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R. P. CRAVEN
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P. G. McDONALD
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SUMMARY

Cyclic female rats were treated with reserpine (5 mg/kg) on the 2nd day of dioestrus (15.00 h) or on the day of pro-oestrus (11.30 h) to produce a total or partial depletion of brain amines. Ovulation was inhibited in 18 out of 21 rats. Intrahypothalamic infusions of 0·4–80 μg dopamine or noradrenaline on the afternoon of pro-oestrus did not restore ovulation in reserpine-treated rats. In normal pro-oestrous rats, 80 μg dopamine significantly inhibited ovulation, whereas 80 μg noradrenaline had no significant effect. Electrochemical stimulation of the basal hypothalamus or the administration of luteinizing hormone induced ovulation only in those animals treated with reserpine at pro-oestrus. The results indicate that reserpine exerts a marked peripheral effect when given on the 2nd day of dioestrus and has a partial effect on the ovaries when administered at pro-oestrus. The failure of monoamines to induce ovulation suggests that some aminergic synapses involved in gonadotrophin release may lie outside the medial basal hypothalamus. In addition, high levels of dopamine appear to exert an inhibitory action on the release of pituitary gonadotrophins.

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P. G. McDONALD
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D. P. GILMORE
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SUMMARY

In the majority of normal cycling female rats, a single injection of norethisterone (0·5 mg.) delayed ovulation by 24 hr. The number of animals showing delayed ovulation was dependent upon the stage of the cycle and the time of day at which the steroid was given. Injection on day 1 (oestrus) and day 3 (dioestrus 2) was most effective (80% delay) followed by day 2 (dioestrus 1, 50% delay) and day 4 (pro-oestrus, 0% delay). Oestradiol benzoate (5 μg.) given to norethisterone-treated rats on day 3 largely overcame the delaying action of the steroid. Similarly the injection of progesterone (1 mg.) on day 4 advanced ovulation by 24 hr. in most of the norethisterone-treated rats. It is suggested that norethisterone exerts its effects at both pituitary and hypothalamic levels.

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P. G. McDONALD
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D. P. GILMORE
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SUMMARY

Electrochemical stimulation of the basal and preoptic hypothalamus, under sodium pentobarbitone anaesthesia, was carried out on the day of pro-oestrus in normal cycling and in ovarian hormone-treated female rats. Control rats ovulated in response to 25, 50 and 100 μA for 60 s in the median eminence and to 10 μA for 60 s in the preoptic area. Oestradiol (1 μg) given 24 h before median eminence stimulation significantly increased the number of rats ovulating. An injection of progesterone (1 mg) 24 h before median eminence stimulation did not affect the number of animals ovulating or the number of ova shed. In contrast, there was a significant reduction in the number of animals ovulating after preoptic stimulation. Stimulation of the median eminence 2–4 h after progesterone administration increased the number of animals ovulating. The results suggest that both oestradiol and progesterone exert a positive feedback effect at or below the level of the median eminence and that the negative feedback effect of progesterone is exerted on the preoptic area.

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P. G. McDONALD
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CYNTHIA DOUGHTY
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Treatment of female rats with testosterone propionate (TP) during the first few days of life induces an anovulatory syndrome which is accompanied by constant vaginal cornification in the adult animal (Barraclough, 1961; Gorski, 1971). Several recent studies have shown that the ring A reduced metabolites of testosterone do not produce sterilization in the female rat (Brown-Grant, Munck, Naftolin & Sherwood, 1971; McDonald & Doughty, 1972). The fact that these compounds cannot be converted to oestrogenic metabolites suggests that aromatization of testosterone could be involved in androgen sterilization. This preliminary report describes the effects of the antioestrogen MER 25 administered to neonatal testosterone-treated female rats.

Female rats were treated on day 5 of life (day of birth = day 1) with either oil, 30 μg TP, 100 or 500 μg MER 25; 100 μg MER 25 plus 30 μg TP given at the same time, or 500 μg MER 25 plus 30

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CATHERINE A. WILSON
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P. G. McDONALD
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SUMMARY

Serotonin (5HT, 100 mg/kg) given subcutaneously between 16.00 and 18.00 h on the day of pro-oestrus, at 17.00 h on day 2 of dioestrus and at 13.00 and 17.00 h on day 1 of dioestrus, inhibited ovulation in adult rats. It was ineffective at 13.00 h on the day of pro-oestrus and on day 2 of dioestrus. The anti-ovulatory effect at 17.00 h during pro-oestrus was reversed by pretreatment with 2–4 mg progesterone or 2·5 mg dipyridamole/kg. The effect at 17.00 h on day 2 of dioestrus was reversed by 2 μg oestradiol benzoate. Subcutaneous injection of 5HT antagonized the ovulatory action of exogenous luteinizing hormone and inhibited the passage of 22Na into ovary, uterus and muscle but not the pituitary. Intraventricular administration of 5HT (200 μg/rat) between 13.00 and 18.00 h during pro-oestrus had no effect on ovulation. These results suggest that subcutaneous administration of 5HT does not inhibit ovulation at a central site, but acts as a peripheral vasoconstrictor preventing the passage of hormones to their target organs.

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P. G. McDONALD
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CYNTHIA DOUGHTY
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SUMMARY

Groups of neonatal female rats were treated once daily for the first 5 days of life with oil, 1 μg testosterone propionate, or 10 μg of one of the following androgens; androstenedione-enol-propionate, 19-hydroxytestosterone propionate, 5α-dihydrotestosterone propionate, 5α-androstanedioneenol-propionate, androsterone propionate, 5α,3α-androstenediol dipropionate, 5α,3β-androstanediol dipropionate. A final group was given 100 μg 5α,3β-androstanediol dipropionate as a single injection on day 1 of life. Only those androgens which are aromatizable were effective in preventing cyclicity whilst the 5α-reduced androgens were ineffective or only partially effective. All treatments significantly increased the ano-genital distance compared with oil-treated control animals. There were no clear relationships between aromatization and the effects on suppressing sexual behaviour after oestrogen and progesterone treatment. The results are discussed in terms of the role of aromatization in the hormonal control of hypothalamic differentiation.

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ROLAND BILLARD
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P. G. McDONALD
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SUMMARY

In order to determine the sites at which oestradiol exerts its positive feed back effect, double-walled cannulae containing the antioestrogen ICI 46,474 were implanted into the preoptic area, median eminence or anterior pituitary. Implants were made at different stages of the cycle and left in place for between 4 and 96 h. Implants in the preoptic area for 24, 48 or 96 h did not significantly inhibit ovulation. Implants placed in the median eminence for 24 h before the critical period significantly inhibited ovulation when compared with controls (P < 0·02). Implantation of antioestrogen in the anterior pituitary for a similar 24-h period was ineffective in blocking ovulation. However, when mixed with cocoa butter and implanted in the anterior pituitary the antioestrogen significantly inhibited ovulation (P < 0·02). The results show that by preventing the action of oestradiol on either the pituitary or the median eminence, ovulation may be inhibited. Ovulation was not affected by implants in the preoptic region which suggests that this area is not involved in the positive feedback action of oestradiol.

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C. BEYER
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N. VIDAL
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P. G. McDONALD
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SUMMARY

The effect of progestins on mating and pseudomale behaviour was studied in ovariectomized rabbits receiving 0·5 μg. oestradiol benzoate twice daily. Single injections of 0·5, 1·0 and 2·0 mg. progesterone resulted in a 50, 75 and 100% inhibition of mating behaviour respectively. In all groups maximum inhibition occurred 24 hr. after progesterone treatment. Pseudomale behaviour was also inhibited by progesterone but the response was more variable. Single injections of 8 or 20 mg. 20α-hydroxypregn-4-en-3-one did not produce a significant inhibition of either mating or pseudomale behaviour. The physiological role of these hormones in regulating sexual behaviour is discussed.

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CYNTHIA DOUGHTY
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JANET E. BOOTH
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P. G. McDONALD
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R. F. PARROTT
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SUMMARY

Groups of neonatal female rats were treated for the first 5 days of life with oestradiol-17β, oestradiol benzoate or a synthetic oestrogen, 11β-methoxy-17-ethynyl-1,3,5(10)-oestratriene-3,17β-diol (RU 2858), in daily doses ranging from 0·5 to 1000 ng. Oestradiol-17β had no effect on adult ovarian cyclicity or sexual receptivity after ovariectomy and oestrogen + progesterone treatment. Ovarian cyclicity was prevented by 100 ng or more oestradiol benzoate/day, and by all doses of RU 2858. Only rats receiving 50 ng oestradiol benzoate/ day or 0·5 ng RU 2858/day showed normal receptivity. The defeminizing action of RU 2858 was at least 100 times greater than that of oestradiol benzoate; it is suggested that this greater potency is due to the low affinity of RU 2858 for the oestradiol-binding protein in the plasma of neonatal rats. These results indicate that defeminization of the neonatal rat brain can be induced by physiological amounts of oestrogen, and are discussed with reference to the action of testosterone.

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CYNTHIA DOUGHTY
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JANET E. BOOTH
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P. G. McDONALD
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R. F. PARROTT
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Department of Physiology, The Royal Veterinary College, Royal College Street, London, NW1 OTU

(Received 24 March 1975)

Neonatal treatment of female rats with testosterone will prevent the cyclic pattern of gonadotrophin secretion and sexual receptivity in adulthood (Barraclough, 1961). This effect probably depends on the production of small amounts of oestrogen from testosterone in the brain (Reddy, Naftolin & Ryan, 1974) since non-aromatizable androgens do not have this effect (McDonald & Doughty, 1974). Antagonism of testosterone-induced masculinization by the anti-oestrogen MER-25 (ethamoxytriphetol; McDonald & Doughty, 1973/74; Doughty & McDonald, 1974) supports this hypothesis. Neonatal treatment with very low doses of the synthetic oestrogen RU 2858 (11β-methoxy-17-ethynyl-1,3,5,(10)-oestratriene-3,17β-diol) will also defeminize the female brain (Doughty, Booth, McDonald & Parrott, 1975). The object of this study was to prevent defeminization, induced by neonatal treatment with RU 2858, with the anti-oestrogen MER-25.

Starting within 24 h of birth (day 1) and continuing for 5

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