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PubMed1994

Excretion rates and metabolites of oestradiol and progesterone in baboon (Papio cynocephalus cynocephalus) faeces.

Two unanaesthetized female yellow baboons (Papio cynocephalus cynocephalus) were infused (i.v.) with [3H]oestradiol and two with [3H]progesterone, early in the follicular phases of their cycles. One month later, the two females infused with [3H]oestradiol were simultaneously infused with [14C]progesterone and [3H]dehydroepiandrosterone. All urine and faeces were collected for 96 h after infusion. The proportion of steroid excreted in faeces (versus urine) was 10.0% for oestradiol and 40% for progesterone. Peak excretion in urine occurred 4.5 h after infusion. Peak excretion in faeces occurred an average of 36.4 h after infusion, with remarkable consistency between steroids. Eighty per cent of faecal oestradiol and progesterone metabolites were excreted as free (rather than conjugated) steroids. Simply boiling (20 min) the dried faecal sample in 90% ethanol proved to be the most rapid and efficient means of extracting these steroid metabolites. High pressure liquid chromatography and immunoreactivity studies revealed that oestradiol was excreted in faeces as oestradiol (36%), oestrone (44%) and a conjugated metabolite that co-eluted with oestrone sulfate (20%). Progesterone was excreted as eight different free forms, only a minor portion of which was progesterone, and what appeared to be a conjugated metabolite that co-eluted with pregnanediol-glucuronide (20%). The free progesterone metabolites were identified by gas-chromatography-mass-spectrometry as epimers of 5-pregnane-3-diol and 5-pregnane-3-ol-one. These data suggest that currently available immunoassays for free oestradiol and oestrone should adequately characterize faecal oestrogen profiles in baboons. However, high variability in crossreactivities of various progesterone antisera to progesterone metabolites in baboons makes antiserum selection a more serious concern in attempts to quantify faecal progestogen dynamics.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Regulation of ovine GnRH receptor gene expression by progesterone and oestradiol.

The objective of this study was to determine whether progesterone prevents the stimulatory effects of oestradiol on GnRH receptor gene expression. In Expt 1, ewes were treated during the luteal phase (days 10-12 of the oestrous cycle) with either one or five subcutaneous implants containing oestradiol (n = 6 per group). Control ewes received no treatment (n = 6). Anterior pituitary glands were collected 16 h after treatment with oestradiol. Steady-state amounts of GnRH receptor mRNA were similar among all three treatment groups despite increased circulating concentrations of oestradiol in implanted ewes at the time of pituitary collection (4.3 +/- 0.6 and 24.7 +/- 2.6 pg ml-1 in ewes treated with one or five implants, respectively, compared with 0.5 pg ml-1 in controls). Experiment 2 was designed to determine whether progesterone was the ovarian factor preventing the stimulatory effects of oestradiol on expression of the GnRH receptor gene in Expt 1. Twenty-five ewes were ovariectomized on day 6 or day 7 of the oestrous cycle and assigned to one of five treatment groups (n = 5 per group). Control ewes received no further treatment. Endogenous luteal phase concentrations of progesterone were replaced in three groups of ewes at the time of ovariectomy via intravaginal implants. Three days after ovariectomy, one group of progesterone-treated ewes received one oestradiol implant, while another group of progesterone-treated ewes received five oestradiol implants. An additional group was treated with five oestradiol implants only, and anterior pituitary glands were collected from all ewes 16 h later. Compared with untreated ovariectomized ewes, treatment with progesterone alone did not affect amounts of GnRH receptor mRNA. In ewes treated with progesterone and either one or five oestradiol implants, steady-state amounts of GnRH receptor mRNA were increased twofold (P < 0.01). Treatment with oestradiol in the absence of progesterone increased amounts of GnRH receptor mRNA threefold (P < 0.001). These results provide evidence that the stimulatory effects of oestradiol on the expression of the GnRH receptor gene are prevented during the natural luteal phase in ewes. However, progesterone does not appear to act independently to mediate this effect.

Analysis of Variance↗

PubMed2002

Regulation of cyclooxygenase activity and progesterone production in the rat corpus luteum by inducible nitric oxide synthase.

This study explores interactions between the nitric oxide synthase (NOS) and the cyclooxygenase (COX) pathways in the regulation of progesterone production in early corpus luteum cells of rats. Nitric oxide (NO), prostaglandin E (PGE) and progesterone production was analysed in luteal cells of the rat corpus luteum exposed to inhibitors of non-specific NOS, inhibitors of inducible NOS (iNOS) and inhibitors of COX. Equine chorionic gonadotrophin (eCG)/hCG-primed rat corpus luteum cells produced NO, PGE and progesterone in a linear manner during 66 h of culture. Exposure of the cells to the non-specific NOS inhibitor, N(omega)-nitro-L-arginine (0.15 mmol l(-1)) for 48 h reduced NO, PGE and progesterone production to 21, 32 and 60% of that of the controls, respectively (P < 0.05 to P < 0.01). Another non-specific NOS inhibitor, N(omega)-methyl-L-arginine, produced similar inhibitions. Exposure of the cultured cells to S-ethylisothiourea (1 mmol l(-1)), a selective inhibitor of iNOS, suppressed the production of NO by 63%, PGE by 69% and progesterone by 48%. These findings indicate that production of PGE is regulated partly by iNOS, and that progesterone is probably regulated indirectly by the secondary changes in PGE. The addition of arachidonic acid to N(omega)-methyl-L-arginine-treated cells resulted in a significant increase in PGE and progesterone production (273 and 186%, respectively) without stimulating NO production. In contrast to the regulation exerted by the NO system on COX activity, the COX system does not modulate NO production in this model. This notion stems from the observation that the COX inhibitors acetylsalicylic acid (5 mmol l(-1)) and indomethacin (5 micromol l(-1)) suppressed PGE by 86 and 89%, respectively, and progesterone by 34 and 57%, respectively, but failed to inhibit NO production. The results from the present study indicate that iNOS-mediated NO production is involved in stimulating PGE synthesis in rat luteal cells, which may upregulate progesterone production.

Animals↗

PubMed2003

Influence of progesterone supplementation during the first third of pregnancy on fetal and placental growth in overnourished adolescent ewes.

Overnourishing adolescent ewes throughout pregnancy promotes maternal tissue synthesis at the expense of placental growth, which in turn leads to a major decrease in lamb birth weight. As maternal dietary intakes are inversely related to peripheral progesterone concentrations in these adolescent dams, it was hypothesized that sup-optimal progesterone concentrations in overnourished dams may compromise the growth of the differentiating conceptus resulting in fewer uterine caruncles being occupied and, hence, fewer placentomes formed. This hypothesis was tested by supplementing overnourished adolescent dams with exogenous progesterone during early pregnancy and determining the impact on pregnancy outcome at term. Embryos recovered from superovulated adult ewes inseminated by a single sire were transferred in singleton to the uterus of peripubertal adolescent recipients. After transfer of embryos, ewes were offered a moderate or high amount of a complete diet (n=11 per group). A further high intake group received a progesterone supplement each day from day 5 to day 55 of gestation (term=145 days) to restore circulating progesterone concentrations to moderate values throughout the first third of pregnancy (n=11). For ewes establishing pregnancies (n=7 per group), live weight gain during the first 100 days of gestation was 66+/-4, 323+/-17 and 300+/-7 g per day, body condition score at term was 2.1+/-0.05, 3.0+/-0.08 and 3.1+/-0.07 units and the duration of gestation after spontaneous delivery was 148+/-1.7, 144+/-0.8 and 143+/-0.8 days for the moderate intake, high intake and high intake plus progesterone groups, respectively. At delivery, fetal cotyledon mass (136+/-12.1 versus 57+/-8.2g, P<0.001) and lamb birth weight (5164+/-151 versus 2893+/-381 g, P<0.001) were higher in moderate intake than in high intake dams. Progesterone supplementation restored circulating concentrations to moderate values during the first third of gestation. Lamb birth weight in the high intake plus progesterone group (4150+/-389 g) was intermediate between the high intake (P<0.02) and moderate intake (P<0.05) groups, but this change in birth weight was not associated with corresponding changes in fetal cotyledon mass (76+/-10.3 g). Moreover, the number of fetal cotyledons was similar in all three groups. Thus, progesterone did not directly affect the growth of the fetal cotyledon but may have influenced placental vascularity, blood flow or nutrient transfer capacity or alternatively the development of the embryonic inner cell mass.

Animals↗

PubMed2004

The human corpus luteum: which cells have progesterone receptors?

Studies comparing the regressing corpus luteum with the rescued corpus luteum have demonstrated that human chorionic gonadotrophin (hCG) has effects on cell types that do not express hCG receptors. As progesterone synthesis is hCG dependent and the corpus luteum has been shown to express genomic progesterone receptors, progesterone is a candidate molecule for these paracrine effects. This study aimed to define the cellular localisation of progesterone receptors in the human corpus luteum using dual-staining immunohistochemistry for genomic progesterone receptors and specific cellular markers. Well-characterised corpora lutea (n = 12) from different stages of the luteal phase were studied. The same distribution was observed in all corpora lutea examined. The steroidogenic cells (3beta-hydroxysteroid dehydrogenase positive) and both theca-lutein (17alpha-hydroxylase positive) and granulosa-lutein (aromatase positive) express progesterone receptors, as do stromal fibroblasts (vimentin positive, fibroblast antigen positive). Vascular endothelial cells (CD31 positive), pericytes (alpha-smooth muscle actin positive), macrophages (CD68 positive) and fibroblasts within the central clot do not express nuclear progesterone receptors. Progesterone is a candidate messenger molecule for the effects of hCG on the matrix metalloproteinase-producing stromal fibroblasts. Some of the effects of hCG on steroidogenic cells may be mediated by progesterone, but its effects on blood vessels and macrophages require alternate paracrine signalling mechanisms. In addition, there appears to be at least two fibroblast populations in the corpus luteum.

Adult↗

PubMed2004

Reproductive tissue selective actions of progesterone receptors.

The steroid hormone, progesterone, plays a central coordinate role in diverse events associated with female reproduction. In humans and other vertebrates, the biological activity of progesterone is mediated by modulation of the transcriptional activity of two progesterone receptors, PR-A and PR-B. These receptors arise from the same gene and exhibit both overlapping and distinct transcriptional activities in vitro. To delineate the individual roles of PR-A and PR-B in vivo, we have generated mouse models in which expression of a single PR isoform has been ablated. Analysis of the reproductive phenotypes of these mice has indicated that PR-A and PR-B mediate mostly distinct but partially overlapping reproductive responses to progesterone. While selective ablation of the PR-A protein (PR-A knockout mice, PRAKO mice) shows normal mammary gland response to progesterone but severe uterine hyperplasia and ovarian abnormalities, ablation of PR-B protein (PRBKO mice) does not affect biological responses of the ovary or uterus to progesterone but results in reduced pregnancy-associated mammary gland morphogenesis. The distinct tissue-specific reproductive responses to progesterone exhibited by these isoforms are due to regulation of distinct subsets of progesterone-dependent target genes by the individual PR isoforms. This review will summarize our current understanding of the selective contribution of PR isoforms to the cellular and molecular actions of progesterone in reproductive tissues.

Animals↗

PubMed2006

Corticotropin-releasing hormone inhibits progesterone production in cultured human placental trophoblasts.

Placental-derived corticotropin-releasing hormone (CRH) seems to play a major role in the mechanisms controlling human pregnancy and parturition. It has been suggested that CRH directly modulates the endocrine function of placental trophoblasts, including the production of estrogen, ACTH, and prostaglandin. In this study, we sought to investigate the effect of CRH, locally produced by placenta, on progesterone production. Percoll-purified placental trophoblasts were obtained from uncomplicated term pregnancies and cultured for 72 h. Progesterone concentration in culture media was measured by RIA. The mRNA transcripts encoding CYP11A1 and HSD3B1, the enzymes for progesterone synthesis, were determined by quantitative real-time reverse transcription (RT)-PCR. Results showed that CRH (10(-8)-10(-6) mol/l) caused a significant decrease in progesterone levels in a dose-dependent manner. The CRH antagonist, alpha-helical CRH 9-41, at 10(-7)-10(-5) mol/l stimulated progesterone secretion. Consistent with this thesis, CRH decreased, whereas alpha-helical CRH increased, the mRNA levels of CYP11A1 and HSD3B1. Since CRH has been shown to activate the phospholipase C-protein kinase C (PKC) signal pathway in placenta, we examined whether the effect of CRH on progesterone synthesis was dependent on PKC signal pathway. Treatment of cells with PKC inhibitor, Gö6976, resulted in a significant increase in progesterone production, and exogenous CRH restored progesterone production. In conclusion, placental CRH exhibits a tonic inhibitory effect on progesterone production in a PKC-dependent fashion.

Carbazoles↗

PubMed1975

Plasma progesterone and its relationship to serum gonadotrophins in immature female rats.

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 mug/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.

Adrenal Glands↗

PubMed1978

Secretion of progesterone during gestation in the rat.

The concentrations of progesterone and 5alpha-pregnane-3,20-dione in ovarian and uterine venous plasma and in the systemic circulation were measured during gestation in the rat. The steroids were quantified by radioimmunoassay after separation on silicic acid micro-columns with the solvent system hexane : ethyl acetate (5 : 2, v/v). The concentration of progesterone in the systemic circulation was highest on days 3--4 and 13--17 of pregnancy; throughout gestation, the concentration of 5alpha-pregnane-3,20-dione was low in relation to that of progesterone and showed no marked changes as gestation proceeded. The level of progesterone in ovarian venous effluent was 10--20 times higher than that in the uterine vein and 20--50 times greater than that in the systemic circulation. The rate of secretion of progesterone by the ovary was highest during days 13--17 of gestation and ovariectomy during this period markedly reduced the levels of progesterone in the peripheral circulation. The concentration of progesterone in the uterine venous effluent was raised compared with the concentration in plasma from the abdominal aorta, especially on days 7 and 9 of pregnancy. These results suggest that, in vivo, the rat placenta synthesizes small amounts of progesterone and secretes it into the maternal circulation. The ovary is the primary source of progesterone during pregnancy and the placental contribution is of secondary importance. Although 4-ene-5alpha-reductase enzyme(s) is present in the ovary and placenta, significant quantities of the reduced progestin 5alpha-pregnane-3,20-dione are not secreted into the systemic circulation during gestation in the rat.

Animals↗

PubMed1980

Onset of synthesis of progesterone by ovine placenta.

The extra-ovarian contribution to progesterone levels in the circulation has been measured in ovariectomized ewes in which pregnancy was maintained by treatment with medroxyprogesterone acetate. Since adrenal production of progesterone is low this procedure allows the determination of placental secretion. Placental production of progesterone has been shown to rise initially between 50 and 70 days of gestation, with a second phase of increase between 90 and 120 days of gestation. Both periods of increased secretion of progesterone were reflected in rises in progesterone production by placental explants in organ culture and in the activity of 3 beta-hydroxysteroid dehydrogenase in the tissue. The activity of 3 beta-hydroxysteroid dehydrogenase exceeded the rate of progesterone production by approximately 30-fold, and it appears unlikely, therefore, that this enzyme is rate-limiting in the synthesis of progesterone. Surgical reduction of the number of cotyledons led to compensation by an increase in weight of individual cotyledons with no significant increase in specific 3 beta-hydroxysteroid dehydrogenase activity or rate of production of progesterone in organ culture. It was concluded that the rise in placental production of progesterone in the middle period of gestation is unlikely to result either from an increase in 3 beta-hydroxysteroid dehydrogenase activity or from exposure to factors stimulating placental growth.

3-Hydroxysteroid Dehydrogenases↗

PubMed1981

Fate of progesterone in the plasma and various tissues of anaesthetized rabbits.

Studies on the metabolism of progesterone in rabbit plasma and tissues during constant infusion of [3H]progesterone revealed a gradual increase in the concentration of progesterone in plasma until a state of equilibrium was attained about 2 h after the start of infusion. The metabolic clearance rate of progesterone was 0.116 l/min and the turn-over time was 0.006 min/ml plasma. Under conditions of equilibrium, the concentration of radioactivity as well as that of labelled progesterone was higher in the tissues than in plasma. On a unit-weight basis, myometrium localized 6.6 nCi, Fallopian tube 5.5 nCi and vagina 6.1 nCi [3H]progesterone/g tissue. A higher concentration of progesterone, 16.5 nCi, was localized in the mammary gland tissue. Skin localized only 0.9 nCi progesterone and the lowest amount (0.34 nCi/ml) was found in plasma. The metabolism of progesterone in tissues differed from that in plasma. In plasma only 5.6% of the infused steroid was recovered as unconverted progesterone and the major amount was metabolized to polar compounds with smaller amounts of 5 alpha-pregnane-3,20-dione, 5 alpha-pregnan-3 beta-ol-20-one and 20 alpha hydroxypregn-4-en-3-one. In the myometrium and Fallopian tubes the major metabolites were 5 alpha-pregnan-3 beta-ol-20-one and 5 alpha-pregnane-3,20-dione respectively. In the vagina, like the myometrium, 5 alpha-pregnan-3 beta-ol,20-one was the major metabolite. 20 alpha-Hydroxypregn-4-en-3-one was the major identified metabolite of mammary gland tissue.

Animals↗

PubMed1981

Role of progesterone in the control of secretion of follicle-stimulating hormone in the immature female rat.

The inhibitory action of FSH secretion of combined oestradiol and progesterone treatment of ovariectomized, immature rat was studied at various ages. At all ages studied (13-35 days) as additional inhibitory action of progesterone, if combined with oestradiol, could be found as compared with the effect of oestradiol alone. Until 20 days of age, the rise in serum FSH concentration as measured 2 days after ovariectomy could be completely prevented by administration of 0.05 microgram oestradiol/100 g body weight or by administration of a lower dose of oestradiol (0.01-0.025 microgram) combined with progesterone (0.5-1.5 mg/100 g body weight). After 20 days neither oestradiol nor the combined oestradiol/progesterone treatment resulted in an FSH concentration similar to that found in intact rats. However, the lowest FSH concentrations were reached by using combinations of oestradiol and progesterone. Using progesterone alone, FSH concentration in ovariectomized rats was significantly reduced between 18 and 30 days of age, but not before or after this period. Taken together with data on uterine weight and serum concentrations of progesterone, these findings suggest that (1) both oestradiol and progesterone exert an age-dependent role in regulating FSH secretion in the immature female rat, and (2) amounts of oestradiol and progesterone capable of maintaining, in ovariectomized rats, uterine weights not different from those in intact rats will maintain near-physiological concentrations of FSH before but not after day 20. Thus, ovarian factors other than oestradiol and progesterone must be involved in the regulation of FSH secretion in the female after 20 days of age.

Animals↗

PubMed1986

Comparison of particle-associated progesterone and oxytocin in the ovine corpus luteum.

The subcellular distribution of progesterone and oxytocin within the ovine corpus luteum was investigated using differential and density gradient centrifugation. Progesterone and oxytocin were associated with particles which sedimented to a density of 1.049-1.054 g/ml and 1.054-1.061 g/ml respectively. Particle-associated progesterone did not, however, display physical or biochemical characteristics consistent with its storage within secretory granules. When particle-associated progesterone was incubated in HEPES buffer at 37 degrees C, 70% of the total progesterone was recovered in the incubation medium. The remaining stable particle-associated progesterone was not affected by treatments which stimulated oxytocin release and which have been shown to cause the release of peptides and biogenic amines from secretory granules. These results suggest that particle-associated progesterone represents the intercalation of progesterone into cell membranes and they do not support the hypothesis that progesterone is stored, in a protein-bound form, in luteal secretory granules.

Animals↗

PubMed1986

Relationships between plasma progesterone levels and testicular testosterone production in the rat fetus: effects of maternal ovariectomy.

The present study was performed to examine whether circulating progesterone regulates testicular testosterone production in the fetal rat. Progesterone levels in fetal plasma were found to increase from day 14.5 to day 16.5; thereafter they reached a plateau between days 16.5 and 18.5 (80 nmol/l) and decreased threefold between days 18.5 and 21.5. The addition of progesterone, within the range of normal plasma concentrations, induced a dose-dependent increase in testosterone produced in vitro by the testes on days 16.5 and 18.5 but not on day 20.5. However, in 18.5-day-old fetuses, individual plasma progesterone levels were not correlated with testicular testosterone production in vivo and in vitro. Furthermore, maternal bilateral ovariectomy induced a significant fall in plasma progesterone in 18.5-day-old fetuses; this was not associated with a reduction in plasma testosterone nor in testicular testosterone content, although the amount of testosterone secreted by the testis incubated in vitro was slightly but significantly reduced. It is concluded that circulating progesterone does not regulate testicular testosterone production in vivo although the testis may use plasma progesterone as a substrate. On day 18.5 after maternal ovariectomy, the decrease in plasma progesterone levels was similar in fetuses and mothers, suggesting that most fetal progesterone originates from maternal plasma.

Animals↗

PubMed1990

Changes in the hypothalamic contents of LHRH-I and -II and in pituitary responsiveness to synthetic chicken LHRH-I and -II during the progesterone-induced surge of LH in the laying hen.

The contents of LHRH-I and -II in the anterior hypothalamus and posterior hypothalamus (including the mediobasal hypothalamus and median eminence) were measured at 90, 180 and 360 min after the i.m. injection of laying hens with progesterone. Whilst no changes were observed in the content of LHRH-I in the anterior hypothalamus, LHRH-I in the posterior hypothalamus tended to fall at 90 and 180 min after injection of progesterone in hens maintained on 16 h light:8 h darkness (16L:8D) and 8L:16D respectively. Pretreatment of laying hens with tamoxifen significantly increased the hypothalamic contents of LHRH-I and -II, raised the basal plasma concentration of LH and modified the LH response to progesterone injection. In hens in which tamoxifen prevented an increase in the plasma concentration of LH after progesterone injection, the content of LHRH-I in the posterior hypothalamus remained unchanged. In contrast, in hens in which progesterone stimulated a steep increase in LH within 90 min, there was a pronounced and significant fall in LHRH-I content of the posterior hypothalamus. No change in the hypothalamic content of LHRH-II was observed during the progesterone-induced surge of LH until plasma concentrations had attained maximal values or started to decline. Then, in hens maintained on 16L:8D, a significant fall in the content of LHRH-II in the anterior hypothalamus was found at both 180 and 360 min after injection with progesterone. Tests in vitro and in vivo of the responsiveness of the pituitary gland to synthetic LHRH-I and -II revealed no change at 90 min after injection of laying hens with progesterone, when plasma concentrations of LH were increasing, but a pronounced reduction when plasma LH concentrations were maximal or falling. These results suggest that LHRH-I mediates in the progesterone-induced increase in the plasma concentration of LH. Although the subsequent decline in plasma LH was associated with a reduced responsiveness of the pituitary gland to LHRH, a significant correlation between the contents of LHRH-I and -II in the anterior hypothalamus and a fall in the hypothalamic content of LHRH-II when plasma LH was maximal or declining allows the possibility of an involvement of this peptide in the neuroendocrine events preceding ovulation.

Animals↗

PubMed1998

Assessment of the mechanism by which prolactin stimulates progesterone production by early corpora lutea of pigs.

Previously, we reported that administration of prolactin (PRL) during the early luteal phase in sows increases plasma progesterone concentrations. In the current study, we searched for the mechanisms by which PRL exerts this luteotrophic effect. The objectives of the study were (1) to examine the effect of PRL and/or low-density lipoproteins (LDL) on progesterone production by porcine luteal cells derived from early corpora lutea, and (2) to assess the ability of PRL to activate phosphoinositide-specific phospholipase C (PI-PLC) and protein kinase C (PKC) in these luteal cells. Ovaries with early corpora lutea (day 1-2 of the oestrous cycle) were obtained from the slaughterhouse. Progesterone production by dispersed luteal cells was measured after treatment with PRL, phorbol 12-myristate 13-acetate or inhibitors of PKC in the presence or absence of LDL. LDL increased progesterone concentration in the incubation medium (304.5 vs 178.6 ng/ml in control, P<0.05). PRL augmented LDL-stimulated progesterone secretion by luteal cells (to 416 ng/ml, P<0.05), but PRL alone did not affect progesterone production (209.6 ng/ml, P>0.05). Staurosporine, a PKC inhibitor, inhibited progesterone secretion stimulated by the combined action of LDL and PRL; however, such inhibition was not demonstrated when cells were treated with the PKC inhibitor, H-7. PKC activation was assessed by measuring the specific association of [H]phorbol dibutyrate (H-PDBu) with luteal cells after treatment with PRL or ionomycin (a positive control). PRL and ionomycin increased H-PDBu-specific binding in early luteal cells by 28+/-5.5% (within 5 min) and 70.2+/-19.3% (within 2 min) over control binding respectively (P<0.05). In addition, PRL did not augment the LDL-stimulated progesterone production in PKC-deficient cells. In contrast with PKC, total inositol phosphate accumulation, as well as intracellular free calcium concentrations, were not affected by PRL in the current study. We conclude that PRL, in the presence of LDL, stimulates progesterone production by early corpora lutea in vitro. Moreover, PRL appears to activate PKC, but not PI-PLC, in these cells. Thus intracellular transduction of the PRL signal may involve activation of PKC that is not dependent on PI-PLC.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2000

Adrenergic influences on coeliac ganglion affect the release of progesterone from cycling ovaries: characterisation of an in vitro system.

The superior ovarian nerve (SON) arrives at the ovary through the suspensory ligament and innervates mainly the ovarian stroma. Most neurones from which the SON fibres originate are located in the complex coeliac and mesenteric ganglia. Taking into account that other ganglia have been shown to have alpha- and beta-adrenergic receptors, and that the coeliac ganglion receives adrenergic fibres from other sympathetic paravertebral and preaortic ganglia, we utilised adrenergic agonists and antagonists specific to the ganglion, to analyse the role of the alpha and beta receptors in ovarian physiology. To that end, it was necessary to develop and standardise an in vitro coeliac ganglion-SON-ovary (coeliac ganglion-SON-O) experimental system that would enable study of the release of steroids in the ovary in the absence of humoral factors. We investigated the effect of adrenergic agents on the liberation of progesterone in the different stages of the oestrous cycle. To this end we placed the coeliac ganglion and the ovary in different compartments, connected through the SON, to produce a system being studied as a whole. Combined neural and hormonal (luteinising hormone (LH)) effects were also examined. Non-specific stimulation with KCl in the ganglion compartment evoked different responses in terms of release of progesterone, depending on the physiological conditions of the cycle; this demonstrated the sensitivity and viability of the system. During pro-oestrus, stimulation of the ganglion compartment with adrenergic agents such as the agonist noradrenaline or the beta-adrenergic antagonist propranolol, did not modify the release of progesterone. In contrast, the alpha-adrenergic antagonist, phentolamine, induced a strong inhibitory response. During the oestrous stage, noradrenaline was inactive, but phentolamine and propranolol exerted a strong stimulus throughout the experiment. On dioestrus day 1 (D1), both noradrenaline and propranolol increased the release of ovarian progesterone, whereas phentolamine had the opposite effect. Finally, on dioestrus day 2 (D2), what was noteworthy was the pronounced inhibitory effect of noradrenaline, whereas phentolamine was inactive and propranolol showed its greatest stimulatory effect. In order to compare the combined neural and endocrine effects on the ovarian release of progesterone, the experiment was carried out during stages D1 and D2, when the corpora lutea are at their peak of activity. Adrenergic agents were added to the ganglion and LH in a final concentration of 50 ng/ml was added to the ovarian comparment. Different effects were observed indicating a differential response to these agents in stimulated and basal conditions. We conclude that the in vitro coeliac ganglion-SON-ovary system is a functional entity because it possesses its own autonomic tone. This is verified because different basal values of progesterone appear in the different stages of the oestrous cycle. In similar fashion, variations of progesterone induced via the neural pathway were observed under different experimental conditions. In contrast, on D2, noradrenaline added to the ganglion compartment had an inhibitory effect on the liberation of ovarian progesterone. This would indicate that, during this phase, noradrenaline may not be the neurotransmitter released in the ovarian compartment, but that other inhibitory molecules might participate in the observed effects. Finally, during D2, the neural input would condition the ovarian response to LH, facilitating the decrease in progesterone necessary to start a new cycle. The experimental scheme is, in our opinion, a valuable tool for the study of peripheral neural participation in ovarian physiology.

Adrenergic Agents↗

PubMed2006

Progesterone initiates Wnt-beta-catenin signaling but estradiol is required for nuclear activation and synchronous proliferation of rat uterine stromal cells.

Progesterone pretreatment of ovariectomized rat uteri increases the number of synchronously proliferating stromal cells in response to estradiol 17-beta. To identify the signals involved in stimulating synchronous proliferation, sexually mature ovariectomized rats were injected with progesterone (2 mg) for 3 consecutive days. Estradiol 17-beta (0.2 microg) was administered to initiate cell cycle entry. Uterine samples were removed at various times after hormone administration and changes in wingless (Wnt) pathway effectors and gene targets were identified by microarray. Progesterone pretreatment decreased glycogen synthase kinase-3beta (GSK-3beta) and increased expression of T-cell factor/lymphoid enhancer factor (TCF/LEF). GSK-3beta protein decreased markedly in the uterine stroma of progesterone-pretreated uteri with the concomitant appearance of beta-catenin in these stromal cells. Translocation of beta-catenin from the cytosol to the nuclei in progesterone-pretreated stromal cells was stimulated in response to estradiol. Beta-catenin binding to TCF/LEF increased (P<0.05) in progesterone-pretreated uteri in response to estradiol. Progesterone stimulated the expression of the Wnt target gene urokinase plasminogen activator receptor (uPA-R) in the periluminal uterine stromal cells. The expression of uPA-R increased in progesterone-pretreated stromal cells in response to estradiol administration. Together, the results indicate that progesterone initiates Wnt signaling in the uterine stroma by down-regulating GSK-3beta. However, nuclear translocation of beta-catenin and sufficient complex formation with TCF/LEF to activate stromal cell cycle entry requires estradiol. Stimulation of a uterine stromal cell line to proliferate and differentiate resulted in beta-catenin accumulation, suggesting that endocrine-dependent Wnt signaling controls proliferation and differentiation (decidualization).

Animals↗