ABSTRACT

Administration of antiprogestagens (2 mg/day) to female rats for 21 days induces high serum prolactin levels. These levels stimulate luteal progesterone production and an increase in ovarian weight. Compared with RU486 (mifepristone) the increase in prolactin is less after treatment with ZK299 (onapristone), an antiprogestagen with lower antiglucocorticoid activity. To study whether cyclic ovulations occur in rats treated with antiprogestagens, 5-day cyclic rats were given daily injections of RU486 or ZK299 (2 mg) from metoestrus (day 1) to pro-oestrus. This treatment advanced the forthcoming ovulation by 1 day; however, the ovulation rate was low. Injection of 10 IU human chorionic gonadotrophin on the afternoon of pro-oestrus (day 3) increased the ovulation rate, but not to the level found in oil-treated rats.

Serum LH concentrations measured from metoestrus to oestrus at 10.00 and 17.00 h were higher in antiprogestagen- than in oil-treated rats from day 2 (17.00 h) onwards. A low preovulatory LH surge was found in antiprogestagen-treated rats on the after-noon of pro-oestrus (day 3). Ovarian histology at the day of oestrus (day 4) confirmed the presence of a low LH surge as, besides ruptured follicles, unruptured follicles with dispersion of cumulus cells were present. The pro-oestrous surge of prolactin was also advanced by 24 h. The magnitude, however, was not different from that in oil-treated rats at day 4.

In conclusion, daily administration of antiprogestagens to 5-day cyclic rats results in increased basal levels of serum LH and advancement of the preovulatory surge of prolactin and LH by 1 day. The ovulatory response is low due to the low pre-ovulatory surge of LH and to a reduced ability of preovulatory follicles to respond to LH.

Journal of Endocrinology (1991) 129, 423–429

ABSTRACT

The effect of prolactin on follicular oestradiol production was studied in rat ovaries in which luteal tissue was absent. A silicone tube containing progesterone was implanted before first ovulation and removed 14 days later. This resulted in the presence of preovulatory follicles 2 days later and ovulation 60 h after removal of the implant. Prolactin concentrations were raised either by injection of purified prolactin or by implantation of pituitary tissue under the kidney capsule. Injections with 100 or 200 μg prolactin starting at the time of removal of the implant (16.00 h on day 0) had no effect on in-vitro oestradiol production by preovulatory follicles obtained on day 2 (day of pro-oestrus). However, implantation of two pituitary glands under the kidney capsule, 2 weeks before progesterone removal, resulted in significantly lower follicular oestradiol production, although ovulation was not inhibited. Lowering of serum prolactin by injections of bromocriptine resulted in an increased follicular oestradiol production.

These results indicate that, in addition to its well-known luteotrophic effect, prolactin can have a direct inhibitory effect on follicular oestradiol production. This effect might contribute to the reduced fertility seen during hyperprolactinaemia.

J. Endocr. (1984) 102, 245–250

Rats with 5-day ovarian cycles were injected daily with 1 mg bromocriptine. This treatment resulted in a change of cycle length from 5 to 4 days and a rapid increase in ovarian weight. The increase in ovarian weight resulted from the accumulation of large numbers of corpora lutea. Normal numbers of corpora lutea were formed during each cycle but luteal bodies did not disappear subsequently. Luteolysis affected only minor foci of luteal tissue and the majority of luteal tissue remained histologically intact throughout the further period of study. The reduction of cycle length from 5 to 4 days occurred when bromocriptine was administered from the day of ovulation only. If treatment was commenced at a later time during the cycle it was not effective.

Treatment with bromocriptine appeared to affect the concentrations of progesterone in the blood during dioestrus. During treatment the rats showed the pattern characteristic for 4-day cycles: typically, the high concentrations of progesterone on the day after metoestrus remained absent. These data suggest (1) that the latter part of the production of progesterone during dioestrus by 'non-functional corpora lutea' is dependent on prolactin and (2) that prolongation of high progesterone production after metoestrus plays an important role in changing the length of the cycle from 4 to 5 days.

Treatment with bromocriptine did not significantly affect the rate of maturation of follicles destined for the next ovulation. It is possible that follicular maturation is not among the critical variables which determine whether normal ovulatory cycles will last for 4 or 5 days.

ABSTRACT

Treatment of female rats for 3 weeks with the antigestagen 1 1β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(prop-1 -ynyl)-estra-4,9-dien-3-one (mifepristone) results in pituitary and ovarian enlargement. The present study dealt with the possible mechanism(s) of these responses.

Ovarian enlargement appeared to be dependent upon prolactin. In the absence of prolactin, during combined treatment with mifepristone and the dopamine agonist 2-Br-α-ergokryptine, ovarian growth was significantly suppressed. It was unclear why persistent hyperprolactinaemia, due to treatment with mifepristone, resulted in persistence of functionally active corpora lutea despite intermittent ovulation, while persistent hyperprolactinaemia due to ectopic pituitary grafts did not.

Pituitary enlargement appeared to be dependent upon the persistence of ovarian oestrogen secretion during the treatment period. Ovariectomy or lactation fully inhibited this response. Pituitary enlargement and prolactin secretion in ovariectomized rats in response to exogenous oestrogen (injections of oestradiol benzoate) were significantly enhanced by additional treatment with mifepristone. It is concluded that mifepristone facilitates the effect of oestrogen on pituitary lactotrophs, thereby enhancing pituitary growth.

Ovarian enlargement during treatment with mifepristone may be specific for rats due to the luteotrophic action of prolactin in these animals. Pituitary enlargement due to facilitation of oestrogen-induced pituitary growth may become a focus of attention when this or similar antigestagenic drugs are being used for prolonged periods in clinical trials, e.g. for limiting steroid-sensitive tumour growth.

Journal of Endocrinology (1990) 124, 425–432

ABSTRACT

Administration of the antiprogesterone RU486 (2 mg/day) for 14 days to rats with a 5-day reproductive cycle resulted in an increase in both ovarian and pituitary weight in contrast with rats with a 4-day oestrous cycle. Luteal progesterone production decreased earlier in 4-day than in 5-day cyclic rats. Treatment of 5-day cyclic rats with antiprogesterone from the day of metoestrus onwards resulted in the advancement of the preovulatory prolactin surge by 24 h. Progesterone production by the corpus luteum was, however, not affected, indicating that in 5-day cyclic rats the corpora lutea are still functionally active at the time of the preovulatory surge of prolactin. They become, therefore, stimulated both in size and progesterone production. In contrast, the corpora lutea in 4-day cyclic rats are functionally inactive at the time of the preovulatory surge of prolactin, and prolactin acts luteolytically. In conclusion, the advancement of the preovulatory surge of prolactin by 24 h accounts, at least in part, for the increase in ovarian weight in 5-day cyclic rats after treatment with antiprogesterone. The results of these experiments do not agree with a direct effect of the antiprogesterone RU486 on progesterone secretion by the corpus luteum.

Journal of Endocrinology (1992) 132, 115–122

SUMMARY

Ovulation-inducing effects of pregnant mare serum gonadotrophin (PMSG) were studied in immature female rats treated on day 5 (day 1 = day of birth) with oil or with 5 or 1250 μg testosterone propionate (TP). The response of rats treated with 1250 μg TP was negligible regardless of the age of the animals and of the dose of PMSG. The response of rats treated with 5 μg TP to PMSG alone was low (36% of rats, with 2·6 ova/ovulating rat), but could be improved by progesterone administration 2 days after PMSG injection (91% of rats, with 14·5 ova/ovulating rat). At every age and dose of PMSG tested the response of animals treated with 5 μg TP to combined PMSG and progesterone treatment was less than that of control animals.

It is concluded that neonatal TP treatment diminishes the release of endogenous ovulating hormone subsequent to PMSG injection. This effect is dependent on the dose of TP used, but already demonstrable in animals treated with 5 μg TP on day 5, which would have been cyclic and fertile after puberty.

Only for the animals treated with 1250 μg TP could a decreased sensitivity of the ovaries to combined administration of PMSG and human chorionic gonadotrophin be demonstrated.

ABSTRACT

Injection of 1 mg bromocriptine at either 08.00 or 16.00 h on the day of oestrus in rats with 5-day oestrous cycles caused a reduction in the duration of progesterone secretion by the corpus luteum during dioestrous, and a shortening of the ovarian cycle by 1 day. These effects were not present when bromocriptine was injected at 08.00 h on the day of metoestrus. The effect of bromocriptine on progesterone secretion by the corpus luteum was reversed by neutralization of the biological activity of LH at dioestrus by injection of 0·5 ml anti-LH serum at 08.00 h at metoestrus. Injection of the antiserum alone prolonged progesterone secretion by the corpus luteum, but had no effect on the length of dioestrus.

These results are interpreted as suggesting (1) that prolactin secretion on the afternoon of oestrus protects the corpus luteum of the rat ovarian cycle against the luteolytic effects of LH secretion during early dioestrus and (2) that prolactin stimulates progesterone secretion in the absence of such a luteolytic action. This response of the corpus luteum of the rat ovarian reproductive cycle to prolactin results in 5-day oestrous cycles.

J. Endocr. (1988) 117, 455–460

ABSTRACT

Since administration of the antiprogesterone RU486 to cyclic rats results in a dissociation of basal LH and FSH secretion we studied its effects on peripheral levels of inhibin, oestradiol and testosterone throughout the oestrous cycle. Cyclic rats were given RU486 (2 mg) twice daily (09.00 and 17.00 h) on metoestrus, dioestrus and pro-oestrus. Oil-treated rats were used as controls.

Serum concentrations of immunoreactive inhibin in oil-treated rats increased from metoestrus to prooestrus and decreased at oestrus. RU486-treated rats had serum inhibin concentrations significantly increased over oil-treated rats at dioestrus and prooestrus, but not at oestrus. At both pro-oestrus and oestrus serum concentrations of LH, testosterone and oestradiol were significantly raised in RU486-treated rats compared with oil-treated controls. In contrast, serum FSH concentrations in RU486-treated rats were decreased on both days. Ovaries from RU486-treated rats showed an increased testosterone content at pro-oestrus, mainly in the interstitial tissue.

The results of thepresent study demonstrate that RU486 has a stimulatory effect on inhibin secretion, and offer an explanation for the decrease in basal serum FSH levels. The low FSH secretion on the morning of oestrus in spite of the low levels of inhibin suggests that progesterone is involved in FSH secretion at this time.

Journal of Endocrinology (1992) 134, 51–57

ABSTRACT

Corpora lutea could be identified under the dissection microscope up to 7 days after formation. They were isolated during the oestrous cycle and pseudopregnancy and the progesterone and 20α-OH-progesterone contents were compared with serum values of these steroids. The pattern of progesterone in serum resembled that found in the corpora lutea. However, the pattern of 20α-OH-progesterone concentrations in serum and corpora lutea were different. While 20α-OH-progesterone concentrations in the corpora lutea showed large variations during the cycle, changes in serum concentrations of 20α-OH-progesterone were relatively small. Measurement of hormone concentrations in isolated corpora lutea is therefore a sensitive method for studying corpus luteum activity.

To study whether corpora lutea derived after ovulation of immature follicles showed deficient luteal activity, rats at dioestrus (2 days before pro-oestrus) were induced to ovulate by the injection of 10 IU human chorionic gonadotrophin (hCG) and subsequent luteal activity was studied by measuring hormone concentrations in the corpora lutea on day 5 of pseudopregnancy. Concentrations of progesterone, but not of 20α-OH-progesterone, in corpora lutea derived from follicles induced to ovulate at dioestrusday 1 were significantly lower than those in corpora lutea derived from follicles induced to ovulate at prooestrus. This difference was observed not only when pseudopregnancy was induced by cervical stimulation but also when it was induced by implantation of a pituitary gland under the kidney capsule. However, in the latter case, corpora lutea already present on the day of hCG injection also became activated.

The present experiments demonstrate that by measuring hormone concentrations in isolated corpora lutea changes in luteal activity can be studied effectively. Moreover, it appears that corpora lutea derived from immature follicles contained less progesterone than those derived from fully mature follicles.

Journal of Endocrinology (1989) 120, 325–330

The present study was concerned with a possible involvement of LH in the process of functional luteolysis in the pseudopregnant rat.

Daily injections with 2 μg ovine LH during pseudopregnancy reduced peripheral and ovarian levels of progesterone in intact and hysterectomized rats and in hypophysectomized rats with a pituitary transplant under the kidney capsule. However, a daily dose of 10 μg LH did not alter the levels of progesterone. A short-lasting decrease in plasma progesterone occurred when endogenous levels of LH were temporarily raised in pseudopregnant rats by a single injection of LH releasing hormone (LH-RH). Treatment with LH or LH-RH, however, did not shorten the duration of pseudopregnancy.

Daily treatment of pseudopregnant rats with 5 or 20 ng oestradiol benzoate, but not with 1000 ng, decreased plasma levels of progesterone. On the other hand, daily treatment with oestradiol benzoate did not affect plasma progesterone in pseudopregnant rats which were hypophysectomized and had an ectopic pituitary gland. Plasma levels of LH were not increased in the animals receiving 5 or 20 ng oestradiol benzoate daily, suggesting that the effect of oestradiol benzoate on plasma progesterone is not through an enhanced secretion of LH. Treatment with oestradiol benzoate did not affect the duration of pseudopregnancy.

In conclusion, low doses of LH can reduce peripheral levels of progesterone during pseudopregnancy, but it seems improbable that LH is involved in the process of functional luteolysis. Furthermore, low doses of oestradiol benzoate can also decrease plasma progesterone, but the mechanisms involved are still not understood.