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PubMed1992

Endothelin-1 as a luteinization inhibitor: inhibition of rat granulosa cell progesterone accumulation via selective modulation of key steroidogenic steps affecting both progesterone formation and degradation.

Endothelin (ET)-1, is a 21 amino acid vasoactive peptide subject to regulation by cellular oxygen tension. However, an increasing body of information now suggests that ET-1 is a multifunctional peptidergic regulator the actions of which are not limited to the vascular system. Although ET-1 has been shown to inhibit the gonadotropin-supported accumulation of progesterone by cultured granulosa cells, the precise cellular mechanism(s) involved remain unknown. It was therefore the objective of this study to examine in greater detail the effects of ET-1 on progestin economy in cultured granulosa cells from immature rats. Treatment with ET-1 was inhibitory to the FSH-supported accumulation of progesterone in a dose-dependent manner, an action characterized by a median inhibitory dose of 2 x 10(-11) M and a maximal inhibitory effect of 90%. This inhibitory action of ET-1 was reversible following extensive washing and could not be accounted for by a decrease in the viable cell mass. Evaluation of the activities of progesterone-forming enzymes revealed ET-1 to be a potent (P < 0.01) inhibitor of cholesterol side-chain cleavage and 3 beta-hydroxysteroid dehydrogenase (HSD)/isomerase (76.1 +/- 1.2% and 47.3 +/- 8.6% inhibition, respectively). Cellular radiolabeling with [3H]pregnenolone confirmed an ET-1-induced inhibition of the FSH-supported accumulation of radiolabeled progesterone. However, this effect was concomitant with enhancement of the accumulation of more distal metabolites, i.e. 20 alpha-dihydroprogesterone, 5 alpha-pregnane-3 alpha, 20 alpha-diol, and 5 alpha-pregnane-3 alpha-ol-20-one. Analysis of the FSH-supported activities of the progesterone-degrading enzymes revealed ET-1 as a potent (P < 0.05) stimulator of 20 alpha-HSD and 5 alpha-reductase (3.6 +/- 1.0 and 1.7 +/- 0.3-fold, stimulation respectively). In contrast, no significant changes were observed in 3 alpha-HSD activity. Taken together, our findings demonstrate that the ET-1 induced inhibition of gonadotropin-supported progesterone accumulation constitutes a complex phenomenon wherein ET-1 inhibits the activities of steroidogenic enzymes concerned with progesterone formation while enhancing the activities of enzymes concerned with progesterone degradation. We speculate that ET-1, possibly of intraovarian origin, acts as a luteinization-inhibitor to suppress premature luteinization at a time when continued preovulatory expression of ET-1 (in the intact but not ruptured follicle) may be contingent upon relative intrafollicular hypoxia.

20-alpha-Dihydroprogesterone↗
PubMed1988

Effects of heat stress on serum progesterone in cyclic ewes and on progesterone and cortisol response to ACTH in ovariectomized ewes.

The daily mean of serum progesterone in cyclic ewes (N = 5) as well as the profile characteristics of progesterone and cortisol in response to an acute single dose (5 i.u./kg liveweight 0.75) of adrenocorticotrophic hormone (ACTH) into ovariectomized ewes (N = 4) was investigated during exposure to a constant thermoneutral temperature of 18 +/- 1 degree C or to a daily cyclic heat stress temperature of 18 degrees C-35 degrees C-18 degrees C, in an environmental chamber. Serum collected daily from the cyclic ewes was assayed for progesterone, while serum collected more frequently for 10 h, on the 14th day of exposure to the respective temperature, from the ovariectomized ewes was assayed for progesterone and cortisol by RIAs. In cyclic ewes, heat stress increased the area under the daily progesterone curve (P less than 0.09) but had no effect on progesterone concentration after the regression of the CL. In ovariectomized ewes, ACTH significantly elevated the response of both cortisol and progesterone (r = 0.75, P less than 0.001) within 10-15 min of injection. In the ovariectomized ewes and during heat stress, the responses of progesterone and cortisol to ACTH were characterized by an initial acute rise, a transient drop, a steep elevation and a gradual but prolonged decline. During thermoneutral temperatures, this biphasic response pattern was not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1979

Plasma progesterone, serum estriol and plasma HPL determinations during the last trimester to detect changes before spontaneous labor. Comparison of progesterone assay using RIA and CPB.

Conflicting results have been published regarding changes in plasma progesterone during the last trimester of pregnancy. Some have demonstrated a fall in plasma progesterone before labor, and this has been taken as a possible explanation of the onset of labor. It has been suggested that the various results could be due to differences in methods for progesterone determination. In this study the progesterone levels were determined by both RIA and CPB. In 11 women the plasma progesterone, human placenta lactogen, and serum estriol were measured weekly during the last trimester of normal pregnancies and immediately after delivery. All samples were analysed radioimmunologically. In order to compare the radioimmunoassay and competitive protein binding techniques (RIA and CPB), the progesterone levels were determined by both methods. This was also done for 80 successive plasma progesterone routine samples drawn from women who were not pregnant or who were in the early stages of pregnancy. Both methods showed a significant rise in the plasma progesterone level during the last 6 weeks before spontaneous labor. However, the values obtained were lower when assayed by CPB than by RIA, presumably because of a higher specificity and a cross reaction in RIA. Serum estriol exhibited increasing values throughout pregnancy, but without a significant rise during the last few weeks. Plasma HPL settled at a constant level during the last few weeks before labor.

Estriol↗
PubMed1986

Progesterone in saliva does not parallel unbound progesterone in plasma.

To assess the potential application of salivary progesterone, in light of the voluminous published information on blood progesterone, I compared plasma and salivary progesterone in paired samples and found that they exhibit similar patterns, both having high concentrations in the second half of the cycle. However, the ratio between values for plasma and saliva changed during the cycle. I observed no concomitant changes in binding of progesterone to plasma proteins, which might have been expected if the concentrations in saliva reflect those of non-protein-bound steroid in plasma. There was some binding of progesterone by salivary proteins, but the proportion of progesterone so bound apparently remained constant during the cycle. Data on progesterone in saliva must therefore be interpreted with awareness of the properties of saliva, and not simply as "free" plasma progesterone.

Blood Proteins↗
PubMed1979

Regulation of cytosol and nuclear progesterone receptors in rabbit uterus by estrogen, antiestrogen and progesterone administration.

A synthetic progestin, 16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione (ORG 2058), was utilized to measure progesterone receptors from the rabbit uterus. This steroid has a high affinity for both cytosol and nuclear receptors, with KD values of 1.2 nM (at 0--4 degrees C) and 2.3 nM (at 15 degrees C), respectively. Administration of estradiol-17 beta or a non-steroidal antiestrogen, tamoxifen, for 5 days to estrous rabbits led to a progressive rise in the cytosol receptor levels: from 34,000 to 120,000 (estradiol-17 beta) and 80,000 (tamoxifen) receptors/cell, without any major influence on the nuclear receptor content. A single intravenous injection of progesterone (5 mg/kg) elicited a 3-fold increase in the mean nuclear receptor content at 30 min after injection (from 18,000 to 48,000 receptors/nucleus). Nuclear receptor accumulation was short-lived and returned to control levels within 4 h after treatment. A second dose of progesterone given 24 h later doubled the nuclear receptor level (from 18,000 to 35,000 receptors/nucleus). The concomitant decline in the cytosol receptor content was twice that accounted for by the nuclear receptor accumulation (70,000 vs. 30,000, and 40,000 vs. 17,000 receptors/cell, after the first and second progesterone injection, respectively). Following progesterone administration, the cytosol receptor level reached a nadir by 30 min, exhibited minimal replenishment within the ensuing 24 h, and remained at approx. 50% of the pretreatment values. After a single dose or two consecutive doses of progesterone, total uterine progesterone receptor content declined to about 60% of the level prior to each dose, a nadir being reached at 2 h after treatment.

Animals↗
PubMed1992

Regulation of estrus and ovulation in mares with progesterone or progesterone and estradiol biodegradable microspheres with or without PGF2alpha.

A single injection of a microsphere preparation, designed to deliver 1.25 gm progesterone and 100 mg estradiol-17beta at a controlled rate, for a duration of 12 to 14 days, produces accurate control of estrus and fertile ovulations in mares. Treatment is followed by PGF2alpha injection 14 days after steroid injection. The objectives of the present study were to determine whether estradiol added to the progesterone treatment or PGF2alpha administered at the end of the steroid treatment regimen, would improve synchronization of estrus and ovulation. A total of 45 cyclic horse mares was randomly assigned to 1 of 5 treatment groups as follows: Group 1 (control, n=9) sterile microsphere vehicle+sterile PGF2alpha vehicle 14 days after treatment with microsphere vehicle; Group 2 (n=9) progesterone and estradiol microspheres+PGF2alpha 14 days after treatment with microspheres; Group 3 (n=9) progesterone and estradiol microspheres+PGF2alpha vehicle 14 days after treatment with microspheres; Group 4 (n=9) progesterone + PGF2alpha 14 days after treatment with microspheres; and Group 5 (n=9) progesterone+PGF2alpha vehicle 14 days after treatment with microspheres. Addition of estradiol (P<0.05) or PGF2alpha (P<0.05) to the treatment regimen increased synchronization efficary by reducing variation in days to ovulation. All treatments significantly reduced variation in days to estrus compared with that of the controls; however, mares in the progesterone groups had an increased incidence of silent or shortened estrous behavior ( 2 days in duration compared with mares treated with progesterone (78 vs 33%, respectively). Therefore, estradiol and PGF2alpha each appear to reduce variation in days to ovulation while estradiol seems to promote better expression of posttreatment estrous behavior.

Journal Article↗
PubMed2006

A proposed mechanism for progesterone regulation of trophoblast MMP2 transcription independent of classical progesterone response elements on its promoter.

BACKGROUND: Progesterone receptor act as ligand-inducible transcription factor in the respective target cells by binding to specific progesterone response elements in the promoter of the target genes. However, despite the lack of the classical progesterone response elements on matrix-metalloproteinase-2 promoter, progesterone has been shown to decrease the activity of this promoter. PRESENTATION OF THE HYPOTHESIS: It has recently been suggested that in addition to interacting with their classical co-activators and co-repressors, progesterone receptor are capable of binding to several transcription factors. By interacting with other classes of transcription factors, progesterone receptor is capable of transcriptional activation through the transcription factors cognate DNA binding site. TESTING THE HYPOTHESIS: Exploring transcription factors and transcription binding sites, interacting with the progesterone receptor in modulation of the matrix-metalloproteinase promoter. IMPLICATIONS OF THE HYPOTHESIS: Identification of additional endogenous progesterone target genes makes it possible to further explore the signaling mechanisms by which the hormone regulates biological actions. Furthermore, the concepts of ligand-driven conformational diversity and selective tissue actions can be exploited in the future for drug development which selectively regulate orphan receptors from the nuclear receptor family.

Journal Article↗
PubMed2003

Immunocytochemical detection of progesterone receptor in the female rabbit forebrain: distribution and regulation by oestradiol and progesterone.

There is no information on the neuroanatomical distribution of the progesterone receptor (PR) in the rabbit. Therefore, we mapped the distribution of PR-immunoreactive cells in the forebrain of ovariectomized female rabbits. Vehicle-injected ovariectomized rabbits showed PR-immunoreactive cells only in the infundibular nucleus (IN) and nucleus X (lateral to the ventromedial hypothalamic nucleus). The injection of oestradiol benzoate (EB; 5 micro g/day for 5 days) increased the number of PR-immunoreactive cells in the IN and in three nuclei of the preoptic region (periventricular, medial, and principal). Abundant PR were also found in the paraventricular nucleus and nucleus X. Administration of progesterone (10 mg/day) for 3 days to EB-treated rabbits (a treatment that induces digging behaviour for the maternal nest and suppresses sexual receptivity and scent-marking) eliminated PR-immunoreactivity from all brain areas analysed except the IN. Thus, one-third of the number of cells seen in the ovariectomized + EB condition persisted in this region despite progesterone injections. Withdrawal of progesterone (and continuation of EB) for 5 (but not for 2) days (in a schedule similar to the one that induces straw-carrying and hair-pulling for the maternal nest) increased the number of PR-immunoreactive cells in all regions analysed. These results show that restricted regions of the female rabbit forebrain express abundant PR which are either: (i). up-regulated by oestradiol and down-regulated by progesterone; (ii). oestradiol-insensitive and down-regulated by progesterone; or (iii). insensitive to both oestradiol and progesterone.

Animals↗
PubMed2000

A putative stimulatory role of progesterone acting via progesterone receptors in the steroidogenic cells of the human corpus luteum.

To further explore the proposed auto-regulatory role of progesterone action in the human corpus luteum (CL), the expression and functional roles of progesterone receptor (PR) isoforms A and B during the luteal phase (LP) of the menstrual cycle were investigated. A total of 27 otherwise healthy patients previously scheduled for surgery were recruited after informed consent. An LH rise was detected, and CL were grouped according to age (Days 2-5 post-LH-rise, early LP; Days 6-10, mid LP; Days 11-14, late LP). Using a semiquantitative reverse transcription-polymerase chain reaction assay, the PR-B mRNA levels, which were 100- to 1000-fold lower than PR-A/B mRNA, were 46% lower (P < 0.05, n = 24) in mid LP, compared to early and late LP. CL tissue levels of progesterone and PR-A/B protein levels were inversely correlated to increasing CL age; i.e., significantly reduced levels were observed in the late LP (r(2) = 0.34, P < 0.01, n = 23). Expression of PR-A/B mRNA as well as PR-A/B protein were detected by in situ hybridization and immunohistochemistry, respectively. Both methods revealed a clear and distinct localization to cells in the steroidogenic layer of the CL. Freshly obtained mid-luteal CL cells were cultured in vitro, and media were analyzed for progesterone concentrations after treatment by incremental doses of hCG and the stable PR antagonist mifepristone, alone or in combination. Mifepristone did not per se alter progesterone synthesis, but when it was added in conjunction with hCG, a dose-related inhibitory response was seen, with a maximal 47% reduction in progesterone output at a 10 microM addition (P < 0.05, n = 3). Collectively, these data implicate a stimulatory role of progesterone receptor-mediated action in the steroidogenic cells of the human CL, which may serve as an important pathway for maintaining functional homeostasis during early pregnancy.

Adult↗
PubMed1977

Progesterone receptors in the chick oviduct. Determination of the total concentration of binding sites in the cytosol and nuclear fraction and effect of progesterone on their distribution.

1. Exchange techniques were developed for measurement of total progesterone receptor binding sites concentration in the cytosol and nuclei of chicken oviduct. 2. The level of progesterone receptor in the cytosol was under both oestrogen and progesterone control. Primary stimulation by oestradiol benzoate increased the receptor concentration from approximately 10 000 sites/cell to approximately 40 000 sites/cell in the magnum cytosol; subsequent withdrawal from oestrogen treatment led to a decrease to approximately 14 000 sites/cell after 6 weeks. After progesterone administration (3 mg/kg) to oestrogen-stimulated, withdrawn chicken, the receptor concentration decreased to approximately 40% of the initial level within the first 4 h; afterwards the receptor level rose again and by 40 h exceeded slightly the initial one. 3. The nuclear levels of the receptor reached a maximum at 1 h after the progesterone injection; however, the gain of the binding sites by the nuclei (approximately 900/nucleus) did not account for their loss from the cytosol. The maximum nuclear receptor level was not influenced by the dose of progesterone within range of 1-10 mg/kg. 4. The extractibility of the nuclear progesterone receptor by 0.5 M NaCl was strongly influenced by preincubation of the nuclei at 30 degrees C; irrespective of this preincubation, approximately 12% of the nuclear receptor resisted extraction with 2 M NaCl/5 M urea.

Animals↗
PubMed2000

Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform.

Progesterone regulates reproductive function through two intracellular receptors, progesterone receptor-A (PR-A) and progesterone receptor-B (PR-B), that arise from a single gene and function as transcriptional regulators of progesterone-responsive genes. Although in vitro studies show that PR isoforms can display different transcriptional regulatory activities, their physiological significance is unknown. By selective ablation of PR-A in mice, we show that the PR-B isoform modulates a subset of reproductive functions of progesterone by regulation of a subset of progesterone-responsive target genes. Thus, PR-A and PR-B are functionally distinct mediators of progesterone action in vivo and should provide suitable targets for generation of tissue-selective progestins.

Animals↗
PubMed1984

Uterine estrogen and progesterone receptors in an estrogen- and progesterone- "resistant" primate.

The squirrel monkey, a New World primate, has elevated plasma estradiol and progesterone concentrations compared to those in the cynomolgus macaque, an Old World primate. We previously reported that uterine progesterone receptor concentrations examined in ovariectomized squirrel monkeys 2 days after estrogen treatment were about one eighth those in identically treated cynomolgus macaques. To examine this in greater detail, we gave estradiol (10 micrograms/kg X day) to ovariectomized squirrel and cynomolgus monkeys for various lengths of time (0, 2, 4, 7, and 14 days), followed by measurement of uterine estrogen and progesterone receptors and assessment of endometrial histology (including glycogen and peroxidase strains), vaginal histology, and cytology. Endometrial and vaginal morphologies showed adequate estrogen effects, as did glycogen and peroxidase stains. Two days of treatment were sufficient to induce both estrogen and progesterone receptors to maximal binding of [3H]moxestrol and [3H]R5020, respectively, in both species. Squirrel monkeys had about one third and one eighth the estrogen and progesterone uterine receptor concentrations, respectively, of cynomolgus monkeys. Receptor affinities in both species were similar. Neither [3H]moxestrol nor [3H]R5020 bound to uterine cytosols from untreated monkeys. We conclude that the increased plasma concentrations of estradiol and progesterone in the squirrel monkey compensate for the decreased estrogen and progesterone receptors in this species.

Animals↗
PubMed1977

Progesterone in the uterus. VIII. Uptake of corticosterone and incorporation of progesterone under concurrent injection of corticosterone into rat uterus.

A study of the subcellular distribution of radioactivity in rat uterus after injection of labelled corticosterone showed that the radioactivity was observed in all fractions from 5 min. to 120 min. A maximum uptake was observed 10 min. after application of the labelled steroid. Competitive uptake of radioactive progesterone and unlabelled corticosterone was assayed 10 min. after injection of the hormone mixture. The ratio between radioactive progesterone and unlabelled corticosterone was 1:1 and 1:2 (moles:moles), respectively. Compared with control experiments with rats which had received radioactive progesterone alone, the results gave evidence that progesterone found in all subcellular fractions and in the total homogenate was not depressed by unlabelled corticosterone. However, unlabelled progesterone reduced the tritiated progesterone in uterine tissue. This observation demonstrates that the uptake of progesterone by rat uterus is specific.

Animals↗
PubMed1975

Mechanism of action of progesterone on amphibian oocytes. A possible biological role for progesterone metabolism.

The ability of various steroids to induce maturation of Pleurodeles waltlii oocytes after incubation has been studied. Progesterone is metabolized during the course of maturation. All metabolites isolated are less efficient than progesterone for inducing germinal vesicle breakdown. Progesterone binding to the 'melanosome' fraction has been studied (KD = 4.5 X 10(-8) M at 4 degrees C). 20BETA-Hydroxy-pregn-4-en-3-one, the main progesterone metabolite isolated from the oocyte, also binds to the melanosome fraction, but with a lower affinity (KD = 1.6 X 10(-7) M at 4 degrees C). At high concentration 20beta-hydroxy-pregn-4-en-3-one induces maturation, but at low concentration it is a competitive inhibitor of progesterone. Progesterone metabolism in Pleurodeles oocytes can be interpreted as an inactivation process, and also as a mechanism for inhibitime progesterone action.

Animals↗
PubMed1990

Regional distribution of progesterone and 5 alpha-pregnane-3,20-dione in rat brain during progesterone-induced "anesthesia".

Progesterone and 5 alpha-pregnane-3,20-dione (5 alpha-DHP) concentrations were measured in seven brain areas and in plasma during "anesthesia" induced by progesterone (1-2 mg IV) in female rats. The highest levels of progesterone were detected in the striatum and hypothalamus (23.3 +/- 5.27 and 22.7 +/- 4.30 micrograms/g +/- SEM, respectively); these concentrations were approximately 1000 times higher than those during the post-ovulatory phase. Highest levels of 5 alpha-DHP were detected in the striatum and hippocampus (11.5 +/- 1.74 and 10.4 +/- 3.15 micrograms/g +/- SEM, respectively). The ratio of 5 alpha-DHP to progesterone was approximately 100 times higher in brain tissue than in plasma. We conclude that a conversion of progesterone to 5 alpha-DHP occurs in the brain during the course of progesterone-induced "anesthesia". This metabolic step may be an important contributory factor to the anesthetic potency of progesterone.

5-alpha-Dihydroprogesterone↗
PubMed2002

Effects of level of feeding and progesterone dose on plasma and faecal progesterone in ovariectomised cows.

The effects of two levels of feeding and two doses of progesterone (P4) on plasma and faecal progesterone metabolites (FP4M) were studied using a total of 24 ovariectomised (OVX), non-lactating, Holstein-Friesian cows. Cows were grazed on improved ryegrass/white clover pastures and allowed ad libitum access to pasture or were restricted to grazing for a total of 4 h per day in two 2 h periods. Progesterone (P4) was administered as one or two, simultaneous, intravaginal progesterone devices (CIDR). The cows were adapted to their pasture supply for 2 weeks before the start of the progesterone treatments. The progesterone devices were administered for 11 days and the cows were dosed with slow release chromic oxide capsules during the P4 treatment to allow faecal output (FO) to be estimated. Daily blood samples for P4 assay and weekly samples for blood metabolite assay were collected. Faecal samples were collected per rectum daily and assayed for pregnanes containing a 20-oxo-, 20alpha- or a 20beta-OH group by enzyme immunoassay (EIA). Daily FO was higher (P < 0.001) for ad libitum than pasture restricted cows (6.3 vs 4.1 kg DM) but was similar for both doses of P4. The average mass of P4 released from a CIDR device over a 11-day period was higher for cows allowed ad libitum pasture compared with those on restricted pasture (0.64 vs 0.60 g; P = 0.04). Plasma P4 concentrations, however, were higher in restricted than ad libitum fed cows (1x CIDR: 1.81 vs 1.41 ng/ml; 2x CIDR: 4.10 vs 3.46 ng/ml). Increasing the progesterone dose significantly (P < 0.001) increased both the concentrations and daily totals of the faecal pregnanes assayed and total FP4M. Restricted pasture cows had higher (P < 0.001) pregnanes and FP4M concentrations than cows fed ad libitum. Daily total faecal pregnane and FP4M did not differ between feeding levels except for faecal 20alpha-pregnane which was highest for ad libitum fed cows (P < 0.05). These results showed that the plasma concentrations of P4 in CIDR-treated OVX cows were negatively associated with the level of feeding. Level of feeding and dose of P4 affected the concentrations of FP4M, but the daily excretion rate of FP4M was not positively influenced by the level of feeding.

Administration, Intravaginal↗
PubMed2002

[Pharmacokinetic comparison of progesterone capsules with a progesterone gel after vaginal administration].

The transvaginal bioavailability of 200 mg progesterone (CAS 57-83-0) from a vaginal capsule (Utrogest 200) compared to a vaginal gel containing 90 mg progesterone per dose was evaluated in 24 healthy young women using a randomised two-period cross-over design. Both treatments were supposed to release comparable amounts of progesterone. Blood samples were taken over a period of 96 h following single administration. Pharmacokinetic evaluation of both formulations was based on progesterone concentrations in serum measured by a validated RIA method. The relative bioavailability was determined as ratio of the AUC0-infinity and cmax together with the 90% confidence intervals. It could be demonstrated that one vaginal capsule containing 200 mg progesterone has a higher bioavailability than a dose of gel containing 90 mg progesterone. After administration of the capsule almost 50% more progesterone was bioavailable than after gel application. Both treatments did not vary with respect to the measured peak concentrations. However, tmax was clearly different. There were no relevant differences in safety profile between the two preparations investigated. Both were well tolerated.

Administration, Intravaginal↗
PubMed1994

Modulatory action of progesterone and progesterone antagonists on hypothalamic-pituitary function.

The ability of ovarian steroids to sensitize and desensitize the pituitary gonadotroph to hypothalamic gonadotrophin-releasing hormone (GnRH) is essential for their modulatory actions on gonadotrophin secretion. The time-dependent actions of progesterone on GnRH-stimulated gonadotrophin secretion from cultured pituitary cells obtained from female rats were examined. Progesterone induced an acute stimulatory effect on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion in cell perifusion studies, from as early as 50 min after the onset of progesterone treatment. Long-term incubation (52 h) of pituitary cells in static culture reduced the responsiveness of the gonadotroph to GnRH. The antiprogestins RU486, ZK 98.299, and ZK 98.734 blocked both the acute facilitatory and the long-term inhibitory action of progesterone. In the absence of progesterone, the antiprogestins per se induced marked inhibitory and stimulatory effects on GnRH-stimulated LH secretion. In brief, short-term treatment of non-oestrogen-primed cells with antiprogestins was ineffective (ZK compounds) or reduced LH secretion (RU486), while long-term treatment was stimulatory. Oestrogen-primed cells exerted exclusively inhibitory effects on GnRH-induced LH secretion. In conclusion, antiprogestins are effective antagonists of progesterone actions in the gonadotroph. However, they exert diverse actions on gonadotrophin secretion in the absence of progesterone, which might interfere with their antagonistic properties.

Animals↗