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Plasma progesterone concentrations in the pregnant guinea-pig are greater than in many species (Heap & Deanesly, 1966; Heap, Perry & Rowlands, 1967) and far higher than those found in the normal cycle (Table 1). The present experiments were intended to compare the effects of subcutaneous progesterone tablets on plasma progesterone levels after ovariectomy with those in normal, non-pregnant and pregnant females.

The ovaries are essential for pregnancy in most guinea-pigs between about Days 14 and 28 (Deanesly, 1963) but from about Day 28 pregnancy will continue normally without exogenous hormones owing to the production of placental progesterone. In this study it was decided to use females in the 1st month of pregnancy when the actual production of progesterone by the placenta is far less than that of the ovary and is well below that reached in later stages (Heap

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V. Rider and R. B. Heap

Summary. Early embryo development and implantation were arrested in ferrets passively immunized with a mouse monoclonal anti-progesterone antibody injected intraperitoneally at 72 and 96 h post coitum (p.c.) or at 72 h p.c. only. In control ferrets injected with mouse serum or 0·9% NaCl, implantation sites were found in all mated females; autopsies were carried out at Day 14 p.c. A total of 34 unimplanted embryos were recovered from the reproductive tract of antibody-treated ferrets and none of these had progressed to the blastocyst stage.

When ferrets were treated with antibody at 72 h p.c. and autopsies were carried out at Day 6p.c., only 1 of 29 embryos recovered had progressed beyond the 4-cell stage in 4 females. In 4 control animals most embryos recovered at Day 6 were at the morula (32%) or blastocyst (28%) stage. Embryos from ferrets treated with antibody were therefore developmentally arrested when recovered 72 h after antibody administration.

Plasma progesterone concentrations were ∼ 6-fold higher in antibody-treated ferrets with unimplanted embryos (711 ± 132 nmol/l; 223 ng/ml) compared with control pregnant females (102 ± 4 nmol/l; 32 ng/ml) at Day 14 p.c. The results are consistent with the hypothesis that the normal course of pregnancy is arrested as a result of antibody binding of progesterone in the circulation, presumably causing a decrease in the amount of progesterone available to target cell receptors, and that heterologous anti-progesterone antibody blocks normal cleavage and embryonic development at an early stage before cavitation.

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I. R. Fleet and R. B. Heap

Summary. Uterine blood flow and myometrial activity were measured simultaneously in anaesthetized sheep 15 days after a sterile (non-pregnant group) or fertile (pregnant) mating. During the peri-implantation period uterine blood flow was similar in both groups of animals, but spontaneous myometrial activity was greatly reduced in pregnant ewes. This 'block' of myometrial activity was associated with circulating levels of progesterone which were significantly higher (2·8 ± 0·8 ng/ml, mean ± s.e.m.) than those in non-pregnant animals (0·4 ± 0·3 ng/ml). Adenosine injected into the uterine artery produced uterine vasodilatation in both groups, but the log dose–response was significantly less in pregnant than in non-pregnant animals (P < 0·001). Myometrial activity was stimulated by adenosine, particularly in the pregnant group (P < 0·001). Vascular and myometrial effects were potentiated by a previous infusion of dipyridamole. Occlusion of the uterine artery produced reactive hyperaemia, and oestradiol infused close-arterially induced vasodilatation after a lag phase of about 30 min. Our results are consistent with a hypothesis that vascular and myometrial cells in the uterus may contain two types of adenosine receptor, one mediating excitatory and the other inhibitory responses, and that both responses are modified by the presence of a conceptus. The results also support the idea that oestrogens produce uterine vasodilatation by increasing the local concentration of vasoactive substances.

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F. A. Harrison and R. B. Heap

Summary. Secretion rates by the major sites of progesterone synthesis were measured during pregnancy in 3 ewes with single fetuses after autotransplantation of the left adrenal and the left ovary (containing the corpus luteum) to the neck. The total production of progesterone measured by tracer kinetics increased from 12·1 ±2·0 (s.e.m.) to 31·3 ± 2·4 μg/min between 66–103 and 133–145 days p.c. Ovarian and adrenal secretion rates measured directly at the same times decreased from 5·2 ± 0·9 to 2·1 ±0·9 μg/min (ovary), or remained unchanged, about 0·03 μg/min (adrenal). The difference between the total production of progesterone and ovarian and adrenal secretion showed that the contribution from other endocrine tissues (presumably the placenta) increased from 6·8 ± 1·5 to 29·2 ± 4·1 μg/min (P < 0·001) during this period.

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In the ferret, the life-span and growth of the CL is dependent on pituitary hormones. Hypophysectomy arrests the development of the CL (Hill & Parkes, 1932) and causes regression of well-developed CL in pseudopregnant ferrets. Section of the pituitary stalk, however, does not inhibit the function of the CL during the first half of pseudopregnancy (Donovan, 1963). Since ovariectomy results in abortion (McPhail, 1935; Galil, 1965), any placental progesterone secretion is apparently inadequate to sustain the normal pregnant state. There is little evidence that placental or uterine factors influence the life-span of the CL. When the products of conception are removed 22, 27 or 30 days post coitum, the CL are indistinguishable 8 to 15 days later from those of normal gestation and oestrus recurs normally, about 7

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M. H. Hamon and R. B. Heap

Summary. Steroid hormone concentrations have been measured in the peripheral plasma of 3 Barbary sheep over 3 breeding seasons. During pregnancy mean progesterone values rose initially and after a small decline between Days 30 and 50, increased again and remained between 17 and 28 nmol/l until the last 2 days of pregnancy. Oestradiol-17β reached a peak of about 300pmol/l during mid-pregnancy, increasing to over 400 pmol/l in the last 5 days of pregnancy. Oestrone sulphate began to increase in concentration from about Day 40 of pregnancy and reached a peak of about 19 nmol/l by Day 120. Following a slight decrease from Day 130, there was a further rise in values just before parturition. Values for these steroids in the Barbary sheep studied were between those expected for domestic sheep and goats.

Keywords: progesterone; oestrogen; pregnancy; Barbary sheep

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Ann C. McRae and R. B. Heap

Summary. Vascular permeability to plasma proteins in uterine implantation and nonimplantation sites (i.e. dye sites and non-dye sites) was assessed quantitatively by a method which accounts for steady-state volumes of distribution. Extracellular fluid volume and uterine blood flow were also determined. On both the evening of Day 5 and the morning of Day 6, vascular permeability to 125I-labelled human serum albumin, extracellular fluid volume and blood flow were significantly increased in implantation sites compared to non-implantation sites. Vascular permeability in implantation sites was increased significantly between Days 5 and 6, whereas that in non-implantation sites was unchanged. This increase in vascular permeability between Days 5 and 6 was not accompanied by further increases in extracellular fluid volume and blood flow. This result shows a dissociation between vascular permeability and extracellular fluid volume immediately after the onset of implantation and raises important questions as to whether the rat uterus undergoes a truly oedematous response at implantation as has been generally accepted.

Keywords: implantation; uterus; vascular permeability; blood flow; oedema

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E. O. Wango, R. B. Heap, and F. B. P. Wooding

Summary. Binucleate cells of sheep and goat fetal placentae comprise about one-fifth of the trophectodermal layer at the feto–maternal interface. When isolated and incubated in vitro they produce the steroids that are synthesized by the placenta in vivo (progesterone in sheep, 5β-pregnane-3α,20α diol in goats). This study demonstrates that progesterone synthesis in binucleate cell preparations in sheep was increased by prostaglandin (PG) E-2, nordihydroguaiaracetic acid (NDGA) and methylisobutylxanthine, but reduced by indomethacin, whereas in goats only NDGA produced any effect (an increase). None of the other compounds tested (luteinizing hormone, follicle stimulating hormone, prolactin, dibutyryl cAMP, A23187 or phorbolmyristic acetate) had any effect. Sheep binucleate cells also produced PGE-2 from arachidonic acid. These results suggest that, in sheep, products of both the cyclooxygenase (producing PGE-2) and lipoxygenase (inhibited by NDGA) pathways of arachidonic acid metabolism have regulatory roles in placental steroid synthesis, but only the lipoxygenase pathway is relevant in goats.

Keywords: progesterone; steroids; placental cells; sheep; goat

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G. Jenkin, R. B. Heap, and D. B. A. Symons

Summary. In sheep the basal concentration of LH in jugular vein plasma was significantly higher during the first 50 days of gestation than in late pregnancy or at parturition. The pituitary response to a single i.v. injection of 200 μg synthetic LH-RH was determined at different stages of gestation and compared with that of anoestrous and cyclic sheep. Pituitary response to LH-RH decreased progressively with advancing gestation: by 56 days after mating the response had declined to 35% and by parturition to 14% of the value in anoestrous sheep. The pituitary response to LH-RH increased after parturition and the pattern of recovery differed in non-lactating and lactating sheep. By 63 days post partum the response to LH-RH in non-lactating and lactating animals had returned to values similar to those in sheep during anoestrus and sheep during the luteal phase of the oestrous cycle.

A decrease in pituitary responsiveness during pregnancy was associated with a decrease in pituitary content of LH. The quantity of LH released in response to a standard injection of LH-RH was linearly related to pituitary LH content.

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D. R. Brigstock, R. B. Heap, and K. D. Brown

AFRC Institute of Animal Physiology and Genetics Research, Babraham, Cambridge CB2 4AT, U.K.

Keywords: growth factors; uterus; cell proliferation; blastocyst


It has often been speculated that uterine secretions (histotrophe) are involved in regulating the attachment, implantation, nutrition and growth of the conceptus (Corner, 1921; Amoroso, 1952; Roberts & Bazer, 1988; Biggers, 1988). However, the factors responsible and the mechanisms involved have not been clearly defined. Work over the past decade has firmly established the involvement of peptide and polypeptide growth factors in the control of animal cell proliferation (see Evered et al., 1985). These results raise the intriguing possibility that uterus-derived growth factors may play a role in regulating the growth of the conceptus. This could occur via a paracrine pathway involving the secretion into the uterine lumen of factors which, on binding to specific cellular receptors, would directly stimulate DNA synthesis and division in cells of