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K. B. Smith, S. F. Lunn and H. M. Fraser


Changes in plasma concentrations of immunoreactive inhibin in the reproductively cyclic, pregnant and ovariectomized female marmoset monkey (Callithrix jacchus) were measured with a heterologous radioimmunoassay. The pattern of inhibin secretion in five marmosets studied individually during four consecutive cycles was shown to resemble that of progesterone. In these animals, data were pooled according to stage of cycle on the basis of plasma progesterone concentrations. Mean values for inhibin were 5465 and 4972 U/l during the early and late follicular phase. Concentrations rose during the luteal phase to 8431, 12 246 and 12 557 U/l for the early, mid- and late luteal phase respectively. The hormonal profile of inhibin during the normal cycle is similar in both marmoset and stumptailed macaque; however, the marmoset has a 28-fold greater level of inhibin during the luteal phase.

In six marmosets in which pregnancy occurred, inhibin concentrations showed no decline at the end of the conceptual cycle and remained increased with respect to the follicular phase throughout the subsequent gestation. Inhibin levels were non-detectable (< 1000 U/l) in ovariectomized and acyclic marmosets.

These results suggest that the corpus luteum is the major source of inhibin in this New World monkey, in common with man and the Old World primates.

Journal of Endocrinology (1990) 126, 489–495

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D E Clark, S K Smith, A M Sharkey, H M Sowter and D S Charnock-Jones


Hepatocyte growth factor (HGF), also known as scatter factor, acts via the c-met receptor resulting in pronounced effects on certain epithelial cells. We hypothesised that HGF would be important in placental development where the trophoblast represents a specialised barrier of epithelial origin. In this paper we examine the expression and production of HGF and its receptor in the human placenta throughout pregnancy. In addition, RT-PCR was undertaken on human embryos to ascertain whether preimplantation embryonic or trophoblast cells were under the influence of this growth factor. In samples from the first trimester of pregnancy in situ hybridisation with a c-met antisense probe detected message expression in villous cytotrophoblast and in decidual glands but not in extravillous trophoblast. Some c-met expression was detected in cytotrophoblast from the second trimester placentae; this declined to negligible levels by term. Staining with an anti c-met antibody largely confirmed these findings but found relatively strong staining of cytotrophoblast at term. HGF was confined to the villous core throughout pregnancy when examined by both in situ hybridisation and immunohistochemistry. Trophoblast was consistently negative for HGF. Pre-implantation embryos examined by RT-PCR were negative for both c-met and HGF mRNA. These results indicate that the HGF may exert an important influence on cytotrophoblast throughout the process of placental formation and growth.

Journal of Endocrinology (1996) 151, 459–467

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A. E. Pekary, S. Bhasin, V. Smith, M. Sugawara, R. S. Swerdloff and J. M. Hershman


Thyrotrophin-releasing hormone (TRH) occurs in high concentrations in the rat ventral prostate and its concentration is regulated in a positive dose–response manner by testosterone in castrated rats. α-Amidation of the tetrapeptide precursor, TRH-Gly, is a rate-limiting step in TRH biosynthesis. To investigate further the hormonal regulation of TRH biosynthesis in prostatic tissue, Sprague–Dawley rats of approximately 250 g were injected s.c. with either physiological saline or 3 mg propylthiouracil (PTU) daily for 5 days. The reproductive tissues were boiled in acetic acid (1 mol/l), dried and extracted with methanol. The methanol extracts were measured for TRH immunoreactivity (TRH-IR) and TRH-Gly-IR by radioimmunoassay. Hypothyroidism induced by PTU significantly increased TRH-IR and TRH-Gly-IR levels in prostate and testis and reduced these levels in epididymis but did not affect the serum concentrations of testosterone compared with those of controls. Corresponding changes in TRH and TRH-Gly in the rat prostate were established by high-pressure liquid chromatography. To control for possible pharmacological effects of PTU on TRH biosynthesis, additional experiments were carried out on castrated rats receiving testosterone replacement and treatment with PTU plus methimazole. Treatment with thyroxine (T4) significantly reduced the increase in prostatic TRH levels due to hypothyroidism, despite the drug-induced blockade of the conversion of T4 to tri-iodothyronine. These effects parallel similar observations made in rat spinal cord and pancreas. This study demonstrates that in the male rat reproductive system the levels of TRH and its immediate biosynthetic precursor, TRH-Gly, are regulated by thyroid hormones.

J. Endocr. (1987) 114, 271–277

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K. A. Nandha, M. A. Benito-Orfila, D. M. Smith, M. A. Ghatei and S. R. Bloom


The N-terminal fragment (PACAP 27) of the novel neuropeptide, pituitary adenylate cyclase-activating polypeptide 38 (PACAP 38), has 68% homology with vasoactive intestinal polypeptide (VIP). The administration of bolus doses of PACAP 38 and its 27 amino acid N-terminal fragment (PACAP 27) caused a rapid but transient dose-dependent hypotensive effect in the anaesthetized rat. The amplitude and duration of the response obtained by PACAP 38 was comparable with VIP whereas PACAP 27 was three times less potent than VIP. Furthermore, radioreceptor binding studies demonstrated that 125I-labelled PACAP 27 and 125I-labelled VIP bound to membranes prepared from blood vessels. Both PACAP 27 and VIP were capable of displacing the other from these binding sites. We propose that the hypotensive effect is via the same receptor type.

Journal of Endocrinology (1991) 129, 69–73

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R N Kulkarni, D M Smith, M A Ghatei, P M Jones and S R Bloom


We have investigated the effects of antisense oligodeoxynucleotides (oligos) to islet amyloid polypeptide (IAPP) mRNA on the expression and secretion of IAPP and insulin, in the clonal β-cell line HIT-T15. Phosphorothioate-modified oligos were cytotoxic compared with phosphodiester (D)-oligos. Of the nine oligos tested using a lipofection reagent, 03, a 30-mer D-oligo complementary to a sequence downstream of the IAPP initiation codon, showed a significant dose-dependent suppression of IAPP mRNA, with a 42% decrease at 7·5 μm, compared with a scrambled (MS03) control oligo (n=3, P<0·01). A subsequent 89% suppression of IAPP release was observed in the 4-h period following antisense treatment (1·78 ± 0·13 (MS03) vs 0·19 ± 0·14 (03) pmol/106 cells per 240 min, n=7, P<0·01). A significant increase in insulin mRNA (100 ± 10% (MS03) vs 124 ± 8% (03), n=3, P<0·05) and insulin content (13·0 ± 0·9 (MS03) vs 17·4 ± 1·4 (03) pmol/106 cells, n=7, P=0·028) was observed following treatment with 03 at 7·5 μm. 08, a 20-mer D-oligo directed to a region of IAPP mRNA further downstream than 03, also showed a decrease in IAPP mRNA and peptide release and an increase in insulin content. No significant changes were observed in the expression and release of the unrelated β-cell peptide, neuropeptide Y. We thus show a suppression of synthesis and release of IAPP in HIT-T15 cells using antisense oligos. The associated increase in insulin mRNA and content in these cells after treatment with IAPP antisense oligos is in accord with an inhibitor action of IAPP on insulin availability.

Journal of Endocrinology (1996) 151, 341–348

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Section of Pharmacology, Academic Division of Medicine and *Field Laboratories, The University, Sheffield, S102TN

(Received 8 July 1975)

The McKenzie (1958) bioassay remains the principal tool for studying the long-acting thyroid stimulator (LATS) and LATS-protector (LATSP), although radioreceptor binding assays are being developed (Manley, Bourke & Hawker, 1974; Smith & Hall, 1974). A dog biscuit met the low-iodine requirements until 1974, when batches contained sufficient iodine to make them unsuitable for use in this bioassay. Bread contains negligible iodine, unless iodated dough conditioner is added (London & Vought, 1965). Thus an investigation was made of the suitability of bread for use in the McKenzie bioassay.

Female, white Swiss mice were bred as described by Loy & Broadhead (1968), the colony being fed on pasteurized breeding diet (Oxoid Ltd). Mice were weaned at 4 weeks, fed on diet 86 (Oxoid Ltd) until body weights were 15–20 g (i.e. usually for 1–2 weeks),

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A method of estimating thyroid function with carrier-free radio-iodine which provides an arbitrary numerical scale of thyroid activity is described. It is suitable for investigating borderline thyroid dysfunction.

The results on over 500 psychiatric patients are given in the form of histograms, and arbitrary limits of normality are defined on the basis of these results.

While there is usually a correlation between the tracer method and the basal metabolic rate, cases exist in which increased thyroid activity, determined by the radio-active method, is associated with normal or subnormal b.m.r. and vice versa. This is explained as a disturbance of the sensitivity of body tissues to thyroid hormone.

The significance of under-sensitivity to thyroid hormone and related problems is discussed, and the importance of considering peripheral sensitivity of the tissues of the body in evaluating an abnormal thyroid activity is emphasized.

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R N Kulkarni, D M Smith, M A Ghatei and S R Bloom


Insulin secretion is regulated by neural and neurohormonal factors. The report of nerves releasing pituitary adenylate cyclase-activating polypeptide (PACAP) – a 38 amino acid peptide – in the endocrine pancreas, suggests it may be important in modulating insulin release. We therefore carried out receptor-binding studies on membranes prepared from the glucose-responsive clonal β-cell line HIT-T15, and also examined the effects of PACAP38, PACAP27 – a C-terminal truncated form of the peptide – and vasoactive intestinal peptide (VIP) on insulin and islet amyloid polypeptide (IAPP) release. We showed by chemical cross-linking that PACAP and VIP stimulate secretion from the clonal cells by binding to a receptor with a molecular weight of 67 kDa (n=4). Binding was saturable when membranes were incubated with 125I-PACAP27 (K d 1·2±0·2 nm; Bmax 415·7±35·3 fmol/mg; n=4) or 125I-VIP (K d 1·3±0·3 nm; Bmax 354·8 ± 42·8 fmol/mg; n=4). We also demonstrated an increase in glucose-stimulated insulin (PACAP27, 366·6 ±25·8% PACAP38, 389·9 ±13·4%; VIP, 342·6± 16·1% of control; all at 1 μm, P<0·01 vs control) and IAPP release (PACAP27, 236·9 ±26·2%; PACAP38, 226·5 ± 10·9%; VIP, 242·9 ± 15·8% of control; all at 1 μm, P<0·01 vs control). Incubation of the cells with these peptides, for a duration of 12 h, in the presence of 5·5 mm glucose, did not alter the expression of insulin or IAPP. These findings suggest that PACAP and VIP stimulate secretion of insulin and IAPP by binding to a 67 kDa protein on clonal β-cells and do not alter the transcription of insulin and IAPP under the conditions tested.

Journal of Endocrinology (1995) 147, 121–130

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H. M. Fraser, K. B. Smith, S. F. Lunn, G. M. Cowen, K. Morris and A. S. McNeilly


The putative endocrine role of inhibin in the control of FSH secretion during the luteal phase in the primate was investigated by immunoneutralization. Antisera against the 1–23 amino acid sequence of the N-terminus of the human inhibin α subunit were raised in a ewe and three macaques. Antisera (10–20 ml) were administered to macaques on day 8/9 of the luteal phase and serum samples collected during the treatment cycle and post-treatment cycle for determination of FSH, oestradiol and progesterone. In addition, localization of inhibin within the macaque ovary at this stage of the luteal phase was investigated using the ovine antiserum. Intense immunostaining was localized within the granulosa-lutein cells of the corpus luteum with absence of staining in the thecalutein cells or other ovarian compartments. Administration of antisera was without significant effect on serum concentrations of FSH when compared with control animals, either during the first 24 h of detailed observation or for the following 10-day period of the late luteal phase and subsequent early follicular phase. These results provide further evidence that the corpus luteum is the major source of inhibin immunoreactivity during the primate menstrual cycle, but fail to support an endocrine role for inhibin in the suppression of FSH secretion.

Journal of Endocrinology (1992) 133, 341–347

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A patient is described who showed evidence of 25 years' duration of intermittent hyperadrenocorticalism due to adrenocortical hyperplasia. The most pronounced clinical symptom was oedema formation, which was shown to be associated with phases of increased adrenocortical activity. Cortisol secretion rates, for example, ranged from 24 to 161 mg./24 hr. There was also potassium depletion.

The response to dexamethasone was repeatedly anomalous, there being a tenfold increase in excretion of urinary 17-hydroxycorticosteroids. Responses to metyrapone and pyrogen were absent but the response to insulin appeared excessive. There was no alteration by dexamethasone in vitro of synthesis of cortisol or corticosterone. Binding of plasma cortisol and corticosteroid-binding globulin were decreased.