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PubMed1998

Progesterone-stimulated intracellular calcium increase in human spermatozoa is protein kinase C-independent.

Indirect studies suggested that protein kinase C (PKC) has a role in sperm motility and the acrosome reaction. Physiological inducers of the sperm acrosome reaction include progesterone, which can increase intracellular calcium ([Ca2+]i), tyrosine phosphorylation of proteins and chloride efflux in human spermatozoa. PKC may be involved in progesterone-stimulated acrosome reaction, although controversial results have been obtained concerning the effect of PKC inhibition on progesterone-stimulated [Ca2+]i increase. In the present study, we investigated the direct effect of progesterone on the activity of PKC, as well as the effect of a panel of PKC inhibitors on progesterone-stimulated [Ca2+]i increase and tyrosine phosphorylation of proteins. We found that progesterone stimulates sperm PKC activity and that PKC inhibition with staurosporine and bisindolylmaleimide partially reversed the effect of progesterone on acrosome reaction, indicating an involvement of the enzyme in the effect of the steroid. We next evaluated the effect of three different PKC inhibitors (sangivamycin, staurosporine and bisindolylmaleimide) on progesterone-stimulated [Ca2+]i increase. Neither short-term (15 min) nor long-term (90 min) preincubation with any of the three compounds had a substantial effect on the stimulatory effect of progesterone on sperm [Ca2+]i. Nor was responsiveness to progesterone affected by either short-term (determining activation of PKC) or long-term (determining down-regulation of PKC) incubation with the tumour promoter phorbol myristate acetate (PMA), a known non-physiological stimulator of PKC. These results indicate that progesterone-stimulated calcium influx is independent of PKC activation. In addition, we found that preincubation with PKC inhibitors had a stimulatory effect per se on tyrosine phosphorylation of sperm proteins. When compared with the appropriate control, the effect of progesterone on tyrosine phosphorylation was slightly (but not significantly) reduced by the inhibitors, sangivamycin, staurosporine and bisindolylmaleimide, but was significantly inhibited by calphostin C. These results do not permit a final conclusion on the involvement of PKC in progesterone-stimulated tyrosine phosphorylation of sperm proteins. However, the lack of effect of PMA on tyrosine phosphorylation indicates that PKC stimulation is not sufficient to induce this effect. In conclusion, our results indicate that PKC plays a role in progesterone-induced acrosome reaction and that progesterone-stimulated PKC activation is downstream to stimulation of calcium influx by the steroid.

Calcium↗
PubMed2002

Progesterone induces dephosphorylation and inactivation of tyrosine hydroxylase in rat hypothalamic dopaminergic neurons.

After in vivo treatment, progesterone initially decreases tyrosine hydroxylase (TH) activity in the TIDA neurons, but subsequently increases TH activity with prolonged treatment. In order to explore the cellular mechanism for progesterone's effect, this study examined the acute inhibitory action of progesterone on TH activity in rat fetal hypothalamic dopaminergic neurons in vitro. Progesterone caused a rapid decrease in TH activity within 1 h, which was sustained for at least 6 h. However, the dopaminergic cells became refractory to progesterone with continuous treatment for 12 h to 10 days. Progesterone (10-100 nM) treatment suppressed TH activity in a concentration-dependent manner. The inhibitory effect of progesterone was dependent on prior exposure to estradiol. Whereas progesterone decreased TH activity, A ring-reduced metabolites of progesterone did not alter TH activity, suggesting that the response was specific to progesterone. Progesterone decreased radiolabeled phosphate incorporation into TH protein. Okadaic acid, a phosphoprotein phosphatase inhibitor, prevented the progesterone-induced suppression of TH activity and phosphate incorporation into TH, implicating dephosphorylation of TH as the cellular mechanism. In contrast, neither TH mRNA levels nor TH protein content was altered after 1 or 12 h of progesterone treatment. Progesterone decreased TH activity after pretreatment of the hypothalamic cells for 2 or 24 h with actinomycin D, an RNA synthesis inhibitor, suggesting that increased transcription does not mediate the effect. These data indicate that the acute progesterone-induced decline in TH activity is caused by dephosphorylation of TH.

Animals↗
PubMed1993

Estrogen-induced calbindin-D 9k gene expression in the rat uterus during the estrous cycle: late antagonistic effect of progesterone.

Progesterone modulates estrogen-stimulated responses in the uterus. Calbindin-D 9k (CaBP9k), a 17 beta-estradiol-responsive gene expressed in the uterus, was used as a marker to examine the interactions between endogenous progesterone and estradiol in the rat. The variations in uterine CaBP9k messenger RNAs (mRNAs) during the rat estrous cycle indicated that CaBP9k gene expression was greatest during the estrogen-dominated phases (proestrus and estrus) and became totally repressed during diestrus, when progesterone predominates. Estradiol was found to be the major controlling factor of CaBP9k gene expression in vivo, progesterone antagonizing estrogen-induced CaBP9k gene expression. The inhibitory role of progesterone was further examined in two experiments. Mature cyclic rats were injected with the progesterone antagonist RU486 before the progesterone surge of proestrus, and the estrous cycle was mimicked in ovariectomized rats by sequential injections of estrogen and progestin. Progesterone did not appear to be involved in the rapid decrease in CaBP9k mRNA during estrus but was implicated in the down-regulation of the estrogen-stimulated CaBP9k gene expression at the end of estrus and during diestrus. This delayed effect of progesterone was confirmed in the ovariectomized rat model. CaBP9k mRNA accumulation in estrogen-primed ovariectomized rats was suppressed by estrogen followed 1 h later by the progesterone agonist R5020. This effect occurred more than 24 h after progestin treatment. The inhibition of the estrogen-induced CaBP9k gene expression in the rat uterus by progesterone is certainly mediated by the progesterone receptor, because progesterone had no effect without estrogen priming or when the antagonist RU486 was used. The delayed progesterone effect probably does not involve depletion of nuclear estrogen receptors, the major rapid mechanism proposed for estrogen inhibition by progesterone in the rodent uterus, or control of estrogen receptor synthesis, as shown by Northern blot analysis of estrogen receptor mRNA.

Animals↗
PubMed1992

The source of pulsatile secretion of progesterone during the human follicular phase.

This study was designed to establish the normal pattern of serum progesterone and the origin of its secretion during the follicular phase of the normal menstrual cycle. In the first study, 12 normal women were studied on 3 occasions each at different times during a single follicular phase. Serum samples were collected every 10 min over 8 h, for 6 h before and 2 h after an injection of naloxone (5 mg iv). The mean serum progesterone remained constant (0.9 nmol/L) across the follicular phase until just before ovulation; individual subjects showed pulsatility of progesterone (1-6 pulses/6 h) but there was no relationship of this to LH pulsatility and no variation of progesterone pulsatility across the follicular phase. Naloxone caused an increase in the mean serum progesterone in the early follicular phase to 1.9 +/- 0.7 nmol/L and in the mid and late follicular phase to 2.1 +/- 0.7 nmol/L and 3.4 +/- 2.5 nmol/L, respectively. The second study was performed to assess the contribution of the residual corpus luteum and the developing follicle to the pulsatile secretion of progesterone. Seven anovulatory women with low levels of serum LH and absent LH pulsatility were studied before and after clomiphene (100 mg/day for 5 days) by collecting blood samples every 15 min for 6 h before GnRH (10 mg iv) and for 2 h afterwards. The anovulatory women had comparable mean serum concentration of progesterone (0.9 +/- 0.5 nmol/L) to normal women and similar frequency of progesterone pulsatility (2.1 +/- 1.1 pulses/6 h). After administration of clomiphene, there was no significant change in progesterone pulsatility (1.7 +/- 1.0 pulses/6 h) despite a substantial increase in LH pulsatility (from none to 3.0 +/- 1.0 pulses/6 h). There was no significant increase in serum progesterone after clomiphene or GnRH which both caused a substantial increase in serum LH. The third study involved eight normal women studied before and after treatment with dexamethasone (2 mg/day for 2 days) to assess the adrenal component of progesterone secretion. Blood samples were collected every 10 min for 6 h before and 2 h after naloxone (5 mg iv). Dexamethasone reduced serum progesterone to below assay sensitivity (less than 0.2 nmol/L) and obliterated progesterone pulsatility. The increase in serum progesterone and cortisol induced by naloxone was blocked by dexamethasone; the naloxone-induced rise of serum LH was not affected by dexamethasone. We conclude that neither the preceding corpus luteum nor the developing follicle are important contributors to the serum concentration of progesterone during the normal follicular phase.(ABSTRACT TRUNCATED AT 400 WORDS)

Activity Cycles↗
PubMed1993

The role of progesterone in regulating human granulosa cell proliferation and differentiation in vitro.

To further elucidate the role of progesterone in regulating granulosa cell function, human granulosa and luteal cells were obtained from follicular aspirates of women undergoing in vitro fertilization and placed in culture. Cells plated at 5 x 10(3) cells/mL doubled after 3 days. In contrast, cells plated at 50 x 10(3) cells/mL did not proliferate, but differentiated, secreting high levels of progesterone. Cells plated at 5 x 10(3) cells/mL and cultured with spent medium from cells plated at 50 x 10(3) cells/mL did not increase in number over 3 days of culture. The growth-inhibiting action of the spent medium was removed by either RU 486 (a progesterone receptor antagonist) or charcoal extraction, but not by heat inactivation. The addition of progesterone to fresh medium also prevented cell proliferation. Progesterone's ability to inhibit cell division was attenuated by either RU 486 or aminoglutethamide, which blocked progesterone synthesis. Further, epidermal growth factor (EGF) stimulated cell proliferation, and continuous exposure to progesterone blocked EGF-induced mitosis. When progesterone was added 2 h after EGF, it did not block EGF-stimulated cell proliferation. Progesterone also increased the percentage of granulosa cells and decreased the percentage of large luteal cells present after 3 days of culture, indicating that progesterone inhibited differentiation. Progesterone's effect on differentiation was dose dependent, reversible, and could be overridden by hCG or 8-bromo-cAMP. These observations suggest that progesterone acts directly on granulosa cells through its receptor to inhibit mitosis and that progesterone mediates its antiproliferative effects within 2 h of mitotic stimulation. Progesterone also blocks differentiation, but this effect of can be overcome by hCG or cAMP analogs. These data indicate that progesterone plays a major role in controlling the number of luteal cells that ultimately develop within a corpus luteum by regulating both granulosa cell proliferation and differentiation.

Aminoglutethimide↗
PubMed1981

Evidence that progesterone does not inhibit the induction of sexual receptivity by oestradiol-17 beta in the rat.

Progesterone-filled constant-release implants facilitated the induction of sexual receptivity in ovariectomized rats given implants of oestradiol-17 beta precisely 32 h before testing, irrespective of the time of implantation. Inhibition by progesterone implants of the behavioural response to an injection of progesterone occurred after the facilitation 32 h after oestradiol implantation. Sexual receptivity could be induced in pseudopregnant rats in the absence of progesterone treatment by injection of 1 microgram oestradiol 32 and 16 h before testing at a time when endogenous serum levels of oestradiol were low and progesterone levels were high. The behavioural response of ovariectomized rats implanted with oestradiol and tested daily was unaffected by implantation of progesterone at the time of oestradiol implantation, although serum levels of progesterone varied with the number of progesterone implants inserted. Inhibition by progesterone implants of the behavioural response to an injection of progesterone 6 h before behavioural testing occurred only if the progesterone implants were present for at least 32 h of a 48 h period. Serum levels of progesterone were raised within 1 h of progesterone implantation and declined within a 6 h period after implant removal. It is concluded that progesterone does not inhibit the behavioral effect of oestradiol and that progesterone does not play an inhibitory role in the regulation of the behavioural oestrous cycle in our strain of rats.

Animals↗
PubMed1975

Progesterone in molar vesicle fluid and theca lutein cyst fluid.

Serum progesterone was estimated by a competitive protein-binding method in the peripheral venous blood in 12 cases of normal pregnancy at the time of delivery and in maternal venous blood, umbilical venoms, and umbilical arterial blood in another 5 cases. Progesterone concentration in the peripheral blood and in the serous fluid of molar vesicles was measured in 18 cases of hydatidiform mole. The theca lutein cyst fluid from 3 patients with hydatidiform mole was also assayed for progesterone. Umbilical cord venous blood and umbilical arterial blood showed a variable concentration of progesterone with a mean fetal-maternal progesterone ratio of 4.7 plus or minus 0.6 and a mean umbilical vein-artery progesterone ratio of 5.7 plus or minus 0.4. Serum progesterone concentration in hydatidiform mole was from 25.0 to 263.2 ng/ml with a mean plus or minus standard error of 101.7 plus or minus 15.2 ng/ml, while the corresponding mole vesicle fluid progesterone concentration ranged from 260.5 to 1842.0 ng/ml with a mean plus or minus SE of 770.9 plus or minus 87.4 ng/ml. The ratio of progesterone in vesicle fluid and in the serum was 4.0 to 52.8 (mean, 7.6). Progesterone concentrations in the theca lutein cyst fluid from 3 patients with hydatidiform mole were 25,428 ng/ml; 7,635 ng/ml; and 4,686 ng/ml. The high fetal-maternal progesterone ratio and umbilical vein-artery progesterone ratio reflect preferential progesterone transfer to the fetus and utilization by the latter. The finding in hydatidiform mole is due to the absence of the fetus and indicates that the molar trophoblast produced progesterone in significant amounts and that theca lutein cysts have a very high but variable concentration of progesterone in their fluid.

Body Fluids↗
PubMed1978

Progesterone receptor in the rat anterior pituitary: effect of estrogen priming and adrenalectomy.

The present study was done to determine if a progesterone receptor is present in rat pituitary. Cytosol was labeled with 3H-progesterone (3HP) or 3H-R5020 (3HR) and subjected to sucrose-glycerol density-gradient centrifugation. Serum progesterone was measured for correlation with progesterone receptor levels. Two 3HP-binding peaks (4S + 6S) were evident in uterine and pituitary cytosols. The 4S peak was eliminated by competition with unlabeled cortisol leaving a single 6S peak (progesterone receptor). Estradiol (E) priming of the male or female rat increased progesterone receptor levels in pituitary cytosol as demonstrated using 3HP and 3HR, and pituitary progesterone receptor bound 3HR with a higher affinity than 3HP. Following adrenalectomy of gonadectomized rats, progesterone receptor levels were increased in pituitary and uterine cytosol of both E-primed and unprimed groups. An inverse relationship was established between serum progesterone and progesterone receptor levels in the uterus and pituitary suggesting that stress-induced adrenal progesterone secretion significantly influences progesterone receptor levels in the rat. These results demonstrate an estrogen-inducible progesterone receptor in the rat pituitary with properties similar to those of the uterine progesterone receptor.

Adrenalectomy↗
PubMed1994

Progesterone and the neural mechanisms of hamster sexual behavior.

Stimulation of both the ventral medial hypothalamus (VMH) and the ventral tegmental area (VTA) by progesterone is necessary to facilitate sexual behavior in female hamsters. Recently obtained evidence indicates that progesterone exerts its behaviorally relevant actions in the VTA by acting on cell membranes. When progesterone conjugated to bovine serum albumin, which cannot permeate the cell membrane, is applied to the VTA concurrent with free progesterone to the VMH, estrogen-primed hamsters become sexually receptive. Since the reverse treatment is ineffective, this suggests that progesterone's nongenomic effects in the VTA may require concurrent genomic activation by progesterone in the VMH. The nongenomic action of progesterone on sexual receptivity may involve the GABAA receptor complex, as progestins are known to modulate this receptor complex. VTA infusions of GABAA agonists enhance, and antagonists inhibit, progesterone's effectiveness on receptivity. Finally, the behavioral effectiveness of progesterone metabolites in the VTA, concurrent with progesterone in the VMH, is consistent with their relative biochemical efficacy at the GABAA complex. These data suggest that progesterone may exert its behavioral effects in the VTA through GABAA. However, it is not yet clear whether progesterone normally acts directly on GABAA in the VTA. Progesterone may also act at some other membrane binding site and GABAA may represent an indirect mechanism for progesterone.

Animals↗
PubMed2004

Do calcium-mediated cellular signalling pathways, prostaglandin E2 (PGE2), estrogen or progesterone receptor antagonists, or bacterial endotoxins affect bovine placental function in vitro?

The major objective of this experiment was to determine whether the bovine placenta could be stimulated to secrete progesterone, since the bovine placenta secretes little progesterone when the corpus luteum is functional. Secondly, we wanted to determine whether reported abortifacients or progesterone or estrogen receptor antagonists affected bovine placental prostaglandin secretion. The ovine placenta secretes half of the circulating progesterone at day 90 of pregnancy and PGE2 appears to regulate ovine placental progesterone secretion. Calcium has been reported to regulate placental progesterone secretion in cattle. Diced 186-245-day placental slice explants from six Brahman and six Angus cows were incubated in vitro at 39.5 degrees C under 95% air: 5% CO2 at pH 7.2 in 5 ml of M-199 for 1 h in the absence of treatments and for 4 and 8 h in the presence of treatments. Treatments were: vehicle; R24571; compound 48/80; IP3; PGE2; CaCl2; cyclosporin A; lipopolysaccharide (endotoxin) from Salmonella abortus equi., enteriditis, and typhimurium; monensin; ionomycin; arachidonic acid; mimosine; palmitic acid; progesterone, androstenedione; estradiol-17beta; A23187; RU-486; or MER-25. Jugular and uterine venous plasma and culture media were analyzed for progesterone, PGE2 and PGF2alpha by radioimmunoassay (RIA). Plasma hormone data were analyzed by a One-Way Analysis of Variance (ANOVA). Hormone data in culture media were analyzed for breed and treatment effects by a Factorial Design (2 breeds, 2-range of days, 21 treatments) for ANOVA (2 x 2 x 21). Since hormone data secreted by placental tissue in vitro did not differ (P > or = 0.05) by breed or range of days of pregnancy, data were pooled and analyzed by a One-Way ANOVA. Concentrations of PGE2 in uterine venous blood were two-fold greater (P < or = 0.05) in Angus than Brahman cows. PGE2 and PGF2alpha in vehicle controls increased from 4 to 8h (P < or = 0.05), but not progesterone (P > or = 0.05) Progesterone in culture media treated with RU-486 increased (P < or = 0.05) at 4 and 8 h compared to vehicle controls and was not affected by other treatments (P > or = 0.05). Concentrations of PGE2 in media at 4 and 8 h were lower (P < or = 0.05) when compared to controls except treatment with PGE2 at 4 and 8h and RU-486 at 8h (P > or = 0.05). PGF2alpha was increased (P < or = 0.05) by RU-486 at 8h and no other treatment affected PGF2alpha at 4 or 8 h (P < or = 0.05). In conclusion, modulators of cellular calcium signalling pathways given alone do not affect bovine placental progesterone secretion at the days studied and progesterone receptor-mediated events appear to suppress placental progesterone, PGF2alpha, and PGE2 secretion in cattle. In addition, PGE2 does not appear to regulate bovine placental progesterone secretion when the corpus luteum is functional and bacterial endotoxin does not appear to affect bovine placental secretion of PGF2alpha or PGE2.

Abortifacient Agents↗
PubMed1998

Treatment with progesterone and 17 beta-oestradiol to induce emergence of a newly-recruited dominant ovulatory follicle during oestrus synchronisation with long-term use of norgestomet in Brahman heifers.

The aim of this study was to determine the effect on ovarian follicular growth and atresia, of acute treatment with either 100 mg of progesterone (n = 10), 200 mg of progesterone (n = 10), 10 mg of oestradiol + 100 mg of progesterone (n = 10), 10 mg of oestradiol (n = 10) or no treatment (n = 10), given on Day 10 of a 17-day treatment with a norgestomet implant in randomly cycling Bos indicus heifers. The fate of the dominant follicle on Day 10, emergence of the new cohort of follicles and the intervals from implant removal to ovulation were recorded by ultrasonography. Plasma concentrations of Luteinizing hormone (LH), progesterone and oestradiol were determined during the time when the norgestomet implant was in place. All treatments resulted in the emergence of a new cohort of follicles within 5 days of administration. The day of emergence of the ovulatory follicle tended to be delayed after treatment with 100 mg of progesterone (2.7 +/- 0.3 days after treatment), 200 mg of progesterone (3.7 +/- 0.5 days after treatment), 10 mg of oestradiol + 100 mg of progesterone (4.4 +/- 0.2 days after treatment) and 10 mg of oestradiol (4.6 +/- 0.4 days after treatment) compared to control heifers (1.4 +/- 1.4 days after time of treatment). The mean interval from implant removal to onset of oestrus was significantly shorter after treatment with 100 mg of progesterone (38.4 +/- 2.6 h) than after treatment with 200 mg of progesterone (61.5 +/- 3.9 h) but otherwise, the mean interval from implant removal to onset of oestrus did not differ. Oestrus synchrony, measured by the sample standard deviation of oestrus onset, was tighter in all treatment groups compared to untreated control heifers. The mean interval from implant removal to ovulation did not differ significantly between groups. The synchrony of ovulation, measured by the sample standard deviation of the interval from implant removal to ovulation, was significantly tighter after treatment with 100 mg of progesterone, 200 mg of progesterone and 10 mg of oestradiol compared to control heifers. Treatment with 10 mg of oestradiol resulted in ovulation in seven of 10 heifers before implant removal, three of which failed to ovulate after implant removal. Progesterone administered on Day 10 lowered plasma LH concentrations (P < 0.05), whereas treatment with oestradiol caused a surge of LH and ovulation. Progesterone administered with oestradiol prevented the LH surge. A combination treatment of oestradiol and progesterone given on Day 10 of a 17-day norgestomet treatment in a range of follicular states resulted in the consistent emergence of a new cohort of follicles which included the eventual ovulatory follicle.

Animals↗
PubMed1989

Hormonal dependence of the metrial gland: further studies on oestradiol and progesterone receptor levels in the rat.

The main objective of the present study was to analyse the hormonal dependence of the metrial gland formed in pseudopregnant animals following massive decidualization. On day 13 of pseudopregnancy (when the metrial gland reaches its maximal development) animals were ovariectomized and given s.c. implants of oestradiol and/or progesterone. A new implant technique for oestradiol delivery is described which provides circulating concentrations of oestradiol in the physiological range. In addition, we extended our previous work concerning oestradiol receptor and progesterone receptor concentrations in the metrial gland of pseudopregnant rats. The low oestradiol receptor concentration which we previously reported up to day 17 was maintained until the end of pseudopregnancy (day 21-1.5 fmol/micrograms DNA), whereas the progesterone receptor concentration remained raised (congruent to 3.5 fmol/micrograms DNA) from day 13 to day 19 and then decreased on day 21. The correlation of metrial gland weight and kinetics of the tissue oestradiol and progesterone receptors contents with the circulating oestradiol and progesterone concentrations lead to the following conclusions. First, the maintenance of the metrial gland is strictly progesterone-dependent. It is unlike the deciduoma which regresses spontaneously, even in the presence of progesterone. Secondly, the production of oestradiol receptor, but not of progesterone receptor, appears to be repressed in the metrial gland under the influence of progesterone. Thus, the tissue retains its ability to respond to progesterone because of a high concentration of progesterone receptor. It is difficult to attribute this high tissue progesterone receptor concentration to oestradiol stimulation since, even at low levels, oestradiol induces tissue regression. We suggest that the high progesterone receptor concentration could be due to constitutive (basal) progesterone receptor production.

Animals↗
PubMed2005

Identification of a 71 kDa protein as a putative non-genomic membrane progesterone receptor in boar spermatozoa.

A putative non-genomic progesterone receptor was identified by Western blot analysis from the membrane fraction but not the cytosolic fraction of boar spermatozoa using monoclonal antibody (mAb) C-262. When the membrane and the cytosolic fractions of boar liver, kidney, uterus and spermatozoa were analyzed with mAb C-262, protein bands with molecular masses of 86 and 120 kDa were detected from the cytosolic fraction of the uterus, whereas a 71 kDa protein was detected from the membrane fraction of spermatozoa. Apparently, while the 86 and 120 kDa proteins from the uterus correspond to the genomic progesterone receptor isoforms A and B in boar, the 71 kDa protein of the sperm membrane fraction seems to be a novel membrane-associated progesterone receptor. Ligand blot assay of the membrane and the cytosolic fractions of boar spermatozoa performed with peroxidase-conjugated progesterone revealed that only the 71 kDa membrane protein binds specifically to progesterone, reinforcing the results obtained from the Western blot analysis. Also ligand blot assays performed in the presence of mAb C-262 demonstrated that mAb C-262 inhibited progesterone binding to the 71 kDa protein in a dose-dependent manner. Ligand blot assays performed in the presence of free progesterone, RU486 or estrogen revealed that binding of peroxidase-conjugated progesterone to the 71 kDa protein was inhibited by free progesterone and RU486 in a dose-dependent manner but not by estrogen, which further confirms that progesterone binds to the 71 kDa protein specifically. Furthermore, the progesterone-induced acrosome reaction was inhibited by mAb C-262 in a dose-dependent manner. These results strongly imply that spermatozoa possess a progesterone receptor in a membrane-bound form and can be influenced by progesterone via non-genomic progesterone receptor.

Acrosome Reaction↗
PubMed2002

Progesterone inhibits human infragenicular arterial smooth muscle cell proliferation induced by high glucose and insulin concentrations.

INTRODUCTION: Diabetes mellitus is a significant risk factor for atherosclerotic peripheral vascular disease. Hyperglycemia and hyperinsulinemia, as encountered in patients with type II diabetes, have been shown to stimulate vascular smooth muscle cell (VSMC) proliferation, a paramount feature in atherosclerosis. Female sex hormones, such as estrogen, have been suggested to inhibit VSMC proliferation. However, the role of progesterone, particularly in patients with diabetes mellitus, has not been examined. Therefore, we studied the effect of progesterone on VSMCs exposed to various concentrations of glucose and insulin. METHODS: Human infragenicular VSMCs isolated from the tibial arteries of five male patients with diabetes undergoing lower extremity amputation were used. Immunocytochemical studies with confocal microscopy were performed for progesterone receptor identification in these VSMCs. Cells were grown to subconfluence, followed by exposure to deprived media with various glucose (100 and 200 mg/dL) and insulin (no insulin and 100 ng/mL) concentrations. Cells were then additionally exposed to physiologic progesterone (10 ng/mL, progesterone group) and compared with a no-progesterone group. Cell count and methyl-(3)H-thymidine incorporation were used to determine cellular proliferation. Cell count with hemocytometry was performed on day 6. DNA synthesis as reflected through methyl-(3)H-thymidine incorporation was measured at 24 hours. RESULTS: Immunocytochemical studies with confocal microscopy showed cytosolic progesterone receptors. The no-progesterone group showed a significant rise in cell count (P <.05) at all concentrations of glucose or insulin compared with the control group containing 100 mg/dL glucose concentration. The no-progesterone group also showed a significant rise in thymidine incorporation (P <.05) in the 100 mg/dL glucose-100 ng/mL insulin group and the 200 mg/dL glucose-100 ng/mL insulin group compared with the 100 mg/dL glucose group. In the cell count studies, progesterone significantly inhibited cellular proliferation in several settings. All cell groups cultured with insulin or an elevated glucose concentration showed a significant (P <.05) antiproliferative effect when exposed to progesterone. With thymidine incorporation, progesterone showed a similar antiproliferative effect in cells stimulated with glucose or insulin. CONCLUSION: Significant reductions in cell proliferation as determined with both cell count and thymidine incorporation suggest that progesterone is an inhibitor of VSMC proliferation induced by our in vitro models of hyperglycemia and hyperinsulinemia. Therefore, progesterone may have a protective role against the atherosclerotic changes associated with type II diabetes.

Aged↗
PubMed1983

Progesterone receptor replenishment in T47D human breast cancer cells. Roles of protein synthesis and hormone metabolism.

T47D are unusual human breast cancer cells that do not require estrogen to synthesize high levels of progesterone receptors. These cells can, therefore, be used to study the mechanisms by which progesterone, freed of estrogen interference, controls the synthesis of its receptors. In a recent paper we described progesterone receptor translocation and a subsequent very rapid nuclear processing step that results in an apparent loss of 60 to 80% of cellular progesterone receptors, 30 to 60 min after progesterone treatment. This paper deals with the replenishment of cellular receptors following processing. If progesterone is removed from cells after 60 min of treatment, cytoplasmic progesterone receptors replenish in 16 to 20 h. However, replenishment occurs even during chronic progesterone treatment; this is an artifact created by the extremely rapid (t1/2 approximately 2 h) metabolism of progesterone in media exposed to cells. If progesterone metabolism is blocked, then replenishment is not seen, probably because the hormone continuously retranslocates the newly replenished sites. There is an early protein synthesis-dependent step; cycloheximide in the first 4 h inhibits replenishment 24 h later, but if cycloheximide is slightly delayed (beyond 4 h), replenishment proceeds normally. In contrast to progesterone, the synthetic progestin R5020 completely suppresses progesterone receptor replenishment even 96 h after its removal from the medium. This compound can bind covalently to receptors and may be very difficult to remove from cells. Clearly, progestin treatment, and by analogy, circulating progesterone, will have profound effects on cytoplasmic and nuclear progesterone receptor levels when these are measured in biopsied human tumors as an adjunct to endocrine therapy.

Breast Neoplasms↗
PubMed1986

Protein synthesis and steroidogenesis in amphibian (Rana pipiens) ovarian follicles: studies on the conversion of pregnenolone to progesterone.

Previous experiments demonstrated that protein synthesis was involved in frog pituitary homogenate (FPH)-induced follicular progesterone production. In this study the metabolic conversion of pregnenolone to progesterone, and involvement of protein synthesis in this specific step of the progesterone synthetic pathway, was investigated in vitro cultured ovarian follicles of Rana pipiens. Fully grown follicles were incubated with frog pituitary homogenates or exogenous pregnenolone and progesterone content of follicle extracts and medium were measured by radioimmunoassay. In the absence of FPH, fully grown follicles converted exogenously added pregnenolone into progesterone in a dose-dependent fashion. Follicular progesterone concentrations were consistently higher than medium levels of steroid throughout the culture period. The conversion of pregnenolone to progesterone at different stages of follicle development was also investigated. The amount of follicular progesterone accumulated after culture with exogenous pregnenolone increased proportionally with follicle size. When fully grown follicles were cultured in the presence of cycloheximide, the inhibitor of protein synthesis blocked FPH-induced progesterone production, but conversion of exogenously added pregnenolone to progesterone was not affected. However, progesterone production was inhibited when cyanoketone (CK), an irreversible inhibitor of the 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), was added in combination with FPH or exogenous pregnenolone. FPH addition after CK pretreatment did not restore the capacity of follicles to convert pregnenolone to progesterone. These results suggest that conversion of pregnenolone to progesterone occurs efficiently even in the absence of FPH over the course of follicle and oocyte growth (vitellogenesis). Furthermore, in fully grown follicles the 3 beta-HSD activity is independent of protein synthesis. The dependence on protein synthesis in the acute action of FPH appears to be prior to conversion of pregnenolone to progesterone and does not involve de novo synthesis of 3 beta-HSD.

Animals↗
PubMed1988

A possible role for progesterone in the preovulatory gonadotropin surge through modulation of LHRH degrading activity.

The preovulatory surge of gonadotropins is triggered by estradiol and enhanced to its full magnitude by progesterone. Progesterone may exert this effect through several mechanisms. One of the mechanisms is through the ability of progesterone to induce an increase in the hypothalamic content and release of LHRH. The purpose of this study was to determine if progesterone might not act through yet another mechanism and facilitate LHRH release of the proestrous gonadotropin surge through modulation of luteinizing hormone releasing hormone (LHRH) degrading activity. Sixty-day-old Sprague-Dawley rats were ovariectomized; 14 days later, the estradiol-progesterone milieu of proestrous was mimicked in these animals through the use of estradiol containing silastic implants and subcutaneous progesterone injections. The LHRH degrading activity of the hypothalamus, pituitary and serum were monitored subsequently at preselected time points. In the hypothalamus, estradiol alone was capable of inducing significant increase in degrading activity; progesterone alone had no effect; however, progesterone subsequent to estradiol priming suppressed the increase induced by estradiol alone. In the pituitary, neither estradiol alone nor progesterone alone nor progesterone subsequent to estradiol priming had any significant effect on degrading activity. In the serum, estradiol induced a rapid and significant increase in activity; progesterone alone suppressed activity; progesterone subsequent to estradiol priming induced a similar but more rapid suppression. Therefore, the overall tendency was for estradiol to stimulate and progesterone to suppress LHRH degrading activity in the tissues studied. The results of this study indicate that progesterone has the capacity to suppress LHRH degrading activity and may be one of the mechanisms capable of increasing the availability of LHRH to the anterior pituitary gland thereby facilitating the preovulatory gonadotropin surges.

Animals↗
PubMed1999

Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen.

OBJECTIVE: The objective of this study was to evaluate the serum levels of progesterone resulting from the application of a progesterone cream to the skin. STUDY DESIGN: Six postmenopausal women were evaluated at a university clinic over a 4-week period. RESULTS: Transdermal estradiol 0.05 mg was applied 2 days before the first application of progesterone (30 mg/d) and was continued throughout the study. Patches were changed twice a week. Progesterone cream was applied once a day for 2 weeks. On day 15 and for the next 2 weeks, the progesterone cream was applied twice daily (60 mg/d). Serum 17beta-estradiol and progesterone were measured at 9 different times over a 24-hour period on day 1 and at weekly intervals for the 4-week duration of the study. Serum 17beta-estradiol concentrations varied among women, with mean concentrations of 40 to 64 pg/mL observed. Consistency in 17beta-estradiol concentrations was found within individual persons throughout the study. Serum progesterone concentrations also varied among women, with mean concentrations ranging from 1.6 to 3.3 ng/mL. After 2 weeks of percutaneous dosing, progesterone concentrations were sustained for at least 8 hours and were consistent within a given person. An appropriate increase in progesterone concentration occurred after 4 weeks compared with 2 weeks of application. Individually, a 0.53 correlation, significant at P <.0001, was seen between the absorption of 17beta-estradiol and progesterone. CONCLUSION: Significant increases in serum concentrations of progesterone were observed in all of the women studied. The percutaneous absorption of progesterone correlates strongly with the absorption of transdermal 17beta-estradiol. There is variance in absorption of progesterone just as with 17beta-estradiol, and the 2 measures are closely correlated. The percutaneous application of progesterone cream appears to be a safe and effective route of administration.

Administration, Cutaneous↗