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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
Search for other papers by J. P. O'SULLIVAN in
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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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Search for other papers by J Sullivan in
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Search for other papers by M Watson in
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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
Search for other papers by SUSAN M. BARLOW in
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Search for other papers by P. J. MORRISON in
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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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Search for other papers by CATHERINE WILSON in
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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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Search for other papers by J. M. ROBSON in
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Search for other papers by CATHERINE WILSON in
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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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The fact that growth hormone (GH) plays an important role in health after the cessation of growth requiring replacement therapy in adult life has only been recognised in the last three decades. This has only been made possible by recombinant technology providing GH supplies required to undertake investigations in the physiology of GH action and the benefits of replacement therapy in patients identified by rigorously validated diagnostic tests for GH deficiency (GHD). Human studies have revealed important regulatory roles in substrate metabolism, sodium homeostasis, body composition, and physical function. GH-induced anabolism is achieved by stimulating amino acid incorporation into protein while reducing oxidative loss simultaneously enhancing lipid utilisation by stimulating fatty acid oxidation and reducing lipid storage. Sodium and fluid retention are enhanced by activating the renin–angiotensin system and distal renal tubular reabsorption. GH stimulates the aerobic and anaerobic energy systems that underpin muscle and cardiovascular function. These pleiotropic actions explain the clinical picture of increased adiposity, reduced lean mass, and impaired physical and psychological function in the GHD adult, all of which are reversed when GH is replaced. Women require a greater replacement dose of GH than men. This is because androgens enhance while oestrogens attenuate GH action. The oestrogen effect is route-dependent, occurring with oral delivery blunting the liver-mediated actions of GH by directly inhibiting GH receptor signalling, global experience spanning over 30 years has attested to the safety, efficacy, and benefits of replacement therapy for adults with GHD.
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Search for other papers by Katie M Sullivan in
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Glucocorticoid overexposure during pregnancy programmes offspring physiology and predisposes to later disease. However, any impact of ethologically relevant maternal stress is less clear, yet of physiological importance. Here, we investigated in rats the short- and long-term effects in adult offspring of repeated social stress (exposure to an aggressive lactating female) during late pregnancy on glucose regulation following stress, glucose–insulin homoeostasis and peripheral expression of genes important in regulating glucose and lipid metabolism and glucocorticoid action. Prenatal stress (PNS) was associated with reduced birth weight in female, but not male, offspring. The increase in blood glucose with restraint was exaggerated in adult PNS males compared with controls, but not in females. Oral glucose tolerance testing showed no effects on plasma glucose or insulin concentrations in either sex at 3 months; however, at 6 months, PNS females were hyperinsulinaemic following an oral glucose load. In PNS males, plasma triglyceride concentrations were increased, with reduced hepatic mRNA expression of 5α-reductase and peroxisome proliferator-activated receptor α (Ppar α (Ppara)) and a strong trend towards reduced peroxisome proliferator-activated receptor gamma coactivator 1α (Pgc1 α (Ppargc1a)) and Ppar γ (Pparg) expression, whereas only Pgc1 α mRNA was affected in PNS females. Conversely, in subcutaneous fat, PNS reduced mRNA expression of 11β-hydroxysteroid dehydrogenase type 1 (11 β hsd1), phosphoenolpyruvate carboxykinase (Pepck (Pck1)), adipose triglyceride lipase (Atgl) and diglyceride acyltransferase 2 (Dgat2) in females, but only Pepck mRNA expression was reduced in PNS males. Thus, prenatal social stress differentially programmes glucose homoeostasis and peripheral metabolism in male and female offspring. These long-term alterations in physiology may increase susceptibility to metabolic disease.
