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ABSTRACT
The non-steroidal antioestrogen tamoxifen (trans-1-(4-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene), widely used in the treatment of breast cancer, and its oestrogenic cis-isomer rapidly inhibited contractile responses of isolated rat myometrium to supramaximal concentrations of oxytocin (1·28 × 10−6 mol/l). Both compounds were effective at concentrations comparable with the plasma concentrations of tamoxifen reached in therapy (i.e. 5 × 10−7to 5 × 10−6 mol/l). Inhibition was too rapid in onset ( < 3 min) to involve changes in RNA transcription and protein synthesis, and was not prevented or reversed by the addition of oestradiol to the bath. We conclude that the inhibition did not involve the classical oestrogen receptor pathway. Oestradiol-17β at concentrations above 10−6 mol/l also inhibited the myometrium and potentiated the effects of the antioestrogens. Our experiments suggest that the antioestrogens and oestradiol act via a similar route with tamoxifen having an equilibrium affinity approximately tenfold greater than that of oestradiol.
J. Endocr. (1984) 103, 383–388
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Abstract
The effects of intravenous somatostatin-28 (S28) infusion on glucose-stimulated and glucagon-like peptide-1(7–36)amide (GLP-1)-augmented insulin secretion were studied in sheep. S28 was infused via a jugular catheter for 15 min at a rate of 1·1 pmol/kg/min either alone or together with GLP-1 and/or glucose. S28 infusion did not significantly lower circulating basal insulin concentrations in fed sheep. Glucose-stimulated insulin secretion was significantly inhibited by S28 infusion, serum concentrations decreasing from about 200 to 150 pmol/l. GLP-1 significantly augmented glucose-stimulated insulin secretion, serum concentrations increasing from about 230 to 280 pmol/l. S28 completely counteracted this effect of GLP-1. S28 infusion also significantly decreased the circulating concentrations of glucose-dependent insulinotrophic polypeptide (GIP) and GLP-1 in fed sheep (from about 110 to 45 pmol/l for GIP and from about 25 to 15 pmol/l for GLP-1). The physiological implications of these observations are discussed with particular reference to the ruminant. It is concluded that S28 may have an important endocrine role in the control of insulin secretion and regulation of nutrient partitioning.
Journal of Endocrinology (1996) 151, 107–112
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ABSTRACT
In ovariectomized ewes, an injection of oestrogen initially inhibits the tonic secretion of LH, and then induces a large release of LH similar to the preovulatory surge in intact ewes. The pattern of hypothalamic secretion of gonadotrophin-releasing hormone (GnRH) into the pituitary portal blood during this biphasic response to oestrogen was investigated in conscious, unrestrained, ovariectomized adult Ile-de-France ewes during the breeding season. The ewes were ovariectomized and implanted with cannulae for portal blood collection on the same day. Seven days later, portal and peripheral blood samples were collected simultaneously every 5 min for 25 h. The ewes were injected with oestradiol-17β (25 μg i.v. and 25 μg i.m.) 6·25 h after the start of sampling. GnRH and LH were measured by radioimmunoassay in portal and jugular plasma samples respectively.
A clear pulsatile pattern of LH secretion was observed before the oestradiol injection in all ewes, followed by the typical biphasic decrease (negative feedback) and increase (positive feedback) in mean concentrations. The sampling period was divided, for analysis, into pretreatment, negative feedback and positive feedback phases. Before injection with oestradiol, the GnRH pulses were clearly defined in portal blood and always synchronized with LH pulses in the peripheral circulation. The frequency was 5·9 ± 0·6 pulses/6 h (mean ± s.e.m.), and the amplitude was 31·6±7·6 pmol/l. During negative feedback, both the frequency (4·2 ± 0·5 pulses/6 h, P<0·01) and amplitude (15·2 ± 4·6 pmol/l, P<0·05) of the GnRH pulses decreased. During positive feedback, there was a large surge in the concentration of GnRH, due primarily to an increase in pulse frequency (11·0±1·3 pulses/6 h, P<0·01). A change in pulse amplitude was not detected, but there was a large increase in the basal level of GnRH (P<0·05). As a consequence of the changes in frequency and amplitude of the pulses, the mean levels of GnRH before injection with oestradiol (5·3 ± 1·0 pmol/l) differed (P<0·05) from those during negative (3·8±0·5 pmol/l) and positive (18·9±4·7 pmol/l) feedback phases.
These results show that the biphasic pattern of LH secretion induced by oestrogen injection in short-term ovariectomized ewes is caused by parallel changes in the secretion of GnRH as well as changes in pituitary responsiveness to GnRH. An abrupt increase in the frequency of GnRH pulses appears to be a key component of the positive feedback mechanism which elicits the oestradiol-induced surges of both GnRH and LH.
Journal of Endocrinology (1989) 123, 375–382
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Department of Physiology, Royal Veterinary College, Royal College Street, London, NW1 OTU, and *Imperial Cancer Research Fund, Lincolns Inn Fields, London, WC2A 3PX
(Received 8 June 1976)
Although the endometrial glands form a prominent part of the uterus of rodents, surprisingly little is known of the factors controlling their secretion, or indeed of the function of the secretion. During pregnancy the glands proliferate on the third day after mating in response to the high levels of oestrogen secreted during pro-oestrus (Finn & Martin, 1967, 1973). Secretion, however, does not become apparent in the lumina of the glands until day 6 of pregnancy. The extent of secretion is difficult to quantitate because it is not possible to collect it. However histological sections, especially after staining with the periodic acid-Schiff's (PAS) technique, reveal clearly the presence of a mucopolysaccharide substance in the lumina of the glands so that an approximate subjective assessment
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SUMMARY
Progesterone treatment significantly altered the response of the mouse uterus to oestradiol-17β. Oestradiol given alone produced many mitoses in the luminal and glandular epithelia but not in the connective tissue stroma. After treatment with progesterone this pattern was reversed and oestradiol produced many mitoses in the stroma but few in the epithelia. Production of stromal cell division was influenced by the dose of progesterone and by the period of treatment; a single day of treatment greatly reduced the numbers of epithelial mitoses produced by oestradiol but did not greatly increase stromal mitosis. At least 3 days' treatment was necessary for a maximal stromal response.
Doses of oestradiol sufficient to inhibit implantation and deciduomata production did not reverse the stromal response but did overcome, in part, the progestational suppression of epithelial mitosis, producing large numbers of mitoses in the luminal but not in the glandular epithelium.
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Destruction of the ventro-medial region of the hypothalamus results in hyperinsulinism (Hales & Kennedy, 1964; Frohman, Bernadis, Schnatz & Burek, 1969) and enlargement of the islets of Langerhans (Coleman & Hummel, 1970; Han, Yu & Chow, 1970), demonstrable a few hours after making the lesion (Martin & Bouman, 1971). These changes are progressive and independent of the ensuing hyperphagia (Han et al. 1970; Martin & Bouman, 1971). Whether this direct hypothalamic effect was mediated by the autonomic nervous system or by a humoral factor was not determined.
We investigated the latter possibility by exposing isolated islets of Langerhans, dissected from mouse pancreas (Hellman, 1970), to the effect of pieces of hypothalamus from either the medial or lateral region. The islets were located in a 10 μl chamber and perfused with Krebs-Ringer bicarbonate buffer supplemented with either 5·6 or 16·7 mm-glucose (Idahl, 1970). An additional chamber containing the hypothalamic tissue - or
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SUMMARY
Estimates were made of the number and distribution of cells undergoing division in the mouse uterus during the first 6 days of pregnancy. There was a spectacular change in the distribution of mitoses between days 3 and 4. On day 3 large numbers of mitoses were present in the luminal and glandular epithelium, with few in the stroma, whereas on days 4 and 5 very large numbers were present in the stroma with few in the epithelia.
On day 6 and late on day 5, in the vicinity of a blastocyst, the area containing decidual cells was free of mitoses. Many mitoses were found in the stroma immediately outside this area and there was evidence that the rate of division here was greater than in segments of the uterus unstimulated by a blastocyst.
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Oestradiol-17β stimulates mitosis in the luminal epithelium but not in the connective tissue stroma of the uterus of the mouse. Treatment with progesterone reverses this pattern so that oestradiol stimulates mitosis in the stroma but not in the epithelium. A single injection of progesterone suppresses the epithelial response to oestradiol, but does not induce a stromal response. This occurs only after three daily injections of progesterone (Martin & Finn, 1968). The following experiment was carried out to determine if all three progesterone injections were necessary, or if a stromal response to oestradiol might develop 3 days after a single injection.
Albino mice were ovariectomized 2 weeks before the start of the experiment. They were not primed with oestradiol (Martin & Finn, 1968) since there is evidence that uterine sensitivity to the hormones changes significantly in the days after priming (unpublished results). The hormones were given s.c. in 0·05 ml. arachis
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SUMMARY
The distribution of cell division in the tissues of the mouse uterus changes in a characteristic manner during the first few days of pregnancy due to changes in the secretion of ovarian hormones. Pregnant mice were ovariectomized at various times and attempts made to reproduce the pattern of cell division with exogenous hormones. The schedule of hormone injections producing a pattern of uterine mitoses which most closely approached that of pregnancy suggested that secretion of both oestrogen and progesterone started about 48 hours after mating and continued, possibly increasing, until after implantation had started. This conflicts with the oestrogen surge hypothesis. Further experiments were carried out to determine the optimum hormone treatment schedules for sensitivity to induction of the oil decidual cell reaction. Multiple small doses of oestradiol allowed the production of greater deciduomas than a single dose, thus again suggesting that the oestrogen surge hypothesis may not be correct.
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SUMMARY
Priming of ovariectomized mice with 0·1 μg. oestradiol-17β for 3 days modified the subsequent cellular response of the uterus to oestrogen and progesterone. A single dose of oestradiol-17β (0·02 μg.), or progesterone (1 mg.), or of both hormones given simultaneously, stimulated mitosis in the epithelial cells of the endometrium (although not in the stromal cells). However, the same hormones administered to primed mice stimulated considerable stromal cell division and reduced epithelial mitosis. The maximal effect was found when both hormones were given on the 4th day after the end of priming. It is suggested that the priming of the uterus by oestrogen secreted by the ovary before mating is concerned in the abrupt change from epithelial to stromal cell division that occurs between days 3 and 4 of pregnancy, and is of importance in the sensitization of the uterus for implantation.
