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SUMMARY
Ovarian follicles develop to the stage where they are competent to ovulate in response to exogenous gonadotrophin at the same rate during early pregnancy as in a normal 4-day cycle in the rat. The length of time during which this competency is retained appears to be shorter than after the blockade of ovulation by pentobarbitone administered at pro-oestrus in rats that are not pregnant. Evidence from oviduct:plasma (O:P) and uterus:plasma (U:P) 131I ratio measurements indicating high progesterone and low oestrogen levels at this stage of pregnancy may be relevant to this finding. Some evidence for a 3-day cycle of follicle development after day 6 of pregnancy was obtained but the high O:P ratios suggest that little oestrogen secretion is associated with this.
Oestradiol benzoate (6·25–100 μg.) administered after day 3 of pregnancy will induce ovulation when competent follicles are present. The thyroid:plasma (T:P) concentration ratio for 131I does not rise in association with ovulation induced by exogenous gonadotrophin. After oestrogen administration, the T:P ratio may increase regardless of whether ovulation is induced or not. The results are discussed in relation to the studies of other workers on the induction of ovulation during pregnancy and to earlier work on the relationship between ovulation and changes in thyroid gland activity.
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SUMMARY
Changes in the uterus:plasma and oviduct:plasma concentration ratios for radioactive iodide after the administration of progesterone at the dioestrous stage of the oestrous cycle have confirmed that significant oestrogen secretion begins on the afternoon of the day of dioestrus in a 4-day cycle. Progesterone injected at dioestrus delays ovulation and the change to a facilitatory effect on luteinizing hormone (LH) release does not occur until early on the day of pro-oestrus, about 12 hr. after the estimated time at which oestrogen secretion begins.
Pentobarbitone (Nembutal) injected at 13.30 hr. on the day of pro-oestrus blocks ovulation, but does not do so when injected 3 hr. later. When injected at either 13.30 or 16.30 hr. in dioestrus, it delays ovulation and may prevent it completely in that cycle. The injection of Nembutal at dioestrus does not appear to prevent the release of gonadotrophin responsible for oestrogen secretion and the delay of ovulation may be due to interference with some of the normal effects of oestrogen secreted at this stage of the cycle on the hypothalamo-hypophysial system. The delay of ovulation is not prevented by the injection of oestrogen with Nembutal at dioestrus but is prevented by the subsequent injection of progesterone at pro-oestrus.
The results are discussed in relation to other studies on the time of onset of oestrogen secretion in the oestrous cycle and to the change in the response to progesterone injection from inhibition to facilitation of LH release following the period of oestrogen secretion.
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SUMMARY
When oestrogen was administered early in the oestrous cycle of the rat on the day of metoestrus, the inhibitory effect of progesterone injected at dioestrus on ovulation was lost and a facilitatory effect was observed; ovulation was advanced by one day. The advancement of ovulation by oestrogen injected at the dioestrus — 1 stage of a 5-day cycle was confirmed; it was shown that this response could be elicited by as little as 0·13 μg. oestradiol benzoate. These results are discussed in relation to other studies on the time of oestrogen secretion in the normal cycle, the alteration of the response of the pituitary to progesterone injection from an inhibitory to a facilitatory effect by previous exposure to oestrogen, and the mechanism of induction of ovulation by oestrogen in the 5-day cycle and in pregnancy. The relevance of these and similar experiments on the induction of ovulation by ovarian steroids in the rat as a guide to what is occurring during the normal cycle is questioned, principally because when ovulation was induced by these means the changes in the activity of the thyroid gland that are associated with ovulation in the normal cycle were not reproduced.
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SUMMARY
Facilitation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion by progesterone was demonstrated in female rats ovariectomized 1–2 months previously and primed with oestradiol benzoate or testosterone propionate 72 h before the second injection of steroid. The priming action of testosterone propionate may be due to conversion to oestrogen as the non-aromatizable androgen, 5α-dihydrotestosterone propionate, did not have this effect. None of the steroid hormone treatments tested facilitated LH or FSH release in male rats castrated as adults or in female rats rendered anovulatory by the injection of androgen or oestrogen on day 4 of postnatal life. This abnormality may be the functional basis of the anovulatory state in these animals.
Of the progesterone derivatives tested in the oestrogen-primed ovariectomized rat only pregn-4-en-20α-ol-3-one and 5α-pregnane-3,20-dione significantly stimulated gonadotrophin secretion. These compounds, which are secreted by the rat ovary, may be involved, together with progesterone, in the initiation of the ovulatory surge of gonadotrophin during the oestrous cycle.
The time-course of the changes in gonadotrophin release in the oestrogen-primed ovariectomized rat in response to progesterone was determined. An initial depression was followed by an increase which was more marked for LH than for FSH. Although sodium pentobarbitone administration will prevent or reverse progesterone-induced gonadotrophin secretion, no clear correlation could be established between the sequence of changes in gonadotrophin secretion observed in the present study and the changes in hypothalamic neuronal activity reported by others to follow similar treatment with steroid hormones.
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The administration of testosterone propionate (TP) to female rats during the neonatal period results in a failure of ovulation as adults. Oestrogens also have this effect and it is possible that it is oestrogen produced from an androgenic precursor that normally acts upon the brain in the male rat (Brown-Grant, 1973). In support of this idea McDonald & Doughty (1972) found that the antioestrogen MER 25 (MER) could prevent the failure of ovulation that would otherwise have followed the administration of TP. Their rats were only studied up to 110 days of age, however, and it is known that the anovulatory state may develop later (Gorski, 1971). Also, if oestrogen is the active agent, it is difficult to see why an antiandrogen should protect the animals against the effects of TP administration though it has been suggested (Brown-Grant, 1973) that the agent commonly used, cyproterone acetate (CA), might be effective
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Optimal conditions for determining the quantitative effect of a single subcutaneous injection of progesterone in oil on the uterus:plasma concentration ratio for radioactive iodide were found to be measurement of this ratio 24 hr. after the injection of steroid in rats ovariectomized 7–10 days previously. Under these conditions there is a linear regression of response on log dose over the range of 156–2500 μg. progesterone.
Reduction of the 20-ketone group or the 4–5 double bond, introduction of 17α- or 21-hydroxyl groups or of an 11-oxo group into the molecule reduces the activity in this test. Steroids with predominantly glucocorticoid, androgenic or oestrogenic activity do not produce this response. The relative potencies of a variety of synthetic steroids derived from progesterone or 19-nortestosterone have been assessed. The results obtained in this test appear to be more closely related to the ability to maintain pregnancy than are those obtained in the usual assays for progestational activity. It is suggested that the uterus:plasma 131I ratio response could be made the basis of an accurate and potentially useful assay method for steroids with progestational properties.
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The uptake of 131I by the thyroid gland increased 72 hr. after the injection of pregnant mare serum gonadotrophin (PMS) into immature female rats whether ovulation occurred or not. PMS failed to produce this effect in male rats but oestrogen administration increased 131I uptake in both male and female immature rats, suggesting that oestrogen was responsible for the effect of PMS in females. Both PMS and oestrogen may increase the uptake of radioactive phosphate by the thyroid of female but not male rats; oestrogen may stimulate thyroid-stimulating hormone (TSH) secretion in immature female rats. These effects of oestrogen in the female made it impossible to determine whether the 'ovulatory surge' in luteinizing hormone secretion in PMS-treated rats was associated with an increased secretion of TSH or not.
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The activity of the thyroid gland is highest during oestrus in regularly cyclic adult female rats, and it has been suggested (Brown-Grant, 1962) that this may be due to a period of hypothalamic stimulation of pituitary TSH secretion during prooestrus. The release of luteinizing hormone that leads to ovulation can be blocked by a suitably timed injection of 'Nembutal' (sodium pentobarbitone) during the day of prooestrus and if the increase in thyroid activity were also inhibited this would provide additional evidence in favour of this concept.
Rats were kept under the same conditions and the vaginal cycles followed in the same way as in earlier studies (Brown-Grant, 1962). Thyroid activity was measured by determining the 2·5 hr. uptake of 131I by the gland on the morning of the predicted day of oestrus. The occurrence or failure of ovulation was determined by the examination of serial sections of the ovaries.
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The female guinea-pig has a fairly long oestrous cycle of 14–16 days, ovulation occurring spontaneously during the limited period of vaginal opening. Possible changes in thyroid gland activity during the cycle have been investigated.
Adult female guinea-pigs were kept under the conditions previously described (Brown-Grant & Pethes, 1960) except that the Diet 18 pellets (E. Dixon and Sons (Ware), Ltd.) were of a lower iodine content (0·000023%) than those used in the earlier experiments. Animals were examined daily and smears were taken every day between 9 and 10 a.m. during the period of vaginal opening. Smears were stained with haematoxylin and eosin. The smear taken 24 hr. after the maximally cornified smear is characterized by the reappearance of large numbers of leucocytes; this day was taken as day 1 of the cycle, ovulation presumably having occurred within the preceding 24 hr. All animals were followed through at least two cycles
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SUMMARY
Young adult male rabbits were thyroidectomized or treated with methylthiouracil and adrenal weights determined after 3 or 6 weeks. No significant changes were seen following thyroidectomy. After 3 weeks of methylthiouracil treatment the mean absolute weight of the adrenal glands, but not the relative weight, was reduced. After 6 weeks both the absolute and relative weights were increased above the control levels, but the differences were not statistically significant. The results are compared with those obtained by other workers for rabbits and for other species.
