Effect of the progesterone antagonist mifepristone on the hypothalamo-hypophysial-ovarian axis in rats

1990 ◽  
Vol 124 (3) ◽  
pp. 425-432 ◽  
Author(s):  
P. van der Schoot ◽  
J. Th. J. Uilenbroek ◽  
E. J. Slappendel
Keyword(s):  
Combined Treatment ◽  
Prolactin Secretion ◽  
Additional Treatment ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Corpora Lutea ◽  
Exogenous Oestrogen ◽  
Steroid Sensitive ◽  
Pituitary Enlargement ◽  
Progesterone Antagonist

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

EVIDENCE OF ANTAGONISM BETWEEN PROLACTIN AND GONADOTROPHIN SECRETION: EFFECT OF METHALLIBURE ON PERPHENAZINE-INDUCED PROLACTIN SECRETION IN OVARIECTOMIZED RATS

1971 ◽  
Vol 51 (4) ◽  
pp. 719-725 ◽  
Author(s):  
M. BEN-DAVID ◽  
A. DANON ◽  
F. G. SULMAN
Keyword(s):  
Combined Treatment ◽  
Virgin Female ◽  
Prolactin Secretion ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Serum Prolactin ◽  
Pituitary Cells ◽  
Similar Treatment ◽  
Gonadotrophin Secretion ◽  
High Doses

SUMMARY Perphenazine has previously been shown to stimulate prolactin secretion in intact and to a lesser degree in ovariectomized virgin female rats. The question whether the oversecretion of gonadotrophins (follicle-stimulating hormone and luteinizing hormone) occurring in ovariectomized animals interferes with the ability of the pituitary cells to secrete prolactin was investigated in sham-operated and ovariectomized rats after separate and combined treatment with methallibure (ICI-33828, a non-steroidal gonadotrophin suppressor) and perphenazine which served as a prolactin releaser. Pituitary and serum prolactin were measured simultaneously by radioimmunoassay. Serum prolactin detected at the end of 5 days' treatment with perphenazine (5 mg/kg/day, s.c.) was found to be increased (81 ng/ml) compared with controls (29 ng/ml). Similar treatment given to ovariectomized animals increased serum prolactin levels from 13·7 ng/ml to only 27 ng/ml. Although high doses of methallibure alone (20 mg/kg/day, s.c.) given to ovariectomized rats for 17 days restored prolactin secretion to the levels occurring in intact non-treated animals, a dose of 10 mg was ineffective. However, when 10 mg methallibure were given to perphenazine-treated ovariectomized rats, serum prolactin rose again to 80·1 ng/ml. These results provide substantial evidence that, when the pituitary is secreting high amounts of gonadotrophin, its prolactin secretion is reduced and its ability to secrete prolactin after perphenazine challenge is limited. Once the gonadotrophic oversecretion is suppressed, more prolactin is secreted and the pituitary can again secrete high amounts of prolactin when challenged by perphenazine. The results show that in rats there exists an antagonism between gonadotrophin and prolactin secretion.

INHIBITION OF PITUITARY PROLACTIN SECRETION BY HUMAN PLACENTAL LACTOGEN IN RATS

1976 ◽  
Vol 71 (1) ◽  
pp. 115-120 ◽  
Author(s):  
HIROSHI NAGASAWA ◽  
REIKO YANAI ◽  
KOREHITO YAMANOUCHI
Keyword(s):  
Prolactin Secretion ◽  
Female Rats ◽  
Placental Lactogen ◽  
Ovariectomized Rats ◽  
Serum Prolactin ◽  
Corpora Lutea ◽  
Human Placental Lactogen ◽  
Vaginal Smears ◽  
Pituitary Prolactin

SUMMARY Intact female rats given twice daily injections of 1 mg human placental lactogen (HPL) showed continued dioestrous vaginal smears and their ovarian corpora lutea were found to be hypertrophied and functional. The serum prolactin level was significantly lower in these rats than in the controls at dioestrus as well as at pro-oestrus. Twice-daily injections of 0·5 or 2 mg HPL to ovariectomized rats decreased serum and pituitary levels of prolactin and increased hypothalamic activity of prolactin inhibiting hormone, although the effect was less at the lower dose. Human placental lactogen had no direct effect on pituitary prolactin secretion in vitro. These findings have demonstrated that HPL, like prolactin itself, inhibits prolactin secretion by acting indirectly on the pituitary through the hypothalamus.

Role of serotoninergic neurones in the control of gonadotrophin and prolactin secretion in the rat

1982 ◽  
Vol 94 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Csilla Ruzsas ◽  
Patrizia Limonta ◽  
L. Martini
Keyword(s):  
Combined Treatment ◽  
Prolactin Secretion ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Serum Prolactin ◽  
Intact Male ◽  
Prolactin Release ◽  
Lh Secretion ◽  
The Brain

The role of brain serotonin (5-hydroxytryptamine, 5-HT) in the control of LH, FSH and prolactin secretion was studied in two groups of experimental animals: intact adult male rats and ovariectomized adult female rats. 5-Hydroxytryptophan (5-HTP), a precursor of serotonin synthesis, and fluoxetine, a specific inhibitor of 5-HT uptake, were given either alone or together. 5-Hydroxytryptophan (50 mg/kg) was administered intraperitoneally and fluoxetine (20 μg/rat) was given into one of the lateral ventricles of the brain. Neither 5-HTP nor fluoxetine given alone affected LH secretion but combined treatment with the two drugs elicited a significant increase in serum LH levels in both intact male and ovariectomized female rats. Fluoxetine and 5-HTP, alone or together, did not modify FSH secretion in either kind of animal. In intact males and in ovariectomized females, 5-HTP induced a significant increase in prolactin release; fluoxetine alone was ineffective. In male animals treated with fluoxetine plus 5-HTP, serum prolactin levels increased but such an increase was lower than that found in the animals treated only with 5-HTP. In ovariectomized rats, the combined treatment induced an increase in serum prolactin levels similar to that found in animals treated with 5-HTP alone. These data suggested that brain serotonin exerts a stimulating effect on LH secretion in both intact male and ovariectomized rats, but that it does not play any role in the control of FSH release in either kind of animal and that central serotoninergic pathways participate in the stimulating control of prolactin release from the anterior pituitary gland. However, some of the data also suggested the possibility of the existence in the brain of serotoninergic systems inhibiting prolactin secretion.

Indomethacin treatment prevents prolactin-induced luteolysis in the rat

1987 ◽  
Vol 112 (2) ◽  
pp. 317-322 ◽  
Author(s):  
J. E. Sánchez-Criado ◽  
K. Ochiai ◽  
I. Rothchild
Keyword(s):  
Corpus Luteum ◽  
Left Kidney ◽  
Prolactin Secretion ◽  
Female Rats ◽  
Silicone Elastomer ◽  
Serum Prolactin ◽  
Corpora Lutea ◽  
Synthesis Inhibitor ◽  
Significant Difference ◽  
Indomethacin Treatment

ABSTRACT Adult female rats were hypophysectomized and their pituitary glands autotransplanted beneath the left kidney capsule on day 2 (day 1 was the day of ovulation). In such rats the pituitary secretes prolactin fairly constantly and the corpora lutea secrete progesterone for several months. To induce the luteolytic effect of prolactin the rats were first injected s.c. with 2-bromo-α-ergocryptine (CB-154) on cycle days 12, 13 and 14 (i.e. 10, 11 and 12 days after operation) to depress prolactin secretion, and then with CB-154 vehicle (70% ethanol) daily until cycle day 21, to allow prolactin secretion to resume. One ovary was removed from each rat on day 15 and the remaining one on day 22. The mean (± s.e.m.) weight of the corpora lutea on day 15 was 1·46±0·06 mg and 0·98±0·07 mg on day 22 (n = 17). In contrast, rats in which the CB-154 treatment was maintained to day 21 had corpora lutea which weighed 1·31 ±0·09 on day 15 and 1·47 ±0·08 mg on day 22 (n = 15). To investigate whether indomethacin, a prostaglandin synthesis inhibitor, affected the luteolytic action of prolactin, the experiment was repeated, but on day 15 (after the removal of one ovary) the groups in which CB-154 treatment was stopped, as well as the group in which CB-154 treatment was maintained, were each divided into two groups. In one, indomethacin-containing silicone elastomer wafers and, in the other, blank silicone elastomer wafers, were placed within the bursa of the remaining ovary. There were no differences in corpus luteum weight on day 15 among any of these groups and the two groups of the first experiment. There was no significant difference in corpus luteum weight between day 15 and day 22 in any of the six groups except for the two groups treated with the CB-154 vehicle and not with indomethacin. Thus, treatment with indomethacin prevented the fall in corpus luteum weight associated with the discontinuation of CB-154 treatment. Serum prolactin levels fell until day 15 in all rats and remained low in those in which the CB-154 treatment was maintained to day 21, but returned to control values in those treated with vehicle after day 14. Serum progesterone levels fell and remained low in all groups. Indomethacin treatment had no effect on the levels of either serum prolactin or progesterone. We conclude that some of the pharmacological effects of indomethacin are to prevent prolactin-induced luteolysis, and we suggest that prolactin induces rapid regression of the corpus luteum by stimulating intraluteal prostaglandin production or by being necessary for the effect of luteolytic prostaglandins. J. Endocr. (1987) 112, 317–322

REDUCTIVE PATHWAYS OF PROGESTERONE METABOLISM IN THE RAT OVARY

1972 ◽  
Vol 69 (1) ◽  
pp. 141-152 ◽  
Author(s):  
A. Zmigrod ◽  
H. R. Lindner ◽  
S. A. Lamprecht
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Prolactin Secretion ◽  
Ovariectomized Rats ◽  
Corpora Lutea ◽  
Microsomal Preparation ◽  
Progesterone Metabolism ◽  
Rat Ovary ◽  
Reducing Activity ◽  
Pituitary Prolactin

ABSTRACT Progesterone underwent extensive reductive metabolism when incubated with a microsomal preparation from rat ovaries in the presence of NADPH. The major products formed were 3β-hydroxy-5α-pregnan-20-one, 5α-pregnane-3,20-dione and 5α-pregnane-3β,20α-diol. Newly formed corpora lutea of pregnancy were almost devoid of any microsomal A-ring reducing activity (5α-reductase and a 3β-hydroxysteroid dehydrogenase) and of soluble 20α-hydroxysteroid dehydrogenase. The behaviour of the A-ring reducing enzymes paralleled that of 20α-ol dehydrogenase in that their activity (i) was high during the oestrous cycle; (ii) declined between the third and seventh day of pregnancy; and (iii) increased sharply in corpora lutea of pregnancy when ergocornine – a drug blocking pituitary prolactin secretion – was given to the rats, yet remained low when prolactin and ergocornine were administered concurrently. However, the A-ring reducing activity did not show the sharp pre-partum rise exhibited by 20α-ol dehydrogenase, thus deviating from a pattern compatible with a co-ordinate control of the three enzymes involved in the metabolic inactivation of progesterone. Contrary to a report in the literature, 5α-pregnane-3,20-dione (20 mg/rat/day) was found to be ineffective when tested for pregnancy or deciduoma supporting activity in ovariectomized rats. The microsomal reductases, if indeed operative in vivo, may restrict the availability of progesterone as an oestrogen precursor.

THE CORPUS LUTEUM-HYPOPHYSIS RELATIONSHIP: THE EFFECT OF PROGESTERONE TREATMENT ON THE RELEASE OF GONADOTROPHINS IN THE RAT

1966 ◽  
Vol 51 (2) ◽  
pp. 231-244 ◽  
Author(s):  
Andrew B. Kaufman ◽  
I. Rothchild
Keyword(s):  
Female Rats ◽  
Ovariectomized Rats ◽  
Corpora Lutea ◽  
Follicle Development ◽  
Significant Elevation ◽  
Once Daily ◽  
Progesterone Treatment ◽  
Gonadotrophin Secretion ◽  
Pituitary Glands ◽  
Weight Method

ABSTRACT The effect of progesterone on pituitary gonadotrophin release has been studied in the rat. Castrated female rats bearing ovarian autotransplants, or unilaterally ovariectomized rats, were given 1 to 5 mg of progesterone daily for intervals from 7 to 28 days, and then killed. The ovaries, uteri, and vaginas were examined grossly and microscopically, and the pituitary glands were assayed for total gonadotrophin content by the mouse uterine weight method. Although treatment with 5 mg of progesterone for 28 days inhibited ovulation, it did not prevent Graafian follicle development (determined histologically) or secretory function (evaluated by the presence of vaginal mucification) in either of the animal preparations. Progesterone treatment was associated with a significant elevation of pituitary gonadotrophic potency in the castrated rats bearing ovarian autotransplants, but not in the unilaterally ovariectomized rats. These findings suggest that the tonic rate of gonadotrophin secretion is unaffected by treatment with 5 mg of progesterone daily. The acute discharge of the ovulation inducing hormone complex (probably primarily LH) is, however, inhibited by such a dose of progesterone, and probably accounts for the inhibition of ovulation. The findings also suggest that the amount of progesterone secreted by the functioning corpora lutea during pseudopregnancy in the rat is equivalent in effect to between 2 and 5 mg of progesterone injected once daily.

Luteolytic and antiluteolytic effect of the antiprogestagen RU486 in pseudopregnant rats

1995 ◽  
Vol 145 (3) ◽  
pp. 449-454 ◽  
Author(s):  
J Th J Uilenbroek ◽  
P van der Schoot ◽  
J A M Mattheij ◽  
J J M Swarts
Keyword(s):  
Plasma Concentrations ◽  
Early Morning ◽  
Prolactin Secretion ◽  
Female Rats ◽  
Corpora Lutea ◽  
Serum Progesterone ◽  
Early Afternoon ◽  
Two Generations ◽  
Pituitary Glands ◽  
High Concentrations

Abstract 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

ROLE OF OESTROGENS AND GONADOTROPHINS IN PERPHENAZINE-INDUCED MAMMOGENESIS

1970 ◽  
Vol 48 (3) ◽  
pp. 365-371 ◽  
Author(s):  
A. DANON ◽  
C. P. WELLER ◽  
F. G. SULMAN
Keyword(s):  
Median Eminence ◽  
Mammary Glands ◽  
Prolactin Secretion ◽  
Female Rats ◽  
Male Rats ◽  
Ovariectomized Rats ◽  
Gonadotrophin Secretion

SUMMARY Treatment of intact or recently (1 day) ovariectomized female rats with 5 mg perphenazine (Trilafon)/kg/day for 5 days resulted in marked lobulo—alveolar differentiation of the mammary glands. Perphenazine failed to stimulate mammogenesis in chronically (12 days) ovariectomized rats, unless they had been primed with oestradiol. However, mammogenic effects in chronically ovariectomized rats were obtained after implantation of minute amounts (2 μg) of oestradiol into the median eminence, or after treatment for 16 days with the non-steroid pituitary gonadotrophin-inhibitor methallibure (ICI 33828; 20 mg/kg/day). Since these latter procedures counteract the gonadotrophin surge after ovariectomy, it would appear that inhibition of gonadotrophin secretion is necessary before prolactin secretion can be stimulated by perphenazine. Castrated male rats responded to perphenazine with lobulo—alveolar differentiation similar to that in intact males. The implications of this difference with regard to the mechanism of pituitary response to gonadectomy are discussed.

Regulation of luteal activity in adult female rats treated neonatally with testosterone propionate

1983 ◽  
Vol 96 (3) ◽  
pp. 417-425 ◽  
Author(s):  
P. van der Schoot ◽  
W. J. de Greef
Keyword(s):  
Plasma Levels ◽  
Testosterone Propionate ◽  
Prolactin Secretion ◽  
Human Chorionic Gonadotrophin ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Normal Female ◽  
Female Rat ◽  
Lower Plasma ◽  
Decidual Tissue

The present study was concerned with the control of luteal activity in female rats which had been treated neonatally with 1·25 mg testosterone propionate (TP). Treatment of such rats in adulthood with 15 i.u. human chorionic gonadotrophin induced ovulation followed by a period of luteal activity. The two daily surges of prolactin secretion, typical for a period of luteal activity in the normal female rat, were not observed in TP-treated females. Instead, higher basal levels of prolactin were observed in TP-treated females than in normal female rats. Furthermore, uterine traumatization at 5 days after ovulation did not result in the formation of decidual tissue. In intact TP-treated females luteal activity, induced and temporarily sustained by an ectopic pituitary transplant, persisted after removal of the pituitary graft. In contrast, in TP-treated females which had been ovariectomized on day 25 of age and had received an ovarian transplant before induction of the luteal phase, luteal activity ended within a week after removal of the ectopic pituitary gland. Females treated with TP which had been ovariectomized on day 25 of life had lower plasma levels of prolactin and higher levels of dopamine in hypophysial stalk plasma than intact TP-treated females when measured at 4 months of age. Treatment of ovariectomized rats with oestradiol-17β increased levels of prolactin in plasma and lowered levels of dopamine in hypophysial stalk plasma. It is concluded that the control of luteal activity in TP-treated females shows 'male' characteristics. However, the presence of the ovaries in such rats leads to decreased hypothalamic release of dopamine and increased plasma levels of prolactin, probably due to increased oestrogen levels. These increased levels of prolactin are sufficient to maintain luteal activity.

EFFECTS OF PROLACTIN ON PITUITARY-ADRENAL FUNCTION IN INTACT AND OVARIECTOMIZED RATS

1978 ◽  
Vol 88 (4) ◽  
pp. 744-753 ◽  
Author(s):  
Silvia B. Vasquez ◽  
Julian I. Kitay
Keyword(s):  
Reductase Activity ◽  
Combined Treatment ◽  
Plasma Corticosterone ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Response To Stress ◽  
Adrenal Response ◽  
Secretion Rates

ABSTRACT The influence of prolactin treatment (100 μg/100 g body wt. sc daily for 7 days) on plasma corticosterone levels, adrenal steroid production in vitro and in vivo and pituitary-adrenal responses to stress were studied in intact and castrated female rats. Prolactin enhanced plasma corticosterone levels and corticosterone production in vitro and in vivo in intact rats after stress. Differences were abolished with ACTH treatment. In contrast, prolactin administration to ovariectomized rats inhibited plasma corticosterone response to stress. Combined treatment with ACTH reversed these findings. A greater in vitro production of corticosterone by adrenal slices and adrenal homogenates associated with an effective inhibition of adrenal 5α-reductase activity were also observed. Secretion of DHB in adrenal venous blood was decreased as well, without changes in corticosterone or THB secretion rates. However, combined treatment with prolactin and ACTH produced greater increments in secretion rates of corticosterone than those obtained with prolactin alone. The data suggest that prolactin treatment to ovariectomized rats has a dual effect: a) adrenal responsiveness to ACTH is enhanced by its effects on adrenal 5α-reductase activity, and b) pituitary-adrenal response to stress is dampered by prolactin treatment. The effects of prolactin on adrenal 5α-reductase activity and corticosterone production in vitro were paralleled in vivo only after the exogenous administration of ACTH. The presence of the gonads apparently prevented the inhibitory effect of prolactin on ACTH secretion and in turn seemed to act synergistically with prolactin to facilitate pituitary-adrenal response to stress.

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