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J. N. MILLS and S. THOMAS

SUMMARY

Renal function has been studied in normal human subjects over some hours after the administration of 250 mg cortisone acetate orally or of 100 mg cortisol intravenously. Increased output of potassium without elevation of plasma concentration, and retention of sodium, were observed regularly both in the course of and without a phosphate infusion. Glomerular filtration rate and renal plasma flow were sometimes markedly elevated, sometimes unaltered. When phosphate was infused in amounts sufficient to saturate tubular reabsorptive capacity, phosphate tubular maximum was often depressed by the hormones, but sometimes unaltered. At normal plasma concentrations the usual relationship between phosphate excretion and plasma concentration or filtered load was undisturbed.

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J. N. MILLS and S. THOMAS

SUMMARY

Phosphate infusions were given to human subjects at a rate which elevated the plasma concentration to three or four times the normal level, and then permitted to fall slowly. In subjects who had taken cortisone by mouth, the plasma phosphate concentration was lower before and throughout the infusion.

Phosphate infusions were also given at a rate which for many hours maintained the plasma concentration at about double the normal level. Intravenous injection of hydrocortisone caused, after a latent period of about 1¼ hr, a sharp fall in plasma phosphate.

Hydrocortisone given intravenously without previous phosphate infusion led, after a similar latency, to a sharp fall in plasma phosphate. Since the phosphate did not appear in the urine, and the volume of extracellular fluid did not expand under the influence of glucocorticoids, it is inferred that the phosphate had become intracellular.

Intravenous hydrocortisone had little effect upon plasma potassium. It produced a small and variable rise in plasma glucose, a small rise in oxygen consumption without consistent change in r.q., and no change in plasma pH.

Oral glucose followed by intravenous insulin caused a large drop in plasma potassium and a small one in plasma phosphate.

Intravenous deoxycorticosterone, in doses which caused a similar sodium retention to that produced by hydrocortisone, did not depress plasma phosphate concentration.

The possible relationship between the changes in plasma electrolytes and carbohydrate metabolism is discussed.

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D. J. S. Sirinathsinghji and I. H. Mills

Human pituitary LH (1200 i.u.) was infused for 4 h (from 10.00 to 14.00 h) into six women with anorexia nervosa and into five women with polycystic ovarian disease (PCO). Plasma dehydroepiandrosterone sulphate (DHAS), androstenediol sulphate, dehydroepiandrosterone (DHA), androstenediol and testosterone were estimated by gas–liquid chromatography in blood samples taken every 2 h from 10.00 to 20.00 h. The values were compared with those obtained at the same times on the previous control day. There were no significant changes in the plasma levels of DHAS and androstenediol sulphate in response to LH at any of the sampling times in either the anorexia nervosa or the PCO patients. In the anorexia nervosa women, plasma DHA levels were significantly increased at 16.00 (P<0·001), 18.00 (P<0·001) and 20.00 h (P<0·05) after LH infusion. In the PCO women, DHA levels increased significantly at 14.00 (P<0·01), 16.00 (P<0·001), 18.00 (P<0·001) and 20.00 h (P<0·001) in response to LH infusion. Plasma androstenediol levels increased significantly in the anorexia nervosa patients at 12.00 (P<0·001), 14.00 (P<0·01) and 16.00 h (P<0·01) in response to LH. Similar increases were also found in the PCO patients at 12.00 (P<0·01), 14.00 (P<0·001) and 16.00 h (P<0·01). Plasma testosterone decreased progressively in the anorexic women in response to LH, becoming significant at 16.00 (P<0·05), 18.00 (P<0·05) and 20.00 h (P<0·01). A similar progressive decrease in plasma testosterone was seen in the PCO women, the levels being significantly lower than controls at 16.00 (P<0·05), 18.00 (P<0·05) and 20.00 h (P<0·05).

The results represent the first experimental evidence for a direct regulatory role for LH on androgen secretion in women. In addition, the data have a significant bearing on the pathogenesis of the PCO syndrome and the development of hirsutism which may be directly related to the high androgen levels in PCO women in whom the levels of LH are normally raised. The data may also offer an explanation for the mechanisms responsible for the low androgen levels in anorexia nervosa patients in whom there is a gonadotrophin deficiency.

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J. N. MILLS, S. THOMAS and K. S. WILLIAMSON

SUMMARY

The magnitude of the influence of endogenous adrenal steroids upon renal excretion of electrolytes has been assessed by observing the changes on administering spironolactone, which blocks, at least in part, the effect of steroids upon the kidney. The findings indicate that endogenous steroids exert a sodium-retaining effect in subjects asleep at night, recumbent or standing in the afternoon, and ambulant and perhaps also recumbent in the morning. Endogenous steroids also promote chloride reabsorption, but the changes are usually smaller. Changes in excretion of potassium and hydrion have been less convincingly demonstrated, but it is believed that sodium reabsorption is by ion exchange for potassium and hydrion, as well as in association with chloride.

If the subject maintains the recumbent posture for 5 hr. from midday, the influence—and probably the production—of endogenous steroids declines steadily, but it is maintained if he stands. The contribution of steroids to the altered renal behaviour on changing posture has been assessed; the low sodium excretion on standing is in part due to a non-adrenal, presumably haemodynamic factor, and in part to aldosterone secretion; and on standing there is a modest but significant fall in potassium excretion due to the non-adrenal factor.

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J. N. MILLS, S. THOMAS and K. S. WILLIAMSON

SUMMARY

The blocking effect of spironolactone ('Aldactone', Searle) has been tested against 100 mg. cortisol, and 0·25 mg. d-aldosterone, given intravenously. The sodium retention induced by either steroid is roughly halved by either a 300 or a 600 mg. dose of spironolactone. The high potassium excretion induced by cortisol is little if at all affected by spironolactone; the acute kaliuretic action of aldosterone is too small and inconstant to permit a clear assessment of blocking action. The implications of the apparent dissociation of the effects of cortisol upon sodium and upon potassium excretion are discussed.

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M. J. IMRIE, J. N. MILLS and K. S. WILLIAMSON

SUMMARY

Cortisol, 15 mg., injected intravenously in nine human subjects at 23.00 hr. increased K+ in urine excreted between midnight and 02.00 hr. but effects on Na+ excretion were variable. No significant changes in creatinine excretion were observed.

In further experiments on one subject cortisol was infused intravenously at 4 or 6 mg./hr. from 21.00 to 02.00 hr. Little regular difference from controls was seen in excretion of either sodium or potassium.

The results are discussed in the light of the suggestion that secretion of cortisol in the morning raises excretion of sodium and potassium from the low night value.

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R. L. REID, N. T. HINKS and S. C. MILLS

SUMMARY

Diabetes, uncomplicated by severe renal damage, was established in ewes, 115–135 days pregnant, by injection of 40 mg. alloxan/kg. body weight. The onset of severe hyperketonaemia was accompanied by loss of appetite and rapid loss of body weight, death ensuing usually after 10–16 days. Blood acetate levels were markedly elevated in the early stages of the syndrome, and declined as feed intake fell. It is concluded that the high levels are a consequence of a block in the metabolism of acetate absorbed from the gut. Levels remained above normal after complete loss of appetite, to a degree correlated with blood ketone level. Fasting blood glucose levels were reduced in pregnant ewes below those of non-pregnant ewes, to a degree which correlated with foetal weight. Hypoglycaemia was recorded in fasting diabetic ewes with triplets. Plasma cortisol levels were only slightly increased after alloxan, except in pre-mortal stages, when very high values were associated with terminal increases in blood glucose, NPN and creatinine levels.

A dose of 20 mg. alloxan/kg. temporarily increased blood glucose levels and induced a transitory diabetes in two of twelve ewes. Hyperglycaemia and mild ketosis occurred, but were not associated with loss of appetite or loss of body weight. A dose of 60 mg./kg. induced a diabetic-uraemic syndrome in three of eight ewes, characterized by gross elevation of glucose, NPN, creatinine, amino-N and cortisol levels. This syndrome occurred in only two of sixteen ewes after 40 mg. alloxan/kg.

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Edouard G A Mills, Waljit S Dhillo and Alexander N Comninos

Reproduction is fundamental for the survival of all species and requires meticulous synchronisation of a diverse complement of neural, endocrine and related behaviours. The reproductive hormone kisspeptin (encoded by the KISS1/Kiss1 gene) is now a well-established orchestrator of reproductive hormones, acting upstream of gonadotrophin-releasing hormone (GnRH) at the apex of the hypothalamic–pituitary–gonadal (HPG) reproductive axis. Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network implicated in sexual and emotional behaviours. We are now forming a more comprehensive appreciation of extra-hypothalamic kisspeptin signalling and the complex role of kisspeptin as an upstream mediator of reproductive behaviours, including olfactory-driven partner preference, copulatory behaviour, audition, mood and emotion. An increasing body of research from zebrafish to humans has implicated kisspeptin in the integration of reproductive hormones with an overall positive influence on these reproductive behaviours. In this review, we critically appraise the current literature regarding kisspeptin and its control of reproductive behaviour. Collectively, these data significantly enhance our understanding of the integration of reproductive hormones and behaviour and provide the foundation for kisspeptin-based therapies to treat related disorders of body and mind.

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P. S. CHEN Jr., I. H. MILLS and F. C. BARTTER

SUMMARY

A method is described for determination of the extent of protein binding of steroids by ultrafiltration after addition of radioactively-labelled steroid tracers of high specific activity. Results obtained with specifically labelled 14C-steroids did not differ significantly from those with steroids randomly labelled with tritium. A number of steroids have been studied with this technique.

The 'S' shaped curve obtained with some corticosteroids by plotting percentage ultrafilterable against steroid added to the plasma confirmed the presence of the corticosteroid-binding protein which has greater affinity for steroid than albumin. This method of plotting the ultrafiltration data afforded a method of assessing the amount of binding protein (or the number of sites). Cortisone, 17-hydroxy-11-deoxycorticosterone, cortisol, and Δ1 cortisol showed this type of curve.

Binding of aldosterone, progesterone and 17-ketosteroids occurred to the same extent in plasma as in 5% albumin. The ultrafilterable fraction of these steroids in plasma was constant over a wide range of total steroid concentration. Binding of testosterone was greater with plasma than with albumin, and did not decrease upon addition of large amounts of testosterone.

Open access

D Pugazhendhi, K A Watson, S Mills, N Botting, G S Pope and P D Darbre

The phytoestrogens genistein, daidzein and the daidzein metabolite equol have been shown previously to possess oestrogen agonist activity. However, following consumption of soya diets, they are found in the body not only as aglycones but also as metabolites conjugated at their 4′- and 7-hydroxyl groups with sulphate. This paper describes the effects of monosulphation on the oestrogen agonist properties of these three phytoestrogens in MCF-7 human breast cancer cells in terms of their relative ability to compete with [3H]oestradiol for binding to oestrogen receptor (ER), to induce a stably transfected oestrogen-responsive reporter gene (ERE-CAT) and to stimulate cell growth. In no case did sulphation abolish activity. The 4′-sulphation of genistein reduced oestrogen agonist activity to a small extent in whole-cell assays but increased the relative binding affinity to ER. The 7-sulphation of genistein, and also of equol, reduced oestrogen agonist activity substantially in all assays. By contrast, the position of monosulphation of daidzein acted in an opposing manner on oestrogen agonist activity. Sulphation at the 4′-position of daidzein resulted in a modest reduction in oestrogen agonist activity but sulphation of daidzein at the 7-position resulted in an increase in oestrogen agonist activity. Molecular modelling and docking studies suggested that the inverse effects of sulphation could be explained by the binding of daidzein into the ligand-binding domain of the ER in the opposite orientation compared with genistein and equol. This is the first report of sulphation enhancing activity of an isoflavone and inverse effects of sulphation between individual phytoestrogens.