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SUMMARY
Progesterone injected intramuscularly at 09.00 h on the day of prooestrus in the 4-day cycle of the rat decreased plasma luteinizing hormone (LH) concentration for 2 to 3 h, but by 5 h after injection had triggered an abrupt, premature, and sustained increase in LH secretion. Between 4 and 5 h after injection sufficient LH had been secreted to raise the plasma LH concentration to more than 20 ng/ml and to induce ovulation in the majority of rats. The facilitatory effect of progesterone on LH secretion could be prevented, or extinguished after it had begun, by the administration of sodium pentobarbitone. The effects observed after administration at the prooestrous stage of the cycle are compared with those seen after progesterone injection under other conditions.
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Dihydrotestosterone propionate (DHTP) administered to intact, 25-day-old rats over a period of 6 days causes a significant decrease in testicular weight. Concurrent administration of gonadotrophic hormone prevents this decrease in testicular weight (Feder, 1971). Similarly, Beyer, Moralí & Cruz (1971) demonstrated that DHTP blocked ovarian compensatory hypertrophy in female rats. These findings and earlier reports (Bottomley & Folley, 1938; Dorfman & Kind, 1966) suggested that dihydrotestosterone suppressed secretion of gonadotrophic hormones. However, direct measurements of plasma concentrations of the gonadotrophins after DHTP treatment of young rats were unavailable. This report offers quantitative data on systemic plasma concentrations of luteinizing hormone (LH) in young male rats treated with DHTP. A previously described radioimmunoassay method was used for LH measurement (Niswender, Midgley, Monroe & Reichert, 1968; Naftolin & Corker, 1971).
In one experiment intact Sprague—Dawley male rats were injected daily with 125 μg DHTP, 375 μg DHTP, 125 μg testosterone propionate (TP)
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The effects of primary and catechol oestrogens on the uterus of the immature rat were compared. Because differences between the in-vivo and in-vitro oestrogenic actions of catechol oestrogens on the secretion of LH had been observed, their effects on a peripheral target organ, the uterus, were examined under similar conditions. In-vivo effects were assessed by measurement of uterine weight, induction of uterine cytoplasmic progestogen receptors, and by histological examination. In-vitro actions were determined by measurement of oestrogen-specific induced protein. It was found that the uterotrophic effects in vivo of 4-hydroxyoestradiol were indistinguishable from those of oestradiol whereas 2-hydroxyoestradiol was only weakly oestrogenic and 2-hydroxyoestrone had no effect. However, in vitro, 2-hydroxyoestradiol was as effective as 4-hydroxyoestradiol or oestradiol in stimulating synthesis of uterine induced protein, and 2-hydroxyoestrone, although less potent than oestradiol, had a significant effect. These results were consistent with the observed effects on the secretion of LH. The differences between in-vivo and in-vitro uterotrophic properties of catechol oestrogens can be explained on the basis of known pharmacokinetic factors.
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Search for other papers by K. BROWN-GRANT in
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Search for other papers by C. S. CORKER in
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SUMMARY
Plasma and pituitary luteinizing hormone (LH) concentrations were measured by radioimmunoassay at different stages of the normal 4- and 5-day oestrous cycle of rats. Plasma levels were low except between the afternoon of pro-oestrus and the morning of oestrus when levels were high but variable. Pituitary LH content and concentration were less consistent but averaged values showed a steady rise from a low level after ovulation to a peak on the afternoon of pro-oestrus, and a rapid fall that evening when plasma levels rose rapidly.
No significant differences were observed in plasma LH between 4- and 5-day cycles; in particular there was no reduction at metoestrus or dioestrus-1 or increase on the evening of dioestrus-2. Plasma oestradiol was already high on the morning of dioestrus-2 in some rats and in all rats by that evening. On the morning of pro-oestrus in the 5-day cycle, plasma oestradiol was still high but somewhat lower than at the corresponding stage in the 4-day cycle.
Blocking ovulation by administration of sodium pentobarbitone at prooestrus in a 4-day cycle prevented the rise in plasma LH and the fall in pituitary content. Blocking generally failed in animals whose plasma LH had reached the level of 20 ng/ml or more at the time of injection. Plasma oestradiol levels on the morning of the expected day of oestrus were higher than normal in animals in which ovulation was blocked by pentobarbitone but were below pro-oestrous values. In the anovulatory state induced by exposure to constant light no major increase in plasma LH was detected after 24 days of illumination or after 3 months exposure. Animals rendered anovulatory by injection of testosterone propionate on the 4th day of postnatal life had low plasma LH levels as adults. All three groups had a low pituitary LH content. The animals exposed to long-term light and those treated with androgen generally had plasma oestradiol concentrations below the peak levels seen on the morning of pro-oestrus in the normal cycle.
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Search for other papers by F. NAFTOLIN in
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SUMMARY
Plasma luteinizing hormone (LH) concentrations were already lower on Day 2 of pregnancy than at the same time after the preceding ovulation in the non-pregnant rat, and fell progressively up to Day 16 of pregnancy. No evidence was obtained of any increase at the time when the ovulatory surge of LH would have occurred if the animal had not become pregnant. Pituitary LH concentration was lower in mated rats on the morning of Day 0 of pregnancy than in unmated controls on the morning of the day of oestrus. Subsequently it increased slowly to reach a level higher than at any stage of the oestrous cycle by Day 8 of pregnancy and remained high until at least Day 16 of pregnancy. Peripheral plasma oestradiol concentration increased late on Day 2 of pregnancy and was still raised on Day 4 but was never more than about one fourth of the peak concentration seen on the morning of prooestrus during the oestrous cycle. There were similar changes in plasma LH and oestradiol concentrations in the 48 h after a single injection of 2·5mg progesterone on the morning of the day of dioestrus, a procedure that delays ovulation by 1 or 2 days. Administration of a synthetic progestational compound (medroxyprogesterone acetate) to pregnant rats delayed blastocyst implantation and the delay was associated with a marked decrease in peripheral plasma LH to levels below those of normal pregnancy.
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Search for other papers by F. NAFTOLIN in
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Search for other papers by K. BROWN-GRANT in
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SUMMARY
The changes in plasma luteinizing hormone (LH) concentration during the first few days after ovariectomy in the rat differ according to the stage of the cycle at which the operation is performed. When carried out at oestrus there was no increase in LH concentration in the first 4 days. After operation at metoestrus the concentration was increased at 3 days but not earlier. Ovariectomy at dioestrus resulted in an immediate increase after 8 h, a subsequent fall, though not to basal levels, and a fairly steady rise thereafter. Ovariectomy at pro-oestrus produced a very large initial rise in plasma LH which probably represents an accelerated release of the ovulatory surge of LH rather than a specific response to ovariectomy. At 24 h after ovariectomy at pro-oestrus levels were below normal and did not increase again for a further 3 days. In contrast, male rats showed a rapid and sustained rise in plasma LH concentration after castration. It is suggested that the different patterns seen in the female may be related to the time that elapsed since the hypothalamo—pituitary system was exposed to high levels of circulating oestradiol. The changes in plasma LH concentration observed after ovariectomy in neonatally androgen-treated rats, rats in persistent oestrus due to exposure to constant light, and rats in early pregnancy are consistent with this hypothesis. Differing responses to the administration of sodium pentobarbitone between male and female rats even 21 days after gonadectomy suggest that there may also be differences in this negative feedback system between the two sexes that are independent of the nature of the gonadal steroid secreted.
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Limbic structures have been implicated in the control of gonadotrophin secretion and sexual behaviour in immature and mature animals and human beings (Schreiner & Kling, 1956; Critchlow & Elwers Bar-Sela, 1967; Velasco & Taleisnik, 1969; Harris & Naftolin, 1970). Although little is known of their cellular metabolism, these areas have been shown to bind radioactivity after the injection of androgens or oestrogens in the intact animal (Pfaff, 1968; Stumpf, Baerwaldt & Sar, 1970). The finding of aromatization of androgens by human foetal hypothalamus (Naftolin, Ryan & Petro, 1971) prompted us to look for the existence of similar enzyme systems in limbic tissues.
Central nervous system tissue was dissected from two 17-week-old (11·5 and 10·5 cm crown-rump length) male foetuses within 30 min of hysterotomy at therapeutic abortions done for psychiatric indications. The pregnancies had been unremarkable and no abnormalities were found in the foetuses. Limbic tissue was sharply dissected utilizing
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Plasma was obtained from adult Wistar rats maintained under 14 h of light and 10 h of darkness and shown by daily vaginal smears to have had two or more cycles of 4 days' duration. Oestradiol-17β concentrations were measured by a micro-modification (Exley, 1969) of the competitive protein binding technique of Corker & Exley (1970). In more than 75% of cases plasma from two rats was pooled (5–7 ml) and duplicate determinations carried out. At concentrations above 10 pg/ml the average variation between duplicates was ±15% of the mean. Below this level, although the mean detectable amount was 6 pg (corresponding to a concentration of about 2 pg/ml) precision was such (average agreement between duplicates ±35%) that values in this range must be regarded as estimates only. Plasma luteinizing hormone (LH) in samples from individual rats was determined by a modification (Naftolin & Corker, 1970) of the radioimmunoassay method of
Search for other papers by J. R. G. CHALLIS in
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McGlll University, Department of Obstetrics and Gynecology, Royal Victoria Hospital, Women's Pavilion, Montreal, Quebec H3A 1A1, Canada
(Received 26 July 1977)
Infusion of prostaglandin E2 (PGE2) into the carotid artery of the foetal lamb increases the concentration of cortisol in the foetal plasma (Louis, Challis, Robinson & Thorburn, 1976) even at stages of pregancy when the foetal adrenal gland is relatively insensitive to endogenous or exogenous adrenocorticotrophin (ACTH; Bassett & Thorburn, 1973; Boddy, Jones, Mantell, Ratcliffe & Robinson, 1974). We have now examined the site of this prostaglandin action in lambs aged 5–6 days, by which time closure of the ductus arteriosus is advanced (see Dawes, 1968), and pulmonary metabolism should separate the effects of prostaglandins administered into the brachiocephalic trunk or descending aorta.
The lambs used in this study were born spontaneously at full term. They were housed with their mothers except during experimental periods. Vascular catheterization with a
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This study describes the presence of a population of oestrogen receptors in cell nuclei from the pituitary gland and brain of untreated and oestradiol-treated ovariectomized rats. The receptors behaved as if they were not occupied by oestradiol. These 'unfilled' oestrogen receptors could be distinguished from occupied nuclear receptor sites on the basis of their ability to bind [3H]oestradiol at low temperatures (0–4 °C). Occupied receptors bound labelled [3H]oestradiol only under exchange conditions at an increased temperature (25 °C). Unfilled and occupied nuclear receptors were physicochemically similar in terms of sedimentation coefficients in sucrose density gradients containing 0·4 m-KC1 (4–5S), equilibrium dissociation constants for reaction with [3H]oestradiol (0·2–0·6 nmol/l) and ligand specificity. In ovariectomized rats, unfilled receptors constituted more than 75 % of the total nuclear receptor population. One hour after i.v. treatment with oestradiol (3·6 μg/kg), both total and unfilled nuclear receptor concentrations increased and then subsequently declined over the next 12 h. The increase in unfilled sites was, however, proportionately less than that occurring in the filled component; at 1 h after oestradiol injection unfilled sites constituted less than 20% of the receptors present in brain and pituitary cell nuclei. The physiological significance of unfilled nuclear oestrogen receptors remains unknown. The observations that they exist in various oestrogen target tissues and that their levels are influenced by oestradiol treatment suggest a possible role for these receptors in the mechanism of oestrogen action.
