Dual regulation of luteal progesterone production by androstenedione during spontaneous and RU486-induced luteolysis in pregnant rats.

The effect of androstenedione on luteal progesterone production was studied during luteolysis preceding parturition as well as that induced by the antiprogestin RU486 in late pregnant rats. Luteal cells from animals on days 19, 20 or 21 of pregnancy and incubated with 10 microM androstenedione increased progesterone production by 99, 136, and 277%, respectively. The animals receiving androstenedione (10 mg/rat s.c.) on day 19 of pregnancy showed an increase in serum progesterone levels, a decline in luteal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity and an increase in corpus luteum weight without modifying 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD) activity on day 21 of pregnancy. Androstenedione and testosterone but not dihydrotestosterone were able to prevent the decrease in serum progesterone concentration and corpus luteum weight observed 58 h after treatment with RU486 (2 mg/kg) on day 18 of pregnancy. However, the three androgens studied inhibited the luteal 3 beta-HSD activity but 20 alpha-HSD activity was not affected, when compared with animals receiving RU486 alone. The co-administration of androstenedione with the aromatase inhibitor 4-hydroxyandrostenedione or with the specific antioestrogen ICI 164,384 did not modify the effects induced by androstenedione in RU486-treated rats, indicating that the action of androstenedione on progesterone production and secretion at the time of luteolysis seems to occur through an androgenic mechanism and is not mediated by previous conversion of the androgens to oestrogens. In all experiments the high luteal 20 alpha-HSD activity, that characterizes a luteolytic process, was not modified by androgens. Androstenedione administered to adrenalectomized rats was also able to prevent the decrease in serum progesterone concentration observed in spontaneous or RU486-induced luteolysis. The administration of androstenedione to RU486-treated rats induced a decrease in luteal progesterone content concomitant with an increase in serum progesterone levels. These studies demonstrate that androgens during luteolysis, are able to stimulate luteal progesterone secretion, prevent the loss in corpora lutea weight and enhance the decrease in 3 beta-HSD activity, without affecting the increase in 20 alpha-HSD activity.

Androstenedione stimulates progesterone production in corpora lutea of pregnant rats: an effect not mediated by oestrogen.

To determine if androstenedione, an aromatizable androgen, has a direct effect on luteal progesterone secretion, collagenase-dispersed luteal cells or whole corpora lutea from pregnant rats were incubated in the presence of the androgen. Luteal cells from 15-day pregnant rats responded to androstenedione in a dose-dependent manner, with an increase in progesterone output at doses of 1 and 10 microM, but with no effect at minor doses of the androgen. Luteal cells obtained from animals on day 4, 9, 15 or 19 of pregnancy and incubated with 10 microM of androstenedione, increased progesterone production by 243, 39, 84 and 146%, respectively. Androgens (androstenedione, testosterone or dihydrotestosterone) but no oestrogens (oestradiol or diethylstilboestrol) at a dose of 10 microM, stimulated progesterone production in incubated luteal cells obtained from 15-day pregnant rats. The time-course pattern of androstenedione-induced progesterone production was studied by superfusion experiments using corpora lutea from rats on day 15 of pregnancy. A significant progesterone output was observed when androstenedione, but not oestradiol, was perfused through the luteal tissue. Intrabursal ovarian administration of androstenedione (10 microM) to 19-day pregnant rats induced a significative increase in serum progesterone levels 8 and 24 h after treatment. These in vivo results confirm the stimulatory effect of androstendione on progesterone production obtained in incubated luteal cells from pregnant rats. This study reports a direct luteotrophic effect of androstenedione in rat corpus luteum, not mediated by previous conversion to oestrogens.

Levonorgestrel inhibits luteinizing hormone-stimulated progesterone production in rat luteal cells.

The effects of the synthetic progestin levonorgestrel (LNG) on basal and LH-stimulated progesterone production were studied in collagenase-dispersed luteal cells obtained from 9-day pregnant rats. Luteal cells responded to ovine LH (oLH) with an increase in progesterone output which was maximal at a dose of 100 ng/ml. No effect of LNG was observed at 0.1-10 microM, but at 100 microM, it inhibited basal progesterone production. On the other hand, a dose of 10 microM LNG suppressed the stimulation of progesterone secretion induced by oLH, dibutyryl-cAMP and pregnenolone. It is suggested that the possible mechanism of action of the progestin involves a post-cAMP site and, in some way, may lead to an interference with 3 beta-hydroxysteroid dehydrogenase activity, which catalyzes the formation of progesterone from pregnenolone, the last step of progesterone biosynthesis. This study provides a different point of view supporting an autocrine control mechanism by which progesterone, the principal steroidogenic product of luteal cells, may exert a negative ultra-short loop regulation of its own biosynthesis.

Suckling-induced prolactin release potentiates mifepristone-induced lactogenesis in pregnant rats.

Suckling, starting at 19:00 h on Day 18 of pregnancy, induced a significant increase in serum prolactin concentration at 20:00 h on Day 19 of pregnancy, but no increase in mammary gland casein or lactose content. Mifepristone (2 mg/kg) injection at 08:00 h on Day 19 of pregnancy induced significant increases in casein, but not in lactose, 24 h after administration. Mifepristone alone did not induce prolactin secretion, indicating that lactogenesis was induced by placental lactogen in the absence of progesterone action. When mifepristone was injected into suckling rats, serum prolactin concentrations were higher than in the untreated suckling rats. Casein in these rats increased significantly 12 h after mifepristone administration and lactose at 24 h after. If the suckling mifepristone-treated rats were given two injections of bromocriptine (1.5 mg/kg) at 12:00 h on Days 18 and 19 of pregnancy, serum prolactin concentrations were not increased by suckling, but casein and lactose concentrations in the mammary gland showed values similar to those obtained in the mifepristone-treated non-suckling rats. Mifepristone can therefore potentiate suckling-induced prolactin release in pregnant rats, demonstrating a direct central inhibitory action of progesterone on prolactin secretion. This suckling-induced prolactin secretion, unable to induce casein or lactose synthesis in the presence of progesterone, enhanced significantly synthesis of these milk components in the absence of progesterone action (rats treated with mifepristone). Fatty acid synthase, which is stimulated by the suckling stimulus in lactating rats, was not modified by mifepristone or suckling in pregnant rats.