the biochemical assessment of ovulation based on progesterone production was the measurement of the concentration of progesterone in plasma; the least satisfactory alternative was determination of the concentration of progesterone in saliva. If blood was not available, measurement of the ratio of pregnanediol to creatinine in a small urine sample was the preferred method.

J. Endocr. (1984) 100, 75–80

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A Albalat, C Liarte, S MacKenzie, L Tort, J V Planas and I Navarro

Tumor necrosis factor-α (TNFα) is a cytokine with multiple biological functions which, in mammals, has been shown to modulate muscle and adipose tissue metabolism. In fish, TNFα has been identified in several species. However, few studies have examined the role of TNFα in fish outside the immune system. In this study, we assessed the effects of human recombinant TNFα and conditioned media from rainbow trout lipopolysaccharide (LPS)-stimulated macrophages (LPS-MCM) on lipolysis in isolated rainbow trout adipocytes. Furthermore, we studied the effects of an LPS injection in vivo on lipid metabolism. In our study, human recombinant TNFα stimulated lipolysis in trout adipocytes in a time- and dose-dependent manner. Similarly, LPS-MCM stimulated lipolysis in trout adipocytes when compared with control conditioned medium. Experiments using specific inhibitors of the MAP kinase pathway showed that p44/42 and p38 are partially involved in the lipolytic effects of TNFα. On the other hand, adipocytes from LPS-injected rainbow trout showed higher basal lipolysis than adipocytes from control fish after 24 h, while this effect was not seen at 72 h. Furthermore, lipoprotein lipase (LPL) activity in adipose tissue of LPS-injected fish was lower than in the controls at 24 h. These data suggest that TNFα plays an important role in the control of lipid metabolism in rainbow trout by stimulating lipolysis in vitro and in vivo and by down-regulating LPL activity of adipose tissue in vivo.

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M. G. Metcalf, D. S. Skidmore, G. F. Lowry and J. A. Mackenzie

Urine for the analysis of pregnanediol was collected weekly for 3 months from 209 menstruant women aged 11–24 years who lived with their parents and from 59 women aged 17–23 years who had left the parental home. Menstrual cycles were classed as ovulatory if the 24-h pregnanediol output in the 12 days preceding menstruation was ≥ 5 μmol on a single occasion or if the total excreted on 2 days, 1 week apart, was ≥ 7 μmol.

In the first group, ovulatory incidence increased with menarchal age. Unfailing ovulation occurred in 22·9, 25·0,44·8,42·9, 63·2, 71·8 and 82·6% of those who were < 1, 1−<2, 2−<3, 3−<4, 4−< 5, 5–8 and 9–12 years from menarche. Comparable figures for the women who lived in flats and hostels were 40·0% (menarchal age, 5–8 years) and 78·6% (9–12 years).

It is concluded that a regular pattern of ovulatory menstrual cycles is established in most young women within 5 years of the menarche, and that departure from the family home is often associated with a regression to a juvenile pattern of anovulatory menstrual cycles.

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E. C. Osborn, P. L. Sugden, J. C. Mackenzie, D. M. Aitken, I. D. Chapman, S. Howes, O. F. Mason, G. V. Rigby and J. Wilson


Angiotensin II and I significantly raised potassium and lowered sodium and chloride ion concentrations in arterial plasma, with peak changes occurring in the first 2 min of a 6-min infusion period. The octapeptide increased the arterial K+ level in a dose-dependent manner, but the response showed tachyphylaxis when multiple infusions of 6-min duration were administered after a recovery interval of only 5 min. Raising the arterial blood pressure by 20–33 mmHg with adrenaline and noradrenaline failed to account for the increase in arterial plasma K+ concentration produced by the two peptides. These findings, in particular the rise in K+ concentration, are discussed in relation to possible mechanisms by which angiotensin II affects arteriolar tone.

J. Endocr. (1985) 104, 143–148

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This study has shown that corpora lutea, stromal tissue and corpora albicantes from human ovaries contain prostaglandin E (PGE) and PGFα, and that the two former tissues can synthesize these prostaglandins during incubation. Enhanced synthesis, especially of PGE, occurred on adding arachidonic acid to the incubation medium, and the presence of prostaglandin synthetase activity was conclusively demonstrated.

In corpora lutea obtained during the early and mid-luteal phase, the mean concentrations of PGE and PGFα were 34·3 and 9·6 ng/g respectively (mean ratio PGE:PGFα = 3·7); similar values were found in three corpora lutea from women at 10–12 weeks of pregnancy. All these corpora lutea contained appreciable amounts of progesterone and oestradiol-17β. Prostaglandin levels were generally lower in corpora lutea obtained during the late luteal phase, although the PGE:PGFα ratio had increased to a mean value of 8·4. In corpora albicantes, the concentrations of both PGE and PGFα were significantly higher than the levels found in corpora lutea (P < 0·01), whilst the mean ratio of PGE:PGFα had fallen significantly to 1·8 (P < 0·01). Prostaglandin levels in stromal tissue varied considerably between individuals. The mean values were significantly lower than those of the corpora albicantes (P < 0·01) but not significantly different to corpora lutea at any stage.

These findings are discussed in relation to the possible role of prostaglandins in ovarian steroidogenesis and corpus luteum regression in man.

Open access

Ping Ye, Christopher J Kenyon, Scott M MacKenzie, Katherine Nichol, Jonathan R Seckl, Robert Fraser, John M C Connell and Eleanor Davies

Using a highly sensitive quantitative RT-PCR method for the measurement of CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) mRNAs, we previously demonstrated that CYP11B2 expression in the central nervous system (CNS) is subject to regulation by dietary sodium. We have now quantified the expression of these genes in the CNS of male Wistar Kyoto (WKY) rats in response to systemic ACTH infusion, dexamethasone infusion, and to adrenalectomy. CYP11B1 and CYP11B2 mRNA levels were measured in total RNA isolated from the adrenal gland and discrete brain regions using real-time quantitative RT-PCR. ACTH infusion (40 ng/day for 7 days, N=8) significantly increased CYP11B1 mRNA in the adrenal gland, hypothalamus, and cerebral cortex compared with animals infused with vehicle only. ACTH infusion decreased adrenal CYP11B2 expression but increased expression in all of the CNS regions except the cortex. Dexamethasone (10 μg/day for 7 days, N=8) reduced adrenal CYP11B1 mRNA compared with control animals but had no significant effect on either gene's expression in the CNS. Adrenalectomy (N=6 per group) significantly increased CYP11B1 expression in the hippocampus and hypothalamus and raised CYP11B2 expression in the cerebellum relative to sham-operated animals. This study confirms the transcription of CYP11B1 and CYP11B2 throughout the CNS and demonstrates that gene transcription is subject to differential regulation by ACTH and circulating corticosteroid levels.