Biomedical subjects

S L Lightman

Publications and source records attributed to S L Lightman.

At least 271 records · Page 15Linked to original sources

PubMed1991

Lactation abolishes corticotropin-releasing factor-induced oxytocin secretion in the conscious rat.

We have assessed the response of plasma oxytocin (OT) to intracerebroventricular CRF-41 in both virgin female and lactating rats. In virgin rats CRF-41 resulted in an increase in plasma OT from 5-30 min after administration. In lactating rats, however, there was a complete abolition of the OT response, even at the highest dose of CRF-41. These data demonstrate another feature of the hormone nonresponsiveness apparent during lactation and suggests that one of the reasons for the lack of stress responses could be a down-regulation of the response to endogenously released CRF-41.

Animals↗

PubMed1991

Inhibition of hypothalamic thyrotropin-releasing hormone messenger ribonucleic acid during food deprivation.

Food deprivation in laboratory rats induces profound changes in the neuroendocrine system. We have investigated the hypothalamic and pituitary responses of the hypothalamo-pituitary thyroid axis to 48-h food deprivation in Sprague-Dawley rats. Peripheral T3 and hypophysial portal TRH were measured by RIA, and TSH beta, PRL, and pro-TRH mRNA were measured using in situ hybridization histochemistry. Peripheral total T3 was greatly reduced in food-deprived rats. Hypothalamic portal blood TRH levels declined significantly with time in control animals. The initial level of TRH in the portal blood of food-deprived rats was significantly reduced compared to that in controls, but did not fall further with time. In situ hybridization histochemistry revealed significantly lower pro-TRH mRNA in the paraventricular nucleus of food-deprived animals, while pro-TRH mRNA in the reticular nucleus remained unaltered. Furthermore, in the anterior pituitary, TSH beta mRNA decreased significantly in food-deprived animals, while PRL mRNA was unaltered. We conclude that the reduction in circulating T3 after food deprivation appears to be due primarily to decreased hypothalamic TRH synthesis and release.

Animals↗

PubMed1991

The effect of human chorionic gonadotropin and pregnancy on the circulating level of relaxin.

The effect of hCG and pregnancy on the circulating levels of relaxin was investigated in 48 women undergoing in vitro fertilization and embryo transfer (ET) for the treatment of infertility. Subjects were allocated randomly to receive hCG (Profasi; 2000 IU, im) or placebo on the day of ET (day 0) and on day 3 after ET (day 3). Samples of peripheral blood were taken on days -4, 6, and 10. An additional sample was taken on day 22 from women who became pregnant. The subjects were allocated retrospectively to 1 of 4 groups: no pregnancy, no hCG (NP); pregnancy, no hCG (P); no pregnancy, hCG (NPH); and pregnancy, hCG (PH). Two patients with blighted ova and one with a tubal pregnancy were excluded from the analysis. The concentrations of relaxin were similar and rose significantly in all groups at each time point (P less than 0.05). On day 6 there was no significant difference in the increment between the groups, but by day 10, circulating levels in the P compared to the NP and those in the PH compared to the NPH group were significantly greater (P less than 0.05). By day 22 the difference between the PH and the P groups was significant (P less than 0.05). Relaxin levels correlated with progesterone levels on day 10 in the NP and P groups (r = 0.633; P less than 0.05 and r = 0.697; P less than 0.05, respectively) and with estradiol levels in the P group only on days 6 and 22 (r = 0.659; P less than 0.05 and r = 0.783; P less than 0.05, respectively). These data demonstrate that in women undergoing in vitro fertilization, relaxin levels increase during the luteal phase, and in those women who establish a pregnancy, the values are significantly greater by day 10. The administration of hCG in the early luteal phase, before implantation, to women who subsequently become pregnant significantly increased the level of circulating relaxin on day 22. The positive correlation between relaxin levels and ovarian steroid levels in the groups not receiving exogenous hCG suggests that a common factor may control the release of both.

Chorionic Gonadotropin↗

PubMed1991

Production of a growth hormone-releasing hormone-like peptide and its mRNA by human lymphocytes.

Human peripheral blood lymphocytes (PBL) contain immunoreactive growth hormone-releasing hormone (irGRH). Both the intracellular content and the release of irGRH from PBL are increased following lymphocyte activation. Although binding of lymphocyte-derived irGRH to a GRH1-44 antibody dilutes in parallel with standard GRH1-44, irGRH elutes earlier on gel chromatography with an apparent molecular weight of approximately 50 kD. On reverse-phase high performance liquid chromatography, irGRH elutes later than GRH1-44. Northern blot analysis also detected the presence of two GRH mRNA transcripts in PBL, one similar in size to the hypothalamic species of 0.75 kb and another larger transcript of approximately 10 kb. Despite these differences in physicochemical behaviour, both the lymphocyte-derived irGRH GRH1-44 were biologically active as demonstrated by enhancing the transcription of growth hormone mRNA both in dispersed rat pituitary cells and in PBL.

Animals↗

PubMed1991

Relaxin levels in ovum donation pregnancies.

STUDY OBJECTIVE: To investigate the relative contributions of the corpus luteum (CL) and the placenta to the circulating levels of relaxin during pregnancy. PATIENTS: Forty-one patients in whom pregnancy had been achieved by ovum donation. RESULTS: Relaxin was not detected in the serum of 36 patients; in the remaining 5, although it was detectable, the levels were markedly reduced when compared with those in normal pregnancies. CONCLUSION: These results demonstrate that the CL is essential for the maintenance of normal circulating levels of relaxin during pregnancy.

Corpus Luteum↗

PubMed1991

Expression of pre-opiomelanocortin (POMC) mRNA in undifferentiated and in vitro differentiated human neuroblastoma cell lines.

Several human neuroblastoma cell lines express transcripts of the proopiomelanocortin (POMC) gene of 0.8 kb and 9.5 kb, thus different from the characteristic pituitary 1.2 kb POMC mRNA. The expression of POMC mRNA decreases when the cell lines are differentiated with retinoic acid or alpha-difluoromethylornithine. Since both POMC and MYCN genes are present on the same chromosome segment (2p23), it is possible that the 2 genes are coamplified and coexpressed. Alternatively the expression of opiate peptides by neuroblastoma cells might act as an autocrine factor or it may modulate the action of tumour infiltrating lymphocytes.

Cell Differentiation↗

PubMed1990

Inhibition of rat corticotropin-releasing factor and adrenocorticotropin secretion by an osmotic stimulus.

This study demonstrates that a chronic osmotic stimulus can influence the hypothalamo-pituitary axis by inhibiting the secretion of basal and adrenalectomy-elevated adrenocorticotropin (ACTH) from the anterior pituitary. In rats given 340 mM NaCl instead of tap water to drink for 12 days, plasma concentrations of ACTH decreased to 105 +/- 27 pM (mean +/- S.E.M., n = 6) compared with control animals (182 +/- 13 pM). In adrenalectomised (ADX) rats given 150 mM NaCl to drink for 12 days, plasma ACTH concentrations were greatly increased (783 +/- 141 pM) but in ADX rats treated with 340 mM NaCl for the same period, plasma ACTH was similar to controls (237 +/- 59 pM). The corticotropin-releasing factor (CRF-41) content of the median eminence (ME) was reduced in ADX rats on 150 mM NaCl (854 +/- 78 fmol) and further reduced in ADX rats given 340 mM NaCl (510 +/- 56 fmol) compared with control animals (1239 +/- 114 fmol), suggesting that the decrease in plasma ACTH concentrations in saline-treated animals is secondary to a decrease in the secretion of CRF-41 from the ME. These data are the first evidence for a central mechanism, independent of glucocorticoid feedback, through which a chronic osmotic stimulus can inhibit the activity of CRF-41 neurons.

Adrenalectomy↗

PubMed1990

Vasopressin antagonist in early postoperative diabetes insipidus.

23 patients without diabetes insipidus before transfrontal (hypothalamic) or trans-sphenoidal (pituitary) surgery were studied prospectively to investigate the pathogenesis of early postoperative diabetes insipidus. 12 patients who underwent trans-sphenoidal surgery and who did not develop diabetes insipidus were used as controls. All received prophylactic corticosteroid replacement. Blood samples were obtained immediately after operation, at the onset of diabetes insipidus, and 24 h later. Immediately after trans-sphenoidal pituitary surgery, plasma vasopressin (AVP) was raised but had fallen to subnormal concentrations by the onset of diabetes insipidus. After transfrontal hypothalamic surgery diabetes insipidus occurred sooner and was associated with high plasma AVP immunoreactivity--but the plasma showed no antidiuretic bioactivity and greatly attenuated the antidiuretic response to standard AVP. Early diabetes insipidus after hypothalamic surgery is associated with release of a substance, presumably an analogue, from the damaged hypothalamo-neurohypophyseal system, which acts as an antagonist to normal AVP activity; after trans-sphenoidal operations diabetes insipidus seems to be caused by failure of AVP release.

Adolescent↗

PubMed1990

Osmotic regulation of methionine enkephalin in the posterior pituitary of the rat.

Methionine (Met) enkephalin is detectable in rat hypothalamic and neurointermediate lobe (NIL) tissue extracts using a specific radioimmunoassay. Reversed-phase HPLC revealed that only the pentapeptide form was present in the extracts. Total amounts of Met-enkephalin in extracts containing the median eminence (ME), supraoptic nucleus (SON), paraventricular nucleus (PVN), or NIL from control animals were 9.7 +/- 1.6, 0.9 +/- 0.2, 25.2 +/- 6.8 and 14.8 +/- 1.2 pmol respectively (means +/- S.E.M., n = 6). In animals given 340 mmol NaCl/l to drink for 5 days, no significant changes occurred in Met-enkephalin content in the SON or ME, but significant decreases were observed in the NIL and PVN (9.8 +/- 0.8 and 13.6 +/- 1.7 pmol, respectively). Amounts of Met-enkephalin in these tissues were further decreased after 12 days of 340 mmol NaCl/l (3.4 +/- 0.4 and 6.0 +/- 0.6 pmol). These data demonstrate that enkephalin immunoreactivity in the NIL is principally in the form of the Met-enkephalin pentapeptide, and that this peptide is released in response to increased plasma osmolality. The concomitant changes in the PVN and NIL tissue content suggest that the PVN is the source of NIL Met-enkephalin.

Animals↗

PubMed1990

Bromocriptine reduces rat thyrotropin beta-subunit mRNA stability.

We have examined the effect of orally administered bromocriptine on TSH beta-subunit messenger (m)RNA in the anterior pituitary glands of Sprague-Dawley rats using in situ and dot-blot hybridization histochemistry. Quantitative in situ hybridization of pituitary sections demonstrated a 60% reduction in TSH beta-subunit mRNA probe binding from rats fed a diet containing bromocriptine 10 mg/kg/day. This was confirmed by dot-blot analysis of nuclear and cytoplasmic pituitary extracts from the same tissue. Hybridization of cytoplasmic extracts of pituitary cells cultured under actinomycin D-induced transcription arrest showed that part of the effect of bromocriptine appeared to be mediated through a change in TSH beta-subunit mRNA stability and implies that the acute influence of dopamine on TSH metabolism may be transduced by control of TSH beta-subunit mRNA catabolism. This suggests a mechanism by which cells with relatively stable tissue specific mRNAs appear to respond rapidly to hormonal effects at the transcriptional level.

Administration, Oral↗

PubMed1990

Substance P and substance K in the median eminence and paraventricular nucleus of the rat hypothalamus.

We have used specific radioimmunoassays coupled with reversed-phase high-performance liquid chromatography (HPLC) to measure and characterise substance P (SP) and substance K (SK) in subdivisions of the rat hypothalamus. SP and SK levels in the paraventricular nucleus (PVN) were 968 +/- 61 and 381 +/- 22 pg respectively; in the supraoptic nucleus (SON) were 210 +/- 21 and 79 +/- 8 pg; and in the median eminence/arcuate nucleus (ME) were 1044 +/- 66 and 451 +/- 20 pg. Reversed-phase HPLC revealed that immunoreactive (ir) SP was present solely in the non-oxidised form in all tissue extracts. The principal form of ir-SK in the PVN and SON coeluted with synthetic SK on HPLC, but some immunoreactivity eluted in a later position. This material represented less then 5% of the total ir-SK in extracts of the PVN and SON, but increased to 35-40% of the total in the ME. Gel chromatography and HPLC characterised this compound as being slightly smaller and more hydrophobic than SK. These results establish that ir-SK is present within the hypothalamus in varying amounts and molecular forms. The location of significant amounts of both SP and SK in the PVN and ME, the principal regions of CRF-41 synthesis and release, is compatible with a role for neurokinins in the modulation of CRF-41 and consequently ACTH release.

Animals↗

PubMed1990

Psychological stress of exposure to uncontrollable noise increases plasma oxytocin in high emotionality women.

Oxytocin (OT), arginine-vasopressin (AVP), memory, and mood changes were measured in relation to the psychological stress of exposure to uncontrollable noise (UN), with the physical stress of exposure to the identical, but controllable, noise (CN) as a comparison. Four experiments were performed. In the first, UN but not CN resulted in OT increases in women but not in men; neither treatment altered plasma AVP. No significant changes were detected in the second study, but in the third women again showed an OT response to UN. In both the first and third study the OT response was found in only a proportion of the women exposed to UN. This result was analysed further in the fourth study, in which the stress-induced OT response occurred in high, but not in low, emotionality women. In the fourth, but not in the third, study there was an indication that OT increases may be associated with a general impairment of memory. There was no evidence to support an enhancement of negative memories after exposure to UN. Exposure to noise generally produced a worsening of mood, with no consistent differences between the UN and CN conditions. This is the first report of an OT response to psychological stress in human subjects.

Adult↗

PubMed1990

Corticotrophin-releasing factor-like immunoreactivity and mRNA in human leukocytes.

Unstimulated normal leukocytes were studied for their expression of corticotrophin-releasing factor (CRF)-like mRNA and peptide. In situ hybridization demonstrated CRF mRNA in T and B lymphocytes and in neutrophils. Northern blot analysis also detected the presence of a CRF mRNA species of approximately 1.7 Kb from lymphocytes and a peptide that reacted with anti-CRF antiserum was also detected by radioimmunoassay. This lymphocyte-derived peptide eluted earlier than standard CRF on high performance liquid chromatography. These findings suggest that regulatory mechanisms within the hypothalamus and the immune system may utilize closely related peptides.

B-Lymphocytes↗

PubMed1990

Changes in a proposed new neuroendocrine marker of oestrogen receptor function in postpartum women.

We describe a novel neuroendocrine test which reflects a central response to activation of oestrogen receptors. This is achieved by measurement of plasma levels of oestrogen-stimulated neurophysin (ESN) following an oestrogen challenge. In normal women the ESN response to ethinyl oestradiol is dose-dependent. This response is attenuated in normal women during the first postpartum month, although it is unchanged in patients with anorexia nervosa, in spite of their similar concurrent hypo-oestrogenic state. The altered puerperal response may result from the acute oestrogen withdrawal which occurs at delivery. The time course of the altered ESN response coincides with the period of maximum risk for puerperal psychosis. The ESN response to oestrogen provides a novel neuroendocrine measure to test the relevance of changes in central oestrogen receptor responsiveness in the pathogenesis of puerperal psychosis.

Adolescent↗

PubMed1990

The blood-brain interface.

The properties of the blood-brain barrier are those of the capillary endothelium in brain. This endothelium contrasts with that elsewhere in being sealed with tight junctions, having a high electrical resistance and low permeability to polar solutes. It is exceptional in having a paucity of pits and vesicles, a specialised enzyme content and a high density of mitochondria. Functionally, a range of transport mechanisms allow rapid movement of certain specific metabolic substrates. Ion pumps are concerned with secretion of brain interstitial fluid and regulation of its ionic concentration. The retinal capillaries are largely identical to those of the brain, but entry of solutes into retina is also determined by the properties of the pigment epithelium, functionally separating the retina from the highly vascular choroid. A clear difference lies in the greater resistance of cerebral microvessels to diabetic damage. The mechanism of this difference is unclear, but may relate to a better control of the brain interstitial fluid at a lower glucose concentration than is possible in the retinal interstitial fluid.

Animals↗

PubMed1990

Inositol phospholipid turnover and intracellular Ca2+ responses to thyrotrophin-releasing hormone, gonadotrophin-releasing hormone and arginine vasopressin in pituitary corticotroph and somatotroph adenomas.

We have studied the inositol phospholipid turnover response to thyrotrophin-releasing hormone (TRH) gonadotrophin-releasing hormone (GnRH) and arginine vasopressin (AVP) in five corticotroph and six somatotroph pituitary adenomas. GnRH (100 nM) increased inositol phospholipid turnover in five of five somatotroph adenomas tested by an average of 36.4 +/- 9.4% (mean +/- SE). In a fifth, which was too small to allow inositol phospholipid turnover to be assessed, GnRH produced a rapid increase in mean intracellular calcium ion concentration. Only one of five corticotroph adenomas responded to GnRH with an increase in inositol phospholipid turnover of 19%. In contrast, all the somatotroph and corticotroph adenomas tested (four of four and five of five respectively) increased inositol phospholipid turnover in response to AVP (100 nM), by an average of 61 +/- 11.8% and 415 +/- 186% respectively. The finding of an inositol phospholipid or intracellular Ca2+ response to thyrotrophin-releasing hormone (TRH) (100 nM) in three of five somatotroph adenomas (Ca2+ increasing from 50 to 175 nM in one and inositol phospholipid turnover increasing by 172 +/- 1.9% and 49 +/- 5.2% in two) and to GnRH in all five somatotroph adenomas concurs with the common clinical finding of paradoxical growth hormone responses to these releasing factors in patients with acromegaly. The lack of such a response in three of the four corticotroph adenomas suggests that the appearance of GnRH and TRH receptors on adenomatous pituitary cells is not common to all cells.

Adenoma↗

PubMed1990

Effect of naloxone on neurohypophyseal peptide responses to breast feeding and breast stimulation in man.

We have investigated the role of endogenous opioid peptides in the release of oxytocin (OT) in response to breast feeding and breast stimulation in humans. Five breast feeding women were studied on two separate occasions within 4 weeks of delivery. Saline or naloxone, 4 mg bolus and 6 mg/h, was administered intravenously, in random order. Blood samples were taken at regular intervals. In the saline-infused group OT rose from a baseline of 1.1 +/- 0.1 pmol/l (mean +/- SEM) to a peak of 7.0 +/- 0.9 after 6 min, and in the naloxone-infused group from 1.0 +/- 0.1 pmol/l to 5.8 +/- 1.3 (P less than 0.05). There were no significant differences between the two groups at any time point. Plasma vasopressin (AVP) did not change. In the second study six women in the luteal phase of the menstrual cycle were investigated on two occasions at least 48 h apart. They were similarly infused with either naloxone or saline in random sequence. A mechanical breast pump provided breast stimulation. In saline-infused women OT levels rose from a baseline of 1.0 +/- 0.1 pmol/l (mean +/- SEM) to a peak of 3.0 +/- 1.1 (P less than 0.05) after 6 min, and in naloxone infused women from 1.1 +/- 0.1 pmol/l to 3.0 +/- 1.4 (NS). There were no differences in OT between the groups. AVP did not change. We conclude that endogenous opioid peptides do not modulate OT release during breast feeding or breast stimulation in women.

Adolescent↗

PubMed1990

Relationship between somatostatin and growth hormone messenger ribonucleic acid in human pituitary adenomas: an in-situ hybridization histochemistry study.

We have used quantitative in-situ hybridization histochemistry to assess the somatostatin (SRIH) and GH messenger ribonucleic acid (mRNA) content of 81 pituitary adenomas. SRIH mRNA was found in the absence of GH mRNA in only one tumour and in the five cases in which GH and SRIH mRNA were both present, SRIH mRNA prevalence was approximately two orders of magnitude less than GH mRNA. However, no direct correlation between GH mRNA, SRIH mRNA and circulating GH levels was evident at the time of surgery. In contrast, there was no detectable SRIH mRNA probe binding to a thyrotroph adenoma, a gonadotroph adenoma, 29 endocrinologically inactive pituitary adenomas, nine lactotroph adenomas, two first trimester fetal and two normal adult pituitary glands obtained 24 and 36 h post-mortem. These findings corroborate previous reports of SRIH release from somatotroph adenomas in vitro and suggest that paracrine or autocrine mechanisms linking SRIH and GH mRNA operate within normal pituitary tissue. As somatotroph adenomas are thought to be predominantly clonal in origin, the data further suggest that GH and SRIH are synthesized in the same or closely related cells.

Adenoma↗