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J. Th. J. Uilenbroek


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

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J. E. Sánchez-Criado, J. Th. J. Uilenbroek and B. Karels


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

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J. Th. J. Uilenbroek and R. van der Linden


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

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P. van der Schoot and J. Th. J. Uilenbroek

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.

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J Th J Uilenbroek, P van der Schoot, J A M Mattheij and J J M Swarts


To study the effects of the antiprogestagen RU486 on luteal activity in pseudopregnant rats, adult female rats made pseudopregnant by sterile copulation were given daily injections with oil vehicle or with RU486 (2 mg/day) either during the entire period of pseudopregnancy (day 1 till day 14) or during the second half of pseudopregnancy (day 8 till day 14). Blood was taken every other day to measure serum concentrations of progesterone. At autopsy, on day 15, the weights of ovaries, isolated corpora lutea and pituitary glands were recorded. In a second study using the same experimental protocol, blood was taken via a jugular vein cannula on days 8, 9, 10 and 11 after induction of pseudopregnancy; on each of these days blood samples were taken at 0700, 0800 and 0900 h, and at 1700, 1800 and 1900 h to measure plasma concentrations of prolactin, LH and progesterone.

Administration of RU486 from day 1 of pseudopregnancy onwards had no effect on the increasing concentrations of serum progesterone during the first half of pseudopregnancy. Thereafter progesterone concentrations increased further in RU486-treated rats whereas they decreased in oil-treated pseudopregnant rats. Administration of RU486 from day 8 of pseudopregnancy onwards resulted in a decline in progesterone concentrations in serum on day 10 followed by ovulation on day 11. Plasma LH concentrations in rats treated with RU486 from day 1 of pseudopregnancy were higher than those in oil-treated rats on days 8, 9, 10 and 11. Treatment from day 8 of pseudopregnancy resulted in low LH concentrations at days 8 and 9 and the presence of a preovulatory surge of LH on the afternoon of day 10 (day of pro-oestrus). Plasma concentrations of prolactin measured in oil-treated rats showed two daily surges of similar magnitude in the morning and afternoon of days 8, 9, 10 and 11. In animals treated with RU486 from day 8 onwards, the afternoon surge on day 9 and the morning surge on day 10 were absent. This demonstrated that the luteolytic effect of RU486 when given during the second part of pseudopregnancy is due to a blockade in the afternoon surge of prolactin on day 9. In animals treated with RU486 from day 1 of pseudopregnancy onwards, prolactin in the early morning samples was low, while prolactin in the afternoon samples was highly elevated.

At autopsy on day 15, the weights of ovaries, corpora lutea and pituitary glands in animals treated with RU486 from day 1 were larger than those in oil-treated rats; this is in line with an increased secretion of prolactin. In contrast, in animals treated with RU486 from day 8, pituitary weight was not elevated and the increase in ovarian weight was due to the presence of two generations of corpora lutea.

In conclusion, whether or not RU486 is luteolytic in pseudopregnant rats depends on the time of administration: injection during the second half of pseudopregnancy inhibits prolactin secretion and induces luteolysis, while administration during the early phase of pseudopregnancy results in high concentrations of prolactin in the early afternoon and therefore prevents luteolysis.

Journal of Endocrinology (1995) 145, 449–454

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J. Th. J. UILENBROEK and J. J. van der WERFF ten BOSCH


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.

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J. Th. J. Uilenbroek, P. J. A. Woutersen and R. van der Linden

To determine changes in steroidogenesis by rat ovaries during sexual maturation, ovaries obtained at various ages (days 10–35) and at the first pro-oestrus were incubated in the absence or presence of LH and the accumulation of steroids in the medium was measured.

Basal and LH-stimulated oestradiol-17β and testosterone release into the medium, expressed in pmol/4 h per mg ovary, was high at day 10 of age and at first pro-oestrus. Between days 20 and 35 basal oestradiol and testosterone release was low and could not be stimulated by LH. Addition of testosterone to the culture medium increased oestradiol production at all ages studied. Release of progesterone occurred at all ages even in LH-free medium. Incubation in the presence of LH resulted in a dose-dependent increase in progesterone with a maximal response at pro-oestrus. Androsterone and 5α-androstane-3α,17β-diol production in the absence or presence of LH was high during the entire prepuberal period. Production of 5α-reduced androgens in response to LH increased from days 10 to 20 but decreased thereafter. Similarly, 5α-reductase activity, measured in ovarian homogenates, increased from days 10 to 20 but was decreased again by first pro-oestrus. A further decrease in basal and LH-stimulated 5α-reduced androgen production occurred after first ovulation.

These results demonstrated age-related changes in steroid release after in-vitro incubation. At day 10 progesterone can be converted to aromatizable androgens allowing production of oestrogens, while after day 10 progesterone is converted to 5α-reduced C19 steroids. The decrease in 5α-reductase activity correlates with an increase in LH-stimulated testosterone and oestradiol production at the first pro-oestrus.

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In immature female rats, low values for concentrations of plasma progesterone were generally found from days 6–15 and from days 25–32 of life. Maximum progesterone concentrations (13·0–14·1 ng/ml), comparable to metoestrous values in the adult rat, occurred on days 20–22. The progesterone appeared to be of ovarian origin since after ovariectomy, on day 18, low progesterone concentrations were found 1 and 2 days later (2·5 ng/ml and 1·3 ng/ml) as compared with control values of 10·7 ng/ml and 14·1 ng/ml. However, adrenalectomy also lowered progesterone concentrations, 1 and 2 days later (6·4 and 4·9 ng/ml).

The effect of progesterone, either alone or in combination with oestradiol benzoate (OB), on serum gonadotrophins was studied in rats ovariectomized on day 18. The highest dose of progesterone (0·15 mg) only slightly diminished the rise in serum luteinizing hormone (LH) after ovariectomy and had no effect on serum follicle-stimulating hormone (FSH).

Oestradiol benzoate in a dose of 0·025 μg/100 g body weight was highly effective in preventing the rise in both LH and FSH concentrations, and OB treatment (resulting in a near-physiological oestradiol concentration) combined with progesterone treatment was more effective than treatment with OB alone.

The results suggest that the amounts of progesterone and oestradiol present in the 20-day-old rat are adequate to cause the decrease in FSH level normally observed in immature female rats around this age.

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P. van der Schoot, J. Th. J. Uilenbroek and E. J. Slappendel


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

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J. Th. J. Uilenbroek, P. J. A. Woutersen and P. D. M. van der Vaart


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