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Y. FOLMAN and G. S. POPE

SUMMARY

Interaction in the immature mouse of potent oestrogens with the weak utero-vaginotrophic (UV) compounds, coumestrol, genistein, dimethyl-stilboestrol, norethisterone acetate and megestrol acetate though sometimes additive at very low doses appeared to be essentially antagonistic at higher doses.

In particular, the weak oestrogens coumestrol and genistein, found in certain plants, markedly inhibited the UV action of potent oestrogens, e.g. oestradiol-17β, oestrone and diethylstilboestrol and this effect may account in part for the anti-oestrogenic activity of extracts of these plants.

Some differences in the ability of different oestrogens to promote uterine growth relative to vaginal growth were observed.

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Y. FOLMAN and G. S. POPE

SUMMARY

Loss of uptake during 24 hr. after administration of [3H]oestradiol showed approximately linear relationships between log uptake and time for uterus and vagina but not for skeletal muscle; these relationships were similar for mice pretreated with oestradiol. Uptake by uterus and vagina was less by about 50% when [3H]oestradiol was given to mice whose uteri and vaginae had reached maximum weight after pretreatment with oestradiol but cessation of growth of these organs was apparently not due to failure of their ability to take up oestradiol.

The relationship of uptake levels maintained in the uterus and vagina during 3 days and their consequent growth rate was studied.

When a second dose of [3H]oestradiol was given at various times after the first, new uptake, measured 1 hr. later, by uterus and vagina (but not skeletal muscle) was greatest when uptake remaining from the first dose was also greatest.

When a single dose of [3H]oestradiol (0·0039–2·5 μg.) was given to previously untreated mice or to mice with considerable oestradiol-induced uterine and vaginal growth, the only indications of any reduction of normal uptake ability were for the uterus when uptake was measured 1 hr. after doses greater than 0·11 μg.

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Y. FOLMAN and G. S. POPE

SUMMARY

Both norethisterone acetate and coumestrol enhanced uptake of [3H]oestradiol by the uterus and vagina measured 1 hr. after injection of the two compounds; the effect was, however, transient. Otherwise all the weak utero-vaginotrophic compounds markedly inhibited uptake of [3H]oestradiol by the uterus and vagina. This inhibition and the accompanying growth responses give further support to the conclusion that the interaction in uterine and vaginal tissue between oestradiol and the weaker utero-vaginotrophic compounds studied involves competition for retention at receptor sites followed by expression of the activity characteristic of the compounds retained.

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H. E. H. JONES and G. S. POPE

SUMMARY

1. Assay of the potency of the recently isolated plant oestrogen, miroestrol, shows that when given subcutaneously in multiple doses it is as potent as oestradiol-17β, and orally more than three times as potent as stilboestrol in producing an increase in uterine weight in the immature female mouse.

2. In the immature female mouse given a single injection of oestrogens, the route of administration influences the magnitude, the latent period, and the duration of the responses in the reproductive tract. In general, the oestrogens act most efficiently on the uterus and vagina when they are given intraperitoneally instead of subcutaneously. It is suggested that this is because there is less chance of absorption rates and metabolism in the animal influencing the oestrogen introduced intraperitoneally.

3. The activity of miroestrol by single injection is described and compared with that of oestriol, oestradiol-17β and stilboestrol. It is at least as effective as oestradiol-17β and stilboestrol in promoting uterine and vaginal growth, and in increasing the amount of fluid which can be expressed from the uterine lumen by gentle pressing.

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H. E. H. JONES and G. S. POPE

SUMMARY

1. A method is described for the isolation of miroestrol from Pueraria mirifica in about 50% overall yield.

2. Details of the oestrogenic potency of two derivatives of miroestrol are given.

3. Evidence is presented for the existence of a second, more water-soluble oestrogen in P. mirifica, and preliminary results are given of assays for oestrogen content of various parts of the P. mirifica plant and of other species of Pueraria.

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A. J. TAIT, G. S. POPE and ELIZABETH JOHNSON

Plasma concentrations of progesterone in non-pregnant female grey squirrels were never greater than 3·2 nmol/l and no significant differences were found between levels in anoestrous, pro-oestrous and oestrous animals. During pregnancy, plasma concentrations of progesterone increased significantly and reached a maximum level of 318 nmol/l at around day 35 of the 44 day period of gestation. After parturition, plasma concentrations of progesterone fell sharply. The corpora lutea of pregnancy began to regress in size at about day 30 of gestation, before the maximum levels of progesterone in the plasma were reached, which suggests that there is an extra-ovarian source of progesterone.

Chromatography of pregnancy plasma extracts showed that no significant amount of 5α-or 5β-pregnane-3,20-dione was present and that progesterone accounted for 90% of the assay-positive material in pregnancy plasma from grey squirrels.

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H. E. H. JONES, H. B. WAYNFORTH and G. S. POPE

SUMMARY

1. The effectiveness of miroestrol in causing cornification of the vagina of the ovariectomized rat, inhibiting pituitary activity of the adult male rat and preventing pregnancy in the mated female rat has been compared with that of hexoestrol and stilboestrol when each oestrogen is administered either subcutaneously or orally.

2. Inhibition of pituitary function and prevention of pregnancy by these substances are directly related to their activity in producing cornification of the vaginal epithelium. Only large doses of oestrogen produce the first two responses fully.

3. When administered subcutaneously miroestrol has about 0·3 of the potency of stilboestrol and 0·25 of that of hexoestrol in each response studied. By oral administration it is 0·8 as potent as stilboestrol and more potent than hexoestrol. Since the potency of miroestrol compared with a given oestrogen administered in the same way is of the same order in each response, it is concluded that these substances are only capable of inhibiting the function of the pituitary and of preventing pregnancy because of their oestrogenic activity.

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G. S. POPE, H. E. H. JONES and H. B. WAYNFORTH

SUMMARY

Extracts of jugular-vein blood of pregnant cows and of cows in oestrus were treated with methanolic HCl and phenolic fractions prepared. Assay by the mouse uterine-weight method failed to detect oestrogen in fractions from cows in oestrus or 2–3 months pregnant but indicated the presence of oestrogen, equivalent to about 1 μg. of oestrone/l. in blood from cows 5–6 months pregnant and about 7 μg./l. in blood from cows 7–9 months pregnant.

The activity of the phenolic fraction from blood of late pregnancy was shown to be due mainly to oestrone, most of which had been present in the blood as a water-soluble derivative.

Similar fractions from blood of cows in oestrus, assayed by the tetrazolium method of Martin, showed a total of 1–10 ng./l. (expressed as oestrone) activity being in the non-ketone and ketone fractions.

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D Pugazhendhi, K A Watson, S Mills, N Botting, G S Pope and P D Darbre

The phytoestrogens genistein, daidzein and the daidzein metabolite equol have been shown previously to possess oestrogen agonist activity. However, following consumption of soya diets, they are found in the body not only as aglycones but also as metabolites conjugated at their 4′- and 7-hydroxyl groups with sulphate. This paper describes the effects of monosulphation on the oestrogen agonist properties of these three phytoestrogens in MCF-7 human breast cancer cells in terms of their relative ability to compete with [3H]oestradiol for binding to oestrogen receptor (ER), to induce a stably transfected oestrogen-responsive reporter gene (ERE-CAT) and to stimulate cell growth. In no case did sulphation abolish activity. The 4′-sulphation of genistein reduced oestrogen agonist activity to a small extent in whole-cell assays but increased the relative binding affinity to ER. The 7-sulphation of genistein, and also of equol, reduced oestrogen agonist activity substantially in all assays. By contrast, the position of monosulphation of daidzein acted in an opposing manner on oestrogen agonist activity. Sulphation at the 4′-position of daidzein resulted in a modest reduction in oestrogen agonist activity but sulphation of daidzein at the 7-position resulted in an increase in oestrogen agonist activity. Molecular modelling and docking studies suggested that the inverse effects of sulphation could be explained by the binding of daidzein into the ligand-binding domain of the ER in the opposite orientation compared with genistein and equol. This is the first report of sulphation enhancing activity of an isoflavone and inverse effects of sulphation between individual phytoestrogens.

Open access

M J F Newson, G R Pope, E M Roberts, S J Lolait and A-M O'Carroll

The neuropeptide apelin is expressed in hypothalamic paraventricular and supraoptic nuclei and mediates its effects via activation of the apelin receptor (APJ). Evidence suggests a role for apelin and APJ in mediating the neuroendocrine response to stress. To understand the physiological role of APJ in regulation of the hypothalamic–pituitary–adrenal (HPA) axis, we measured ACTH and corticosterone (CORT) plasma levels in male and female mice lacking APJ (APJ knockout, APJ KO) and in wild-type controls, in response to a variety of acute stressors. Exposure to mild restraint, systemic injection of lipopolysaccharide (LPS), insulin-induced hypoglycaemia and forced swim (FS) stressors, elevated plasma ACTH and CORT levels in wild-type mice. Acute mild restraint significantly increased plasma ACTH and CORT to a similar level in APJ KO mice as in wild-type mice. However, an intact APJ was required for a conventional ACTH, but not CORT, response to LPS administration in male mice and to insulin-induced hypoglycaemia in male and female mice. In contrast, APJ KO mice displayed an impaired CORT response to acute FS stress, regardless of gender. These data indicate that APJ has a role in regulation of the HPA axis response to some acute stressors and has a gender-specific function in peripheral immune activation of the HPA axis.