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5-Hydroxytryptamine (5-HT) will interfere with pregnancy in mice at all stages, resulting in death of the foetuses (Poulson, Botros & Robson, 1960). The mechanism by which the drug acts in the second part of gestation, when it usually kills the foetuses within 15–60 min. of administration to the mother, has been investigated and the following possibilities are considered:
(1) 5-HT exerts a direct toxic effect on the foetuses. Its concentration in the foetuses has been determined following an injection into the mother of a dose of 0·5–1·5 mg. 5-HT which is rapidly lethal to the foetuses, but is without any obvious acute toxic effect on the mother. The foetal content of 5-HT 1 hr. after injection into the mother was found to be 0·117 μg./g. (average of foetuses from 16 mice), and by this time all of the foetuses were dead. In contrast, direct injection of 1–5 μg. of 5-HT
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Abstract
In order to identify the molecular weight forms of bioactive and immunoactive inhibin in human plasma, plasma/serum was sequentially fractionated by immunoaffinity chromatography (using immobilised inhibin α subunit antiserum), reversed phase HPLC and preparative SDS-PAGE. The electroeluted gel fractions were assayed for inhibin in vitro bioactivity and immunoactivity, the latter by RIA. Initial experiments examined human follicular fluid as an inhibin-rich source. Bioactive and immunoactive fractions of 30, 35, 53, 65 and ∼120 kDa were identified in addition to bio-inactive, immunoactive fractions of 26 kDa and 32 kDa. These molecular weights correspond to those of known inhibin forms and are attributed to differing degrees of glycosylation of the inhibin α subunit and variable processing of the α and β inhibin subunits.
Fractionation of male plasma pools revealed the presence of higher molecular weight immunoactive forms (55–120 kDa) as well as 28–31 kDa forms although the molecular weight distribution of activity between pools varied. To assess if the molecular weight pattern was modified by storage and/or subsequent fractionation, protease inhibitors were added initially to plasma and fractionated as above. The molecular weight distribution of immunoactivity was largely unaffected by the treatment, indicating that minimal processing had occurred. Postmenopausal serum itself showed low to undetectable activity. The addition of recombinant human 31 kDa inhibin to postmenopausal serum resulted in a molecular weight profile of inhibin immunoactivity consistent with the presence of 31 kDa inhibin. Fractionation of a serum pool from women undergoing gonadotrophin stimulation, in which inhibin levels were elevated, showed a range of bioactive and immunoactive inhibin forms over the 30–120 kDa range. A good correspondence between activities was observed.
It is concluded that: 1. inhibin exists in plasma/serum as a range (28–120 kDa) of molecular weight forms. 2. In female serum, the majority of inhibin isoforms appear to be bioactive. 3. This fractionation procedure provides a basis for investigating the forms of inhibin in plasma and provides a means of assessing the specificity of new assay methods.
Journal of Endocrinology (1995) 144, 261–269
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SUMMARY
Plasma corticosterone levels were measured in the pregnant and non-pregnant mouse after acute and chronic stress. Acute surgical stress in the non-pregnant mouse increased plasma corticosterone from a mean resting level of 2·3 to 50·6 μg/100 ml 1 h after operation. By 24 h after operation, levels had fallen back to 7·6 μg/100 ml. In the pregnant mouse an acute surgical stress on day 14 of pregnancy increased plasma corticosterone levels to 525 μg/100 ml 1 h after surgery from a resting value of 80 μg/100 ml, with a return to resting levels by 24 h. During the chronic stress of 24 h restraint, plasma corticosterone levels in the non-pregnant mouse reached a peak (81·0 μg/100 ml) 1 h after the start of restraint and were still raised (mean 24·0 μg/100 ml) after 24 h. In the pregnant restrained mouse a peak value of 733 μg/100 ml was seen at 1 h, with levels maintained at around 500–600 μg/100 ml during the next 16 h of restraint. Increased levels of 268 μg/100 ml were still present at 24 h. After the chronic stress of 24 h food deprivation, plasma corticosterone levels in the non-pregnant and pregnant mice were raised after 7 h to levels slightly lower than those observed in the restrained groups, and at 24 h levels in the respective restrained and fooddeprived groups were similar, suggesting that food deprivation is a powerful chronic stressor in the mouse.
During chronic stress in the pregnant mouse where plasma corticosterone levels of around 600 μg/100 ml were maintained for some hours, protein binding studies indicated that 10 μg/100 ml was free, unbound corticosterone. The physiological and pathological consequences of such high levels of free corticosterone during stress in pregnancy are discussed.
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SUMMARY
Plasma corticosterone levels were measured throughout pregnancy and on the first day post partum in the mouse. During the first half of pregnancy plasma corticosterone levels rose from the non-pregnant value of 2·3 μg/100ml to 15·2 μg/100 ml on day 10. During the second half of pregnancy there was a sharp rise, levels reaching a peak of 138·3 μg/100ml on day 16. Following parturition there was a rapid fall to 18·3 μg/100 ml on the morning of the first day post partum. Adrenalectomy on day 15 resulted in an 80% fall in plasma corticosterone levels indicating that most of the steroid was of adrenal origin. The remaining portion of the corticosterone was found to be of foeto-placental origin, and in the chronically adrenalectomized animal this source was capable of maintaining high blood levels of corticosterone (67 μg/100 ml). The foeto-placental unit also provides the main secretory stimulus to the adrenal gland, but the mechanism by which it does this is not understood.
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Abstract
Previous work has shown that enzymatic digestion of human placental tissue can induce the production of the cytokine interleukin-1β. Most studies of the feto-maternal interface of human pregnancy have used decidual cells prepared in a similar way, but the effects of tissue dissociation on the production of growth factors, cytokines, prostaglandins or hormones have not been investigated. Our studies show human decidual explants produce substantially lower levels of a range of factors than do human decidual cells cultured under the same conditions, indicating that induction may be a general process during the dissociation of tissues in vitro as the production of interleukins-1β, -6 and -8, granulocyte-macrophage colony-stimulating factor, transforming growth factor-β2, tissue necrosis factor-α, prostaglandins E2 and F2α, and prolactin were all affected. The induction of cytokine production (expressed per mg tissue protein) ranged from 10- to 300-fold, indicating that isolated cells cultured in vitro may not reflect accurately the in vivo situation.
Journal of Endocrinology (1996) 151, 309–313
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SUMMARY
A number of derivatives of the mono-amine oxidase inhibitor (MAOI) compound, phenelzine, have been shown to have an anti-fertility effect, when administered both before and after implantation in mice. The action of the compounds in the pre-implantation period (days 1–6) is reversed by progesterone and by prolactin; both have to be given with 0·05 μg oestradiol/mouse during days 4 and 5 to induce implantation. When the oestrogen treatment is omitted implantation is delayed by 2–3 days. This seems to be due to a transient antagonism of the action of luteinizing hormone (LH), which is necessary for the secretion of oestrogen which in turn is necessary for implantation. In addition, the MAOI compounds appear to inhibit the release of pituitary hormones necessary for the maintenance of pregnancy. In the pre-implantation period the important pregnancy-maintaining hormone seems to be prolactin, and after implantation LH seems to become the main luteotrophin.
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Departments of Medicine and Histopathology, St George's Hospital Medical School, Cranmer Terrace, London, SW17 ORE
(Received 4 May 1978)
There are now many reports of the growth of various human malignant tumours such as colonic carcinoma and malignant melanoma in the 'nude' athymic mouse (Rygaard & Povlsen, 1969), but there are few instances of human benign tumours being transplanted successfully into these animals. Nevertheless, the possibility of using the 'nude' athymic mouse as a vehicle for maintaining pituitary adenomatous tissue in a viable state for a prolonged period under conditions which are more physiological than those of tissue culture has been examined.
Pituitary adenomas were obtained from seven patients undergoing craniotomy for the treatment of acromegaly and from three patients without acromegaly where the tumour was removed because of visual impairment. Part of the tissue was fixed in formol–saline for light microscopy, part was fixed in 4% glutaraldehyde in phosphate
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SUMMARY
Some derivatives of phenelzine have been shown to interrupt pregnancy in mice, when given after implantation, i.e. on days 7–10. Pregnancy can be maintained in mice treated with these compounds and in mice hypophysectomized on day 7 by administration of suspensions of whole mouse pituitaries, of human chorionic gonadotrophin or of progesterone given with a basic concentration of oestrogen. Prolactin was ineffective in maintaining pregnancy. The action of the phenelzine derivatives could also be reversed by 0·5–1 μg. luteinizing hormone and by 0·05 μg. oestradiol. The compounds antagonized the action of progesterone in maintaining pregnancy in ovariectomized mice and this indicates that they act on the uterus. There may be, in addition, a more central action, e.g. on the ovary or on the pituitary but this would be masked by the peripheral (i.e. uterine) effect.
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Many studies have implicated the insulin-like growth factors (IGFs) and insulin-like growth factor-binding protein-1 (IGFBP-1) in the control of the feto–maternal interface of human pregnancy, but many of the data are from cell lines derived from primary trophoblast or from extravillous trophoblast. We have obtained highly enriched villous cytotrophoblast (VCT) from first trimester and term human placentae, and investigated the effects of IGF-I, IGF-II and phosphoisoforms of IGFBP-1. First trimester villous trophoblast cells were regulated by all these factors. IGF-II increased cell numbers 3.5-fold after 96 h in culture, and IGF-I had less effect (1.5-fold increase) (both P<0.05). IGF-II also had a greater effect on the levels of matrix metalloproteinase (MMP)-2 and MMP-9. Phosphorylated and non-phosphorylated iso-forms of IGFBP-1 added alone increased cell numbers and MMP levels (P<0.05). IGFBP-1 did not modify the effects of IGF-II on cell numbers or on MMP production. Term VCT numbers and MMP production in vitro were unaffected by IGFs (P>0.05). Cell numbers were increased only by 100 nM IGFBP-1 isoforms (P<0.05), whereas MMP levels released from term cells were optimally increased by 1–10 nM IGFBP-1. Overall, our data show that IGFs regulate only first trimester, but not term, VCT. IGFBP-1 regulates VCT from both gestations, but the effects are concentration and end-point specific. In particular, first trimester cell numbers are more affected by low levels of IGFBP-1, whereas high levels of IGFBP-1 are needed to increase MMP and the converse applies to term VCT; low levels of IGFBP-1 have more effect on MMP levels.
