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P. S. BROWN and M. WELLS

SUMMARY

The follicle-stimulating hormone (FSH) content of urinary gonadotrophic extracts was assayed by its effect on the ovarian weight of immature mice when given in conjunction with 40 i.u. human chorionic gonadotrophin. About three-quarters of all routine assays gave values of λ between 0·15 and 0·30. Precision was slightly increased when the material was given in three rather than in five injections. Correction of ovarian weight for body weight was either invalid or of no value in reducing variance. Removal of between-litter variance increased precision considerably. Mice of three randomly bred colonies were all satisfactory, and inbred C57BL mice were also suitable for the assay. C3H mice were less sensitive.

The efficiency of different methods of extracting FSH from urine was examined. The method of Johnsen (1958) using precipitation with tannic acid was considered the most satisfactory and gave extracts of high potency and low bulk.

Limited experiments in which purified human pituitary FSH was assayed with and without added luteinizing hormone, gave results compatible with the assumption that the method is specific for FSH.

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P. S. BROWN and M. WELLS

SUMMARY

The response to gonadotrophins in an assay based on the induction of ovulation in immature mice was reduced by treatment of the experimental animals with barbitone. The responses to follicle-stimulating hormone and luteinizing hormone (LH) were reduced to a similar degree. Lack of specificity of the assay for LH is probably not due simply to the endogenous secretion of this hormone.

Progesterone and oestradiol-17β had no definite effect on the assay but norethynodrel significantly reduced the slope of the dose-response line. Feeding the mice with methylthiouracil increased the sensitivity to a small but significant extent.

Assays depending on the induction of ovulation in immature, pregnant and mature dioestrous mice were compared. Mice of the first two types gave more sensitive and precise assays of human urinary gonadotrophin.

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WENDY B. BROWN and J. M. FORBES

The role of the pineal gland in mediating the stimulatory effect of long daylength on blood levels of prolactin was investigated in 24 growing castrated sheep. Eight were pinealectomized, eight were sham-pinealectomized and eight remained as unoperated control animals. After a preliminary period with 12 h light:12 h darkness (12L: 12D) pairs of similar sheep were allocated to photoperiods of 16L: 8D or 8L: 16D for 15 weeks. Each animal was individually fed at the same level as its partner exposed to the other daylength. Blood samples were taken weekly by jugular venepuncture. On two occasions, once in the preliminary period (12L: 12D) and again 41 days after the start of the subsequent photoperiods, samples were taken through indwelling jugular catheters at frequent intervals for 24 h. The plasma samples were assayed for prolactin by radioimmunoassay and concentrations were higher in samples taken by jugular puncture.

There was a consistent positive effect of daylength on plasma prolactin in sheep with pineal glands that did not occur in pinealectomized sheep. In contrast, pinealectomy did not block the marked rise in prolactin that occurred at dusk. It appears that the effect of the photoperiod on levels of plasma prolactin throughout the day and night is not mediated by the same mechanism as that which controls the surge of prolactin at dusk in the sheep.

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K. BROWN-GRANT and M. B. TER HAAR

SUMMARY

The possible occurrence of long-term changes in gonadotrophin control mechanisms following the administration of oestrogen to adult female rats has been studied. Administration of 2·5 mg oestradiol benzoate (OB) to normal female rats at 60 days of age did not result in failure of ovulation at 120 days of age but significant impairment of the LH and FSH responses to progesterone after ovariectomy and oestrogen priming was observed at 160–180 days of age. Treatment with the same dose of OB at 60 days of rats injected with 10 μg testosterone propionate on Day 4 of postnatal life resulted in an increased incidence of failure of ovulation at 120 though not at 150 days of age but did not further impair the already reduced gonadotrophin response to progesterone at 160–180 days of age. Removal of the ovaries at 60 days of age did not modify the effects of oestrogen given at 60 days of age in either group nor did ovariectomy at 60 days improve the response of neonatally androgen-treated rats to progesterone at 160–180 days of age. The increases in plasma prolactin and TSH levels in response to oestrogen priming after ovariectomy were not affected in any of the experimental groups.

The administration of a long-acting oestrogen preparation (oestradiol cyclopentyl propionate, 2·5 mg at 60 days of age) to normal female rats suppressed ovulation and depressed plasma LH and FSH concentrations for at least 90 days; anterior pituitary weights were greatly increased and plasma prolactin concentrations were very high.

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M. X. ZARROW and K. BROWN-GRANT

SUMMARY

The effect of age and dose of a single injection of pregnant mare serum gonadotrophin (PMS) on spontaneous ovulation in immature Wistar rats is described. Ovulation could be induced by human chorionic gonadotrophin (HCG) at least 6 days before it occurred when pregnant mare serum gonadotrophin alone was given. Chlorpromazine was shown to block pregnant mare serum gonadotrophin-induced ovulation at a dose level (0·25 mg. in a 60 g. rat) which has no effect on the ovulatory response to human chorionic gonadotrophin. Higher doses interfered with the action of injected human chorionic gonadotrophin. Ovulation could be induced in the chlorpromazine-blocked animals by the systemic injection of an extract of bovine median eminence, but the sensitivity was too low to use this response for an assay method.

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S M Rosenthal and E J Brown

Abstract

Muscle is an important target tissue for insulin-like growth factor (IGF) action. We have previously demonstrated that treatment of myoblasts with IGF-II decreased IGF-I receptor biosynthesis and steady-state mRNA levels. In addition, muscle cell differentiation was associated with a marked increase in the expression and secretion of IGF-II followed by similar down-regulation of the IGF-I receptor, suggesting an autocrine role for IGF-II in this process. To explore further the mechanisms by which IGF-II decreases IGF-I receptor expression in BC3H-1 muscle cells, dose–response studies of IGF-I and -II treatment on the amount of IGF-I receptor mRNA were carried out. In addition, to determine whether IGF-II decreases IGF-I receptor expression by stimulating receptor protein degradation, pulse/chase experiments with [35S]methionine/cysteine were carried out. Both IGF-I and -II induced significant down-regulation of IGF-I receptor mRNA. At low concentrations, IGF-I was more potent than IGF-II in inhibiting IGF-I receptor mRNA accumulation, suggesting that IGF-I receptor down-regulation induced by IGF-II is mediated principally through the IGF-I receptor in these cells. In addition, IGF-II decreased IGF-I receptor expression by stimulating receptor protein degradation as demonstrated by pulse/chase analysis of metabolically labelled receptors. Thus, IGF-II induces IGF-I receptor down-regulation in muscle cells through multiple mechanisms, including decreasing IGF-I receptor mRNA and stimulating IGF-I receptor protein degradation.

Journal of Endocrinology (1994) 141, 69–74

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M. WELLS, T. KHOSLA and P. S. BROWN

SUMMARY

An assay method depending on the induction of ovulation in immature mice has been applied to the assay of human urinary gonadotrophin, human chorionic gonadotrophin, pregnant mare serum gonadotrophin, and sheep and rat pituitary gonadotrophins. Valid parallel line assays were obtained in all cases, and the sensitivity and precision of the assay were such as to make it suitable for application to clinical studies.

Experiments with mixtures of gonadotrophins, and the use of a barbiturate to suppress gonadotrophin secretion, indicate that the assay was not specific for LH. It is suggested that the lack of specificity may be due in part to the secretion of a variable amount of gonadotrophin by the pituitaries of the test animals.

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C. M. TAPPER and K. BROWN-GRANT

SUMMARY

The secretion rate (SR) of oestradiol in rats at different stages of the oestrous cycle was determined by measuring the concentration of this hormone in ovarian vein plasma by a competitive protein binding method utilizing rabbit uterine cytosol. The plasma metabolic clearance rate (MCRP) for oestradiol was determined in groups of rats of the same strain and housed under the same conditions by giving a single intravenous injection of tritiated oestradiol-17β and measuring the rate of disappearance of labelled hormone from the plasma. From the relationship SR = MCRP × plasma concentration, predicted values for the plasma oestradiol concentration were obtained and shown to be close to those obtained by direct analysis of peripheral plasma.

The MCRP for oestradiol was not greatly influenced by the stage of the oestrous cycle, the dose of oestradiol-17β injected, ovariectomy 18 h previously or by a sham-operation immediately before the injection of labelled hormone. The anaesthetic used did affect the MCRP; the value for adult female rats injected under ether anaesthesia was about 970 ml/h but under Avertin anaesthesia clearance rates of about 1500 ml/h were obtained. Ligation of the bile duct acutely reduced the MCRP but functional nephrectomy had no immediate effect. Sub-total hepatectomy 18 h previously reduced the MCRP considerably. A small decrease in MCRP was observed when the labelled hormone was administered in third trimester human pregnancy plasma and the MCRP was lower in rats on Day 14 of pregnancy than in rats examined during the oestrous cycle.

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K. BROWN-GRANT and M. R. SHERWOOD

SUMMARY

When testosterone propionate was administered to pregnant guinea-pigs over a short period (days 33–37) of gestation a high proportion of the female offspring exhibited a characteristic syndrome. The time of the first vaginal opening was delayed and its duration reduced. Subsequent periods of opening were fairly regular in occurrence but were shorter in duration than in normal animals; the 'cycle' length was usually slightly longer. Continuous vaginal opening was not observed but during the periods of opening, vaginal smears containing many cornified cells and no leucocytes were obtained. During the periods of vaginal opening no lordosis response to manual stimulation could be elicited nor did the animals mate when run with males. The increase in body weight was normal up to about 150 days of age and slightly, but not significantly, less than that of controls between 150 and 200 days of postnatal life. As adults some masculinization of the external genitalia was observed. At autopsy the weights of the uteri, ovaries, adrenal and anterior pituitary glands were much greater than those of control animals at any stage of the cycle. Histological examination showed that the ovaries contained many antral follicles but no luteal tissue. Enlargement of the glands and metaplastic changes in the epithelium were observed in the uteri. The pituitaries showed an excess of cells containing large, densely packed eosinophilic granules.

This early androgen syndrome is compared with that produced by hypothalamic lesions in the guinea-pig and with the changes produced in other species by the administration of androgenic steroids during prenatal or early postnatal life.

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Sarika Paul and Timothy M Brown

Endocrine systems function as key mediators of adaptive responses to the external environment. As a reliable predictor of many salient variations in the external world, the light environment thus constitutes an influential source of control over neuroendocrine function. Accordingly, the vast majority of endocrine systems display 24-h variations in activity that are aligned to daily changes in external illumination. While the neural mechanisms responsible for driving these rhythms are still incompletely understood, circadian and light-dependent signals relayed via the suprachiasmatic nucleus of the hypothalamus (SCN) play a key role. Retinal projections to the SCN provide information from rods, cones and melanopsin, which, together, encode variations in the amount and spectral content of ambient light over the solar day. This sensory input, in turn, drives acute modulations in SCN cellular activity and aligns daily rhythms in the electrophysiological output of individual clock neurons. Neural outputs from the SCN can therefore convey both rapid and longer-term information about the light environment to other hypothalamic nuclei responsible for neuroendocrine control. In this review we summarise current understanding of the specific neural pathways by which the light environment influences key neuroendocrine axes, with a particular focus on the retinal and SCN-dependent circuits involved and their known sensory properties.