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M. Héry, M. Faudon, G. Dusticier, and F. Héry

In order to determine the temporal relationships between variations in 5-hydroxy-tryptamine (5-HT, serotonin) metabolism in the suprachiasmatic nucleus (SCN) and the cyclic LH surge, and also to check whether implantation of oestradiol capsules might modulate 5-HT metabolism in the SCN, we carried out a parallel study of 5-HT content in the SCN and median eminence, and 5-HT metabolism in the SCN and supraoptic region in vitro. These experiments were performed on intact male rats, ovariectomized females and ovariectomized females implanted with oestradiol.

It was only in ovariectomized rats implanted with oestradiol, in which we have described the existence of a clear-cut circadian rhythm of LH secretion, that we found fluctuations in the content, synthesis and utilization of 5-HT. The content and synthesis were characterized by a peak between 12.00 and 15.00 h, whereas utilization was 50% higher at 09.00 and 19.00 h than at 15.00 h. These fluctuations in 5-HT content and metabolism were specific to the SCN; the median eminence and the supraoptic region did not show such variations. They were also specific to ovariectomized rats implanted with oestradiol, since the patterns of 5-HT content and metabolism in the SCN were the same in males and ovariectomized females and did not differ from those in the median eminence, the supraoptic region or the whole hypothalamus.

These results suggest that 5-HT terminals in the SCN play an important role in the control of cyclic LH secretion at a critical period. Moreover, oestradiol seems to be partly responsible for the fluctuations of 5-HT metabolism in the SCN of ovariectomized rats implanted with oestradiol.

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Six rams of an ancient breed of domesticated sheep (Soay) were subjected to an artificial light régime of alternating periods of long days (16 h light:8 h darkness) and short days (8 h light: 16 h darkness) which induced seasonal development and regression of the testes during a period of 36 weeks. Over 2000 blood samples were taken, and the changes in plasma levels of FSH, LH and testosterone were related to the cycle of testicular activity. During long days plasma levels of gonadotrophins became very low and the testes regressed to about 20% of their maximum size; there was a corresponding reduction in plasma testosterone levels. When the rams were returned to short days reproductive development was again stimulated after 2–3 weeks with a progressive increase in plasma FSH and LH levels and consequent hypertrophy of the testes. It took about 16 weeks of short days for testicular activity to become maximal.

Blood samples collected at hourly intervals for 24 h on ten occasions during the study revealed transitory peaks in plasma FSH and LH levels indicative of episodic release. Changes in gonadotrophin secretion were modulated primarily by alterations in the frequency of episodic release; < 1 spike per 24 h during long days increased to a maximum of 10 spikes/24 h under short daylengths. The peaks of FSH release were of smaller amplitude than those of LH, although during periods of frequent episodic release basal levels of FSH were increased to a greater extent than those of LH.

A circadian rhythm was observed in the plasma levels of FSH, LH and testosterone, which was related to increased gonadotrophin release during the dark phase of the 24 h cycle; changes in blood haematocrit were also observed. The circadian changes appeared to be correlated with the activity cycle of the animals which in turn was dictated by daylight. A possible interrelationship between the circadian cycle and the seasonal cycle is discussed.

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G. S. Kamstra, P. Thomas, and Janet Sadow

The secretion of corticotrophin releasing activity (CRA) from the isolated rat hypothalamus incubated in vitro was investigated under various conditions of incubation and of pretreatment of donor animals providing hypothalami. Media from hypothalamic incubations were assayed for CRA by a validated double in-vitro bioassay technique which differentiates CRA from vasopressin.

A circadian rhythm was found in the secretion of CRA in vitro from isolated hypothalami obtained from animals killed at different times of the day. Secretion of CRA increased significantly at 19.00 h (dusk) compared with the secretion rate at 07.00 h, in synchrony with a rise in plasma corticosterone levels. In addition, both plasma corticosterone concentrations and CRA secretion in vitro were higher at 07.00 h than at 19.00 h after exposure of the donor animals to a reversed light cycle for 7–10 days.

Hypothalami obtained from animals chronically treated with betamethasone in the drinking water showed a diminished secretion of CRA in vitro. Exposure of untreated animals to ether vapour for 2 min immediately before death significantly increased the subsequent secretion of CRA in vitro. Ether exposure did not significantly affect the secretion of CRA in vitro from hypothalami of betamethasone-treated rats. There was a close correlation between plasma corticosterone levels and in-vitro CRA release after these treatments. The results suggest that the secretion of CRA examined in this way is a phenomenon which can reflect the changes which occur in the activity of the hypothalamo-pituitary-adrenal system in vivo during the 24-h cycle, after glucocorticoid treatment and after ether stress.

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The relationship of plasma prolactin concentration and renal electrolyte excretion has been investigated in six normal male volunteers. In two studies, 80 mg frusemide were administered at 18.00 h on Day 1 and followed by dietary sodium restriction. In study A, after 38 h of sodium depletion, a second dose of frusemide was administered at 08.00 h on Day 3. In study B, after 14 h of sodium depletion, the effect of administration of 100 mg spironolactone or 45 mg prorenoate potassium (another aldosterone antagonist) at 08.00 h on Day 2 was compared with that of a placebo.

After the first dose of frusemide in study A, the mean plasma prolactin concentration correlated negatively with the urinary Na and K excretion over 5 h. After 38 h sodium depletion, the plasma prolactin concentration correlated positively with urinary Na excretion following the second dose of frusemide. In study B, after Na depletion for 14 h the plasma prolactin concentration at 08.00 h on Day 2 had a positive correlation with the 24 h urinary log10 Na:K ratio following placebo administration and had negative correlations with the true urinary log10 Na:K ratio following spironolactone and prorenoate potassium administration.

Neither acute Na deprivation nor the administration of single doses of frusemide, spironolactone or prorenoate potassium appeared to affect the normal circadian rhythm of plasma prolactin concentrations which remained constant for each subject throughout the 3 months covered by the investigation.

The correlations of plasma prolactin concentration to renal excretion of electrolytes, with no evidence for a negative feedback control mechanism, suggest an indirect relationship between prolactin and renal function.

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The concentration of prolactin in serum after oestrogen and progesterone injection into spayed rats was measured by radioimmunoassay.

After a single injection of 5 μg oestradiol benzoate (OB) into long-term ovariectomized rats, serum prolactin concentrations showed a circadian rhythm with high levels in the afternoon and almost no changes in the morning. Peaks of prolactin occurred 2, 3 and 4 days after the injection. Below a dose of 1 μg OB, the response was dose-dependent, but the response was then maximal.

In spayed rats primed with 5 μg OB, the injection of 2 mg progesterone 2, 3 or 4 days later resulted in a significant increase in serum prolactin. This response, in contrast to that of oestrogen, occurred in the morning and in the evening and was found to be dose-dependent. The rise in serum prolactin after injection of 1 mg progesterone also showed a close relationship to the priming dose of OB. Progesterone had no effect in spayed, untreated animals. Maximal levels of prolactin were attained 3–4 h after the s.c. injection of progesterone. The release of prolactin which can be induced either by OB or by progesterone was blocked by the administration of progesterone injected 1 day before the expected release would occur. These results indicate that progesterone exerts both facilitatory and inhibitory effects on prolactin secretion. Male rats were found to be less sensitive to the ovarian steroid treatment.

It is suggested that oestrogen could be responsible for the rise in prolactin observed at pro-oestrus and progesterone for the increase in prolactin in pseudopregnancy and pregnancy.

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J Lund, J Arendt, SM Hampton, J English, and LM Morgan

The circadian rhythms of many night-shift workers are maladapted to their imposed behavioural schedule, and this factor may be implicated in the increased occurrence of cardiovascular disease (CVD) reported in shift workers. One way in which CVD risk could be mediated is through inappropriate hormonal and metabolic responses to meals. This study investigated the responses to standard meals at different circadian times in a group of night-shift workers on a British Antarctic Survey station at Halley Bay (75 degrees S) in Antarctica. Twelve healthy subjects (ten men and two women) were recruited. Their postprandial hormone and metabolic responses to an identical mixed test meal of 3330 kJ were measured on three occasions: (i) during daytime on a normal working day, (ii) during night-time at the beginning of a period of night-shift work, and (iii) during the daytime on return from night working to daytime working. Venous blood was taken for 9 h after the meal for the measurement of glucose, insulin, triacylglycerol (TAG) and non-esterified fatty acids. Urine was collected 4-hourly (longer during sleep) on each test day for assessment of the circadian phase via 6-sulphatoxymelatonin (aMT6s) assay. During normal daytime working, aMT6s acrophase was delayed (7.7+/-1.0 h (s.e.m.)) compared with that previously found in temperate zones in a comparable age-group. During the night shift a further delay was evident (11.8+/-1.9 h) and subjects' acrophases remained delayed 2 days after return to daytime working (12.4+/-1.8 h). Integrated postprandial glucose, insulin and TAG responses were significantly elevated during the night shift compared with normal daytime working. Two days after their return to daytime working, subjects' postprandial glucose and insulin responses had returned to pre-shift levels; however, integrated TAG levels remained significantly elevated. These results are very similar to those previously found in simulated night-shift conditions; it is the first time such changes have been reported in real shift workers in field conditions. They provide evidence that the abnormal metabolic responses to meals taken at night during unadapted night shifts are due, at least in part, to a relative insulin resistance, which could contribute to the documented cardiovascular morbidity associated with shift work. When applied to the 20% of the UK workforce currently employed on shift work, these findings have major significance from an occupational health perspective.

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Ingram JR, JN Crockford, and LR Matthews

Seasonal changes in the activity and responsiveness of the adrenal gland in red deer (Cervus elaphus) stags were quantified by measuring 24 h endogenous cortisol secretory profiles and plasma cortisol responses to either administration of exogenous ACTH or a standardised stressor during November (period of velvet growth), February (pre-rut), April (mid-rut) and July (post-rut) (southern hemisphere) using a remote blood sampling device (DracPac). Ultradian rhythms in the concentration of plasma cortisol were observed resulting from the episodic secretion of cortisol from the adrenal cortex at a mean rate of 0.8 pulses/h. Circadian rhythms in plasma cortisol concentrations were also found in 11 out of the 20 complete 24 h profiles (mean amplitude, 3.8+/-1.4 ng/ml). Seasonal rhythms in mean 24 h plasma cortisol concentrations and cortisol pulse parameters were also observed. Mean 24 h plasma cortisol concentrations were higher in November (12.5+/-1.0 ng/ml) than in February (6.3+/-1.0 ng/ml), April (4.0+/-1.0 ng/ml) or July (4.2+/-1. 0 ng/ml). Cortisol pulse height, nadir and amplitude were all significantly higher in November than at other times of the year (P<0.01). Peak cortisol concentrations following infusion of ACTH(1-24) (0.04 IU kg(-1)) were higher (P<0.05) in November (55.8+/-2.7 ng/ml) and lower (P<0.001) in April (33.7+/-1.8 ng/ml) than those in February and July (48.7+/-2.0 ng/ml and 45.4+/-2.0 ng/ml respectively). The area under the cortisol response curve was significantly smaller (P<0.05) in April (266.6+/-15.3 ng/ml/190 min) than at other times of the year (February, 366.1+/-15.3 ng/ml/190 min; July, 340.7+/-15.3 ng/ml/190 min and November, 387.8+/-21.2 ng/ml/190 min). These data demonstrate that the adrenal gland of the red deer stag exhibits ultradian, circadian and seasonal rhythms in activity, and that its responsiveness to ACTH varies with season. November, a period of reproductive quiescence in the southern hemisphere, with new antler growth and rapid weight gain, is associated with higher mean plasma cortisol concentrations and a greater responsiveness to exogenous ACTH. In contrast, the breeding season is associated with lower adrenal activity and responsiveness.

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The incorporation of [35S]methionine into protein of the anterior pituitary and discrete brain areas was measured following the administration of antibodies to oestrogen, ovariectomy, or adrenalectomy on the afternoon of dioestrus. The antibody to oestrogen deleted the circadian rhythms of methionine incorporation normally observed in the various brain areas together with the peaks of incorporation normally observed in the median eminence area and anterior pituitary on the evening of pro-oestrus. The peaks of incorporative activity normally observed in the preoptic area and amygdala (relative to the putamen) at 03.00 h on the day of pro-oestrus were also deleted. Administration of the antiserum on the morning of pro-oestrus failed to alter the pattern of methionine incorporation normally observed on the evening of pro-oestrus.

Ovariectomy performed at 16.00 h of dioestrus blocked the preovulatory rise of luteinizing hormone (LH) (as did the antibody to oestrogen) and inhibited the peak of methionine incorporation normally observed in the anterior pituitary on the evening of pro-oestrus. However, for the peak in the median eminence to be inhibited, ovariectomy had to be performed on the morning of the preceding oestrus. Adrenalectomy alone, or adrenalectomy with ovariectomy, performed on the afternoon of dioestrus did not affect the levels of methionine incorporation in the brain or anterior pituitary at 18.00 h on the day of prooestrus.

Animals which had been ovariectomized and injected with 2·5 μg oestradiol benzoate on the morning of oestrus showed significantly increased levels of methionine incorporation in all the brain areas and the anterior pituitary at 18.00 h of expected pro-oestrus. The administration of antibody to oestrogen to a similar group of animals on the afternoon of expected dioestrus inhibited the rise at 18.00 h of expected pro-oestrus. The apparent discrepancy between the results obtained with ovariectomy and the antiserum appeared to be due to the ability of the antiserum to neutralize the activity of oestrogens retained by the tissues.

The present results suggest that the changes in incorporation of methionine into protein in the brain and anterior pituitary are brought about by the action of endogenous oestrogen: there appears to be a steady summative effect on the median eminence throughout the oestrous cycle together with a short-lived effect occurring during pro-oestrus and affecting the anterior pituitary.

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M. B. ter HAAR and P. C. B. MacKINNON


Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were measured by radioimmunoassay in groups of Wistar rats at 6-hourly intervals during the course of a 4-day oestrous cycle. In addition to a surge at about 18.00 h on the day of pro-oestrus, a circadian rhythm in LH levels was observed which was accentuated during metoestrus. FSH levels showed a protracted periovulatory rise which reached peak levels at about 03.00 h on the day of oestrus. A daily rhythm was not observed.

The incorporation of [35S]methionine (injected subcutaneously 1 h before death) into the trichloroacetic acid-precipitable proteins of the anterior pituitary and of discrete brain areas implicated in the control of gonadotrophin release, was also measured. An increase in protein synthetic activity was observed in the anterior pituitary and the area of the median eminence on the evening of pro-oestrus with peak levels coinciding with the LH surge at 18.00 h on the day of pro-oestrus. An increase in protein synthetic activity relative to that in a 'control' area (the putamen) was observed in the preoptic area and in the amygdala 15–18 h before the LH surge. It is suggested that these changes in protein synthetic activity are associated with the train of neural and humoral events leading to ovulation.

After ovariectomy, protein synthetic activity in all areas investigated was at the low levels observed during the oestrous cycle. Daily injections of 20 μg oestradiol benzoate into intact females led to levels of protein synthesis as great as, or greater than, the maximal levels observed during the oestrous cycle.

Measurements of variations in total protein concentration/unit wet weight of pituitary or brain tissue showed that they were apparently unrelated to variations in protein synthetic activity. Protein concentration appeared to be high in all the brain samples taken at oestrus and low in those taken at metoestrus. Furthermore, superimposed upon a marked daily rhythm, there was a peak of protein concentration on the evening of dioestrus both in the preoptic area and in the area of the median eminence.

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E. S. Maywood, M. H. Hastings, M. Max, E. Ampleford, M. Menaker, and A. S. I. Loudon


The aim of this study was to develop a radioimmunoassay for the measurement of endogenous circulating melatonin concentrations in the Syrian hamster, and then to determine the effect of various photic manipulations upon this endocrine signal. In experiment 1, pineal-intact or pinealectomized adult male Syrian hamsters, housed under a long photoperiod (LD; 16 h light:8 h darkness) for 2 weeks, were then either maintained on LD or transferred to a short photoperiod (SD; 8 h light:16 h darkness) for a further 8 weeks. The profile of serum melatonin concentrations was determined from blood samples taken by cardiac puncture at intervals over a 24-h period. Radioimmunoassay revealed that daytime concentrations were at or below the limit of sensitivity of the assay (≥ 50 pmol/l). Under both photoperiods, the concentration of melatonin in the serum of pineal-intact animals rose 4–5 h after the onset of darkness, and the peak amplitude of the melatonin rhythm was not significantly different between the SD- or LD-housed animals (200–250 pmol/l). Premature exposure of animals to light during the dark phase of LD caused a precipitous decline in circulating concentrations to daytime values within 15 min and they remained there for several hours. In animals which experienced an uninterrupted night on either LD or SD, the most striking difference in the rhythm of endogenous melatonin secretion was the duration. Animals housed under LD had high levels until the start of the light period, a peak duration of 3·7 h. In contrast, animals housed under SD exhibited a peak duration of 10 h, levels falling 1·5 h before the start of the light period. The nocturnal increase in serum melatonin concentration was abolished in pinealectomized animals. Serum levels in these animals were not significantly different from those observed in pineal-intact animals during the light phase, being at, or very close to, the limit of sensitivity of the assay.

In experiment 2, animals were housed under LD prior to transfer to continuous darkness for 10 days, during which time their locomotor activity rhythms were recorded. Animals were then chronically cannulated and serial blood samples were removed from the jugular vein at hourly intervals, starting 48 h after surgery. A pronounced circadian rhythm in plasma melatonin concentrations was observed, with levels rising significantly 3 h after the onset of activity and falling 10 h later. During subjective day, levels were at or below the limit of sensitivity of the assay. At the end of the study, pineal melatonin was also measured at intervals across the circadian cycle. This revealed a very close correlation between the plasma and pineal concentrations of melatonin, the duration and phase of both nocturnal peaks being equivalent. These results confirm that the duration of the nocturnal secretion of melatonin varies in proportion to the length of the dark phase, that this rhythm is endogenously driven, and that peak physiological levels of melatonin in this species are of the order of 200 pmol/l.

Journal of Endocrinology (1993) 136, 65–73