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PubMed1997

Uterine response to progesterone in prepubertal gilts.

During early pregnancy, progesterone stimulates the secretion of proteins and other molecules that support the developing conceptus. Some gilts are able to support conceptus development as early as 110 days of age. The objective of this study was to evaluate the onset of responsiveness of the prepubertal uterus to progesterone. Thirty gilts were assigned to receive 2.2 mg progesterone kg-1 body mass per day or corn oil daily for 14 days starting at 6, 46, 76, 106, and 136 days of age. Hysterectomies were performed the day after the last treatment of progesterone, and the uterine horns were weighed and flushed with sterile saline (0.85% NaCl). Recovered flushings were analysed for total luminal protein, retinol binding protein, uteroferrin, prostaglandin E and prostaglandin F. An interaction between age and progesterone occurred for uterine wet mass (P < 0.001). Progesterone did not affect the uterine mass of gilts that underwent hysterectomy at 20 days of age, but did increase the uterine mass (P < 0.05) in other age groups. Progesterone increased (P < 0.01) the amount of total luminal protein in all but the youngest gilts. An increase in the amounts of retinol binding protein and uteroferrin (P < 0.001) by progesterone was first observed in 90-day-old gilts. Prostaglandins exhibited a different age-related pattern. The amount of prostaglandin E was increased (P < 0.001) by progesterone treatment in gilts aged 90-150 days, with a greater (P < 0.05) response at 120 days than at 90 days old. The response at 150 days old decreased (P < 0.05) to that observed at day 90. The response of prostaglandin F to progesterone followed a similar age-related pattern. Therefore, uterine responsiveness to progesterone develops between 20 and 90 days after birth, and uterine mass responds earlier than the secretory responses measured in our study.

Acid Phosphatase↗
PubMed2004

Effects of metformin treatment on luteal phase progesterone concentration in polycystic ovary syndrome.

The causes of luteal phase progesterone deficiency in polycystic ovary syndrome (PCOS) are not known. To determine the possible involvement of hyperinsulinemia in luteal phase progesterone deficiency in women with PCOS, we examined the relationship between progesterone, luteinizing hormone (LH) and insulin during the luteal phase and studied the effect of metformin on luteal progesterone levels in PCOS. Patients with PCOS (19 women aged 18-35 years) were treated with metformin (500 mg three times daily) for 4 weeks prior to the test cycle and throughout the study period, and submitted to ovulation induction with clomiphene citrate. Blood samples were collected from control (N = 5, same age range as PCOS women) and PCOS women during the late follicular (one sample) and luteal (3 samples) phases and LH, insulin and progesterone concentrations were determined. Results were analyzed by one-way analysis of variance (ANOVA), Duncan's test and Karl Pearson's coefficient of correlation (r). The endocrine study showed low progesterone level (4.9 ng/ml) during luteal phase in the PCOS women as compared with control (21.6 ng/ml). A significant negative correlation was observed between insulin and progesterone (r = -0.60; P < 0.01) and between progesterone and LH (r = -0.56; P < 0.05) concentrations, and a positive correlation (r = 0.83; P < 0.001) was observed between LH and insulin. The study further demonstrated a significant enhancement in luteal progesterone concentration (16.97 ng/ml) in PCOS women treated with metformin. The results suggest that hyperinsulinemia/insulin resistance may be responsible for low progesterone levels during the luteal phase in PCOS. The luteal progesterone level may be enhanced in PCOS by decreasing insulin secretion with metformin.

Adolescent↗
PubMed1994

Specific binding sites for progesterone in subcellular fractions of the porcine corpus luteum.

Subcellular fractionation of porcine corpus luteum (CL) homogenates on continuous sucrose gradients has previously demonstrated that most of the endogenous progesterone of the CL was associated with a unique particulate fraction. Exogenous radiolabelled steroids were also sequestered with some specificity by this fraction. We now report that this particulate fraction is capable of binding high levels of exogenous 3H-labelled progesterone (and pregnenolone) in vitro, but only in the presence of the saponin, digitonin. Binding was dependent on the pH, temperature and duration of incubation, and showed specificity and high affinity for progesterone (Kd, 79 nM). Androgens, oestrogens and pregnenolone competed for porcine luteal [3H]progesterone binding sites, but only at much higher concentrations, whereas cholesterol, a number of progesterone receptor agonist and antagonist analogues and inhibitors of 3 beta-hydroxysteroid dehydrogenase and C17-hydroxylase/C17,20-lyase did not compete. Analysis of profiles for a number of luteal cell-surface membrane and intracellular organelle markers confirmed previous studies showing the association of an NADH-cytochrome C reductase with this fraction. Moreover, the content of endogenous progesterone associated with particulate subcellular fractions isolated from porcine granulosa cell (GC) and CL homogenates at different stages of the luteal phase and early pregnancy waxed and waned with the stage of the luteal phase (and the secretory activity of the CL). Binding of [3H]progesterone in vitro equilibrated at the same buoyant density as endogenous progesterone: levels of both were highest during the mid-luteal phase and during early pregnancy, lower in early and late luteal CL, and undetectable in corpora albicantia. In contrast, relaxin secretory granules were readily resolved from progesterone binding sites. We propose that these particulate progesterone binding sites may be involved in the sequestration and/or packaging of newly-synthesized steroid for secretion by the luteal cell, or may mediate actions of progesterone within the luteal cell.

Animals↗
PubMed1997

Effect of alteration of maternal plasma progesterone concentrations on fetal behavioural state during late gestation.

Placental progesterone synthesis exposes the fetus to high levels of progesterone and progesterone metabolites during late gestation which may influence fetal behaviour. To determine the role of maternal progesterone synthesis in the control of fetal arousal state and fetal breathing movements (FBM), the effect of raising and lowering maternal progesterone concentrations was examined in chronically catheterised fetal sheep. Fetal and maternal vascular catheters, fetal tracheal and amniotic fluid catheters as well as electrodes for recording fetal electrocortical (ECoG), electro-ocular (EOG) and nuchal muscle electromyographic (EMG) activity were implanted between 118 and 122 days gestational age (GA). Progesterone, 100 mg, administered twice daily i.m. for 3 days (130-133 days GA) resulted in a marked elevation in maternal plasma progesterone concentrations (370 +/- 121%, n = 5, P < 0.05), but had no effect on fetal plasma concentrations. Fetal EOG episodes and the duration of fetal behavioural arousal were significantly suppressed throughout the progesterone treatment period (74.4-81.1% and 58-65% respectively, P < 0.05, n = 5). Four ewes received Trilostane (25 mg i.v.), a 3 beta-hydroxysteroid dehydrogenase inhibitor, between 136 and 140 days GA. Maternal and fetal progesterone concentrations were significantly lowered by 60 min after treatment (19.8 +/- 8.0% and 39.5 +/- 24.3% respectively, P < 0.05). The incidence of fetal EOG activity increased from a pretreatment level of 26.8 +/- 1.5 min/h to 30.3 +/- 2.8 min/h at 1-6 h and to 35.0 +/- 1.7 min/h (P < 0.05) during the 7-12 h after Trilostane treatment. The duration of FBM episodes was significantly higher at 1-6 h and 7-12 h after Trilostane treatment (19.5 +/- 3.0 and 23.6 +/- 5.5 min/h respectively, P < 0.05) compared with pretreatment levels (11.2 +/- 1.2 min/h). We conclude that increasing maternal progesterone levels suppresses fetal EOG activity and behavioural arousal, whereas reducing maternal progesterone synthesis leads to an elevation of EOG activity and FBM.

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

Progesterone therapy during early pregnancy and embryonal survival in primiparous weaned sows.

The experiment was conducted in primiparous sows to determine whether progesterone supplementation during early pregnancy could improve embryonal survival and to confirm a functional relationship between progesterone concentrations in the postovulatory period and embryonal survival. Thirty-four primiparous sows were fed for ad libitum intake from farrowing to d 21 of lactation, restricted to 50% of ad libitum intakes between d 22 and 28, weaned on d 27, and then fed for ad libitum intake from weaning until d 28 of gestation. The number of pigs per litter was standardized to nine within 48 h after farrowing. After mating, sows were allocated either to be treated with ethyl oleate (control group) or to receive progesterone (P4) therapy (progesterone group) as 2 mg of P4/kg(.75) i.m., every 12 h from 36 to 96 h after onset of standing estrus. There was no difference in the weaning-to-estrus interval (123.5 +/- 5.7 vs 123.1 +/- 5.9 h) and number of corpora lutea (18.1 +/- .4 vs 18.3 +/- .5) between the control and progesterone sows (P > .05). Compared with a more gradual increase in control sows, plasma progesterone concentrations in progesterone sows increased immediately from .6 +/- .1 ng/mL at 36 h after onset of standing estrus to 6.3 +/- .5 ng/mL (P < .001) 12 h later and remained high. Total number of embryos, total embryonal survival rate, number of viable embryos, and viable embryonal survival rate on d 28 of gestation in control sows were greater than in progesterone sows (13.3 +/- 1.0 vs 8.5 +/- 1.1; 73.1 +/- 4.7 vs 47.3 +/- 5.4%, P < .005; 12.6 +/- .9 vs 7.1 +/- .9, and 69.5 +/- 4.2 vs 39.7 +/- 4.8%, P < .0005; respectively). Embryonal survival in control sows was comparable to that in previous experiments using the same primiparous sow model, and the relationship between plasma progesterone and embryonal survival seemed similar. However, using the treatment schedule adopted, progesterone not only failed to reverse the presumed detrimental effect of increased catabolism in the late lactation period on embryonal survival, but also adversely affected the number of embryos at d 28 in 7 out of 15 progesterone-treated sows.

Animals↗
PubMed2006

Diet-induced alterations in progesterone clearance appear to be mediated by insulin signaling in hepatocytes.

Factors that affect progesterone clearance from plasma and by hepatocytes in culture were examined in a series of experiments. In Exp. 1, the objective was to determine whether an increase in hepatic portal blood acetate or propionate could alter progesterone metabolism by the liver. For ewe lambs gavaged orally with sodium propionate compared with those gavaged orally with sodium acetate, serum progesterone concentrations began to diverge as early as 0.5 h after administration and were greater (P < 0.05) at 3 and 4 h after administration. The objective of Exp. 2 was to determine the effect of a single oral gavage of either sodium acetate or sodium propionate on peripheral insulin and glucagon concentrations. Ewes gavaged orally with sodium propionate had greater (P < 0.05) insulin concentrations at 0.5 and 1 h after gavage than ewes gavaged with sodium acetate. Furthermore, glucagon concentrations were greater (P < 0.05) at 0.5, 1, and 2 h for ewe lambs gavaged orally with sodium propionate compared with those receiving sodium acetate. The third experiment investigated the rate of in vitro progesterone clearance by cultured hepatocytes in response to treatment with different concentrations of insulin and glucagon. Progesterone clearance was reduced (P < 0.05) with the addition of 0.1 nM insulin compared with the control. Furthermore, there was a greater reduction (P < 0.05) in progesterone clearance in response to 1.0 and 10 nM insulin compared with the control and 0.1 nM insulin. No change was observed in progesterone clearance in hepatocytes treated with either physiological (0.01 and 0.1 nM) or supraphysiological (1.0 nM) glucagon. Supraphysiological concentrations of glucagon (1.0 nM) negated the effects of either 0.1 or 1.0 nM insulin on progesterone clearance by hepatocytes. However, with physiological concentrations of glucagon (0.1 nM) and 1.0 nM insulin, glucagon was not able to negate the reduction in progesterone clearance caused by insulin. These data are consistent with a paradigm in which elevated hepatic portal vein propionate increases plasma insulin in ruminants, which decreases progesterone clearance, thereby increasing serum progesterone concentrations.

Acetates↗
PubMed1980

Comparison of milk and blood plasma progesterone concentrations in cycling and pregnant mares.

Progesterone concentrations were measured in milk and blood plasma for 15 mares throughout a normal estrous cycle and early pregnancy to determine the feasibility of utilizing progesterone in milk as an indicator of pregnancy. Samples were obtained daily from foaling until diagnosis of pregnancy by rectal examination at 30 to 35 days of gestation. Progesterone in milk and blood plasma was quantified by radioimmunoassay. Mean progesterone concentrations (+/- SE) in plasma from foaling to foal heat and during estrus, luteal phase and pregnancy were .51 +/- .09 ng/ml, .53 +/- .08 ng/ml, 3.88 +/- .26 ng/ml and 4.22 +/- .09 ng/ml, respectively; progesterone concentrations in milk during the same periods were 1.57 +/- .16 ng/ml, 1.41 +/- .06 ng/ml, 4.26 +/- .21 ng/ml and 4.14 +/- .09 ng/ml respectively. Progesterone concentrations in milk were higher than concentrations in plasma only from foaling to foal heat and during estrus. Days of the estrous cycle on which milk and (or) blood plasma progesterone concentrations could be used to detect pregnancy were determined. Progesterone concentrations in milk from seven of the mares on each day from day 1 to 25 of a normal estrous cycle (nonpregnant) were compared to progesterone concentrations in milk from the same seven mares on days 1 to 25 of a subsequent fertile estrous cycle (pregnancy). (The first day that mares refused to accept the stallion respectively.) Identical comparisons were made of progesterone concentrations in blood plasma. Significantly lower progesterone concentrations were observed in milk from nonpregnant mares from days 17 to 22 and in blood plasma from nonpregnant mares from days 15 to 22.

Animals↗
PubMed1992

Vaginal progesterone administration in physiological doses normalizes raised luteinizing hormone levels in patients with polycystic ovarian syndrome.

A raised luteinizing hormone (LH) level is a typical finding in the polycystic ovarian syndrome (PCOS). This inappropriate elevation of LH is thought to interfere with normal follicular development and ovulation. The resulting chronic anovulation is associated with the absence of the luteal phase increase in secretion of progesterone and inhibin. Progesterone can exert both a positive and negative feedback action on LH secretion, but inhibition is thought to occur following prolonged exposure to progesterone. Therefore, the aim of this study was to see if exogenously administered progesterone in physiological doses would normalize circulating LH concentrations in patients with PCOS. Vaginal progesterone was administered twice daily in a dose of 100 mg, at 12 h intervals, to ten women with PCOS. Serum samples were taken on alternate days for radioimmunoassay of follicle stimulating hormone (FSH), LH, estradiol, progesterone and inhibin. To determine the effect of progesterone on LH secretory dynamics in PCOS, LH pulse studies were carried out prior to treatment, and on day 10 of progesterone administration in four of the ten subjects. Mean serum progesterone concentrations reached 51 nmol/l by 4 days after exogenous progesterone treatment, and remained in the mid-luteal phase range, as established in 12 normal cycles, during the use of the vaginal suppository. The mean serum LH concentration had fallen significantly (p < or = 0.01) after 8 days of treatment, and continued to fall progressively until the end of progesterone administration. Serum LH concentrations had fallen into the normal follicular phase range by 14 days (mean 5.5, range 3.4-10.9 IU/l; normal follicular phase range 1.8-10.0 IU/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Estradiol↗
PubMed1996

Transvaginal progesterone supplementation increases serum insulin-like growth factor-binding protein-1 levels.

The objective of this study was to assess the effect, which might be mediated by progesterone-dependent insulin-like growth factor-binding protein-1 (IGFBP-1), of micronized progesterone supplementation through different administration routes (oral or vaginal) on successful pregnancy. A total of 299 anovulatory women were treated with clomiphene citrate (100 mg/day on days 5-9 of the menstrual cycle) to stimulate follicular growth. Human chorionic gonadotropin (hCG, 10,000 IU) was injected intramuscularly when at least one follicle was > 20 mm in diameter as monitored by transvaginal ultrasonography. Micronized progesterone (300 mg/day, at bedtime) was used as supplementation of progesterone randomly by oral (n = 153) or vaginal (n = 146) administration from approximately 36-48 h after hCG administration until the following menstrual period or the 10th week of gestation from the last menstrual period. As a control, 18 apparently healthy females with at least three regular menstrual cycles immediately before the present study were also recruited but no interventions were made. Serum levels of progesterone, IGFBP-1, insulin-like growth factor-I (IGF-I) and insulin were determined on day 8 after hCG administration (day 0 indicates the day of hCG administration; progesterone supplementation group) or on day 21 of the menstrual cycle (controls). In the midluteal phase higher progesterone and lower IGFBP-1 levels were observed in the serum from patients supplemented with oral progesterone than in those using vaginal progesterone. Total and continuing pregnancy rates were also higher in the patients using oral than in those using vaginal progesterone (p < 0.04, by the zI-test). However, there was no difference in serum IGF-I or insulin level between the groups. It was concluded that oral administration of micronized progesterone at bedtime appears to be a convenient method of luteal supplement, whereas vaginal supplementation during the luteal phase might directly stimulate endometrial production of IGFBP-1, which possibly, in turn, deters embryo implantation and results in a decrease in the pregnancy rate.

Administration, Intravaginal↗
PubMed1987

Relative binding affinity of antiprogestins ZK 98.299 and ZK 98.734 for progesterone receptors in the endometrium and myometrium of bonnet monkeys.

Progesterone bound with high affinity to the endometrial and myometrial cytosol of ovariectomized bonnet monkeys pretreated with estradiol benzoate and progesterone. The equilibrium dissociation constant (Kd) of 3H-progesterone was 4.5 nM and 5.5 nM and the binding capacity was 1.7 nM and 1.4 nM for the endometrial and myometrial receptors, respectively. This experimental 'model' was used to assess the relative binding affinity (RBA) of progesterone, ZK 98.299 and ZK 98.734. The tested compounds showed competitive binding to cytoplasmic progesterone receptors. The RBA of progesterone in the endometrium (100) was more than that of ZK 98.299 (25.1) and ZK 98.734 (17.8). A similar RBA pattern was observed in the myometrial cytosol. Both ZK 98.299 and ZK 98.734, like progesterone, displaced the 3H-progesterone bound to the receptors. The administration of ZK 98.299 or ZK 98.734, during the mid-luteal phase, has been reported to shorten the cycle length in bonnet monkeys and marmosets, respectively. These compounds, therefore, appear to intercept the progesterone action by blocking progesterone binding sites in the target tissue. Since ZK 98.299 has higher binding affinity than ZK 98.734, it may be a more potent progesterone antagonist.

Animals↗
PubMed1985

Comparison of pregnancy diagnosis by milk progesterone on day 21 and day 24 postbreeding: field study in dairy cattle.

Milk samples collected at 21 and 24 d after breeding were used to diagnose cows as pregnant, questionable, or not pregnant with high, intermediate, or low progesterone in the milk. Total agreement of pregnancy diagnosis in cows by milk progesterone at 21 d postbreeding and diagnosis by return to estrus or palpation of reproductive organs was 85.8% (77.4% on pregnant progesterone diagnosis and 97.2% on not pregnant progesterone diagnosis). Total agreement of diagnosis by progesterone at 24 d postbreeding and diagnosis by estrus or palpation was 88.4% (83.5% on pregnant progesterone diagnosis and 95.3% on not pregnant progesterone diagnosis). Although total accuracy of cows diagnosed both pregnant and not pregnant by milk progesterone on d 24 postbreeding was greater than diagnosis on d 21 postbreeding when cows in estrus by d 24 were deleted from the data, other comparisons for effect of day on accuracy of diagnosis were not different. Total accuracy of diagnosis on d 24 was not increased by using milk progesterone on both d 21 and 24. Samples collected on the day of breeding indicated that 18 of 960 (1.9%) had intermediate or high progesterone. Fourteen (1.5%) additional cows had progesterone above levels expected for a cow in estrus.

Animals↗
PubMedDate not supplied

Uses of progesterone in clinical practice.

Progesterone is the natural progestagen produced by the corpus luteum during the luteal phase. It is absorbed when administered orally, but is greater than 90% metabolized during the first hepatic pass. This greatly limits the efficacy of once-daily administration and also results in unphysiologically high levels of progesterone metabolites, particularly those reduced at the 5-a position. These metabolites can cause dizziness and drowsiness to the point of preventing the operation of a motor vehicle. Synthetic progestins, such as medroxyprogesterone acetate and norethindrone acetate (NETA), have been specifically designed to resist enzymatic degradation and remain active after oral administration. However, these compounds exert undesirable effects on the liver and often cause severe psychological side effects. The permeability of the skin does not allow for administration of progesterone in the quantities normally produced by the corpus luteum, i.e., up to 25 mg/day during the mid-luteal phase. To avoid this problem, synthetic progestins such as NETA have been administered transdermally. These compounds, though, just like synthetic estrogens administered non-orally, retain undesirable hepatic effects even when administered transdermally. Transvaginal administration of progesterone is a practical non-oral route available for administering progesterone. Early experience was gained with vaginal suppositories, which lack manufacturing controls. Recently, a new progesterone gel formulation has been designed for vaginal use. The clinical acceptability of this product has been enhanced by the bioadhesive characteristics of its polycarbophil-based gel, which conveys controlled and sustained-released properties. Investigations have shown that because of local direct vagina-to-uterus transport, which results in a preferential uterine uptake of progesterone, this formulation given in conjunction with physiological amounts of estradiol produces endometrial changes similar to those seen in the luteal phase, despite plasma progesterone levels that remain subphysiologic. Studies in infertility show that vaginal progesterone in this form allows secretory transformation of the endometrium and the development of pregnancy despite providing low systemic progesterone concentrations. Fewer side effects occur when used for hormone replacement than typically encountered with progestins and oral progesterone. Uses in patients with infertility and hypoestrogenism and secondary amenorrhea are reviewed.

Administration, Intravaginal↗
PubMed1991

Mechanism of the HDL2 stimulation of progesterone secretion in cultured placental trophoblast.

Lipoprotein cholesterol (C) supports the high rate of progesterone production by the human placenta as endogenous cholesterol synthesis is low. To study underlying mechanisms whereby lipoproteins, including high density lipoprotein-2 (HDL2), stimulate progesterone secretion, trophoblast cells were isolated from human term placentas and maintained in primary tissue culture. Lipoproteins were added at several concentrations and medium progesterone secretion was determined. HDL2 (d 1.063-1.125 g/ml) as well as low density lipoproteins (LDL) (d 1.019-1.063 g/ml) but not HDL3 (d 1.125-1.21 g/ml) stimulated progesterone secretion in a dose-dependent manner, with HDL2 cholesterol entering the cell and serving as substrate for progesterone synthesis. Conversely, LDL and HDL2 produced a significant decrease in [2-14C]acetate incorporation into cell cholesterol. Cholesterol-depleted lipoproteins did not stimulate progesterone secretion. The stimulating effect of LDL was abolished by apolipoprotein modification by cyclohexanedione or reductive methylation and by the addition of anti-LDL receptor antibody or 10 microM chloroquine to the medium. [14C]acetate conversion into cholesterol was accelerated by these procedures. However, HDL2 stimulation of progesterone secretion and reduction of [14C]acetate incorporation into cholesterol was not blocked by chemical modification of apolipoproteins, anti-LDL receptor antibody, or chloroquine. Treatment of HDL2 with tetranitromethane or dimethylsuberimidate also did not block the stimulation of progesterone. To determine whether the capacity of HDL2 to deliver cholesterol to the trophoblast cells was restricted to subfractions differing in apoE content, HDL2 was chromatographed on heparin-Sepharose and three fractions (A, B, and C) were obtained. Fraction A was poorest in apoE and free cholesterol, fraction B contained the majority of cholesterol, and fraction C was the richest in apoE and free cholesterol. When added to trophoblast cells, fraction A stimulated little progesterone secretion, fraction B stimulated moderately, and fraction C did so greatly. Modification of these subfractions with cyclohexanedione or reductive methylation did not inhibit these effects. In conclusion, HDL2 stimulated progesterone secretion in human trophoblast cell culture. Contrary to LDL, the HDL effect was not mediated by apolipoproteins or the LDL receptor pathway. The ability of HDL2 to stimulate progesterone secretion is consistent with the passive transfer of free cholesterol to the cell membrane from a physicochemically specific subfraction of HDL. This mechanism may be an auxiliary source of cholesterol for human steroidogenic cells.

Antibodies, Monoclonal↗
PubMed1990

Serum disposition of exogenous progesterone after intramuscular administration in bitches.

Progesterone was administered IM to 6 adult anestrous bitches at a dosage of 2 mg/kg of body weight. Serum progesterone concentrations were measured prior to progesterone administration and for 72 hours thereafter. The serum progesterone concentration time data were analyzed by use of a pharmacokinetics modeling computer program. The mean (+/- SD) peak serum progesterone concentration (34.3 +/- 7.8 ng/ml) was reached at 1.8 +/- 0.2 hours after progesterone administration. The mean serum progesterone concentration was 6.9 +/- 1.4 ng/ml at 24 hours and 2.0 +/- 0.4 ng/ml at 48 hours after progesterone administration. By 72 hours after administration, mean serum progesterone concentration was 0.9 +/- 0.2 ng/ml, which was comparable to serum progesterone concentrations prior to injection. The mean half-life of the absorption phase was 0.5 hours (range, 0.3 to 0.7 hours). The mean half-life of elimination was 12.1 hours (range, 9.5 to 13.8 hours). By analysis of the data, it was established that a dosage of 3 mg/kg, when the hormone was given IM to dogs once a day, would maintain serum progesterone concentration greater than 10 ng/ml.

Animals↗
PubMed1988

Heterogeneity of progesterone receptor distribution in human endometrial adenocarcinoma.

The clinical response of advanced endometrial adenocarcinoma to progestin therapy does not correlate perfectly with biochemically assayed progesterone receptor status of the tumor. We have previously suggested that heterogeneity of progesterone receptor at the cellular, tumor, and tissue levels, not detectable by the biochemical assay, might contribute to this discrepancy. A monoclonal antibody, hPRa-1, generated against human progesterone receptor, was used in the present study to immunohistologically define the heterogeneity of progesterone receptor distribution in primary endometrial carcinomas. Twenty-four hysterectomy specimens removed for the treatment of endometrial adenocarcinoma were examined by biochemical assay of progesterone receptor and immunohistochemistry. In two cases, in which tumor occupied almost all of the endometrial lining, more extensive sampling was performed with removal of four noncontiguous sites. Each site was subdivided for immunohistochemistry and biochemical assay of progesterone receptor. When present, progesterone receptor localization was confined to the nuclei of target cells. Variability in the distribution and intensity of staining was consistently observed within the tumors. Of 24 tumors 15 were determined to be progesterone receptor positive by biochemical assay, while 12 of 24 tumors displayed immunolocalization for progesterone receptor. The correlation of the results by the two methods was high (20 of 24 cases, 83%), and the discrepancies in three cases appeared to reflect tissue and tumor heterogeneity. Immunolocalization has demonstrated that heterogeneity is present at the tumor, tissue, and cellular level within endometrial carcinomas, and the failure of some progesterone receptor-positive (by biochemical assay) tumors to respond to progestin therapy may reflect false positive results due to contamination of progesterone receptor-negative tumors by adjacent benign endometrium or myometrium.

Adenocarcinoma↗
PubMed1984

Role of blood cells in degradation of progesterone in bovine blood.

The nature of progesterone decline in samples of bovine blood as affected by whole blood incubation time and temperature was investigated in 3 experiments. In 2 experiments, progesterone concentrations were determined in plasma, in hemolyzed (by freezing and thawing) blood, and in washed blood cells and blood cell washes before and after 8 hours of incubation at 22 C to study the effect of RBC on detected progesterone. In the third experiment, the effect of alteration in RBC metabolism on progesterone degradation by these cells was studied by using potassium oxalate-sodium fluoride as anticoagulant. Results of these experiments indicated that (a) progesterone was significantly reduced because of whole blood incubation time and temperature, (b) lost progesterone was not detectable on or in blood cells indicating chemical degradation of progesterone, (c) intact blood cells were needed to obtain the decrease in the progesterone, (d) a small amount of circulating blood progesterone was associated with blood cells, and (e) degradation of bovine blood progesterone by blood cells was dependent on the glycolytic process. Potassium oxalate-sodium fluoride anticoagulant and refrigeration provided the best progesterone results when blood samples were not processed immediately after collection.

20-alpha-Dihydroprogesterone↗
PubMedDate not supplied

Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53.

Progesterone inhibits the proliferation of normal breast epithelial cells in vivo, as well as breast cancer cells in vitro. But the biologic mechanism of this inhibition remains to be determined. We explored the possibility that an antiproliferative activity of progesterone in breast cancer cell lines is due to its ability to induce apoptosis. Since p53 and bcl-2 genetically control the apoptotic process, we investigated whether or not these genes could be involved in the progesterone-induced apoptosis. We found a maximal 90 percent inhibition of cell proliferation with T47-D breast cancer cells after exposure to 10 microM progesterone for 72 hours. Control progesterone receptor negative MDA-231 cancer cells were unresponsive to these two concentrations of progesterone. After 24 hours of exposure to 10 microM progesterone, cytofluorometric analysis of T47-D breast cancer cells demonstrated 43 percent had undergone apoptosis without signs of necrosis. After 72 hours of exposure to 10 microM progesterone, 48 percent of the cells had undergone apoptosis and 40 percent demonstrated "leaky" membranes. Untreated cancer cells did not undergo apoptosis. Evidence proving apoptosis was also demonstrated by fragmentation of nuclear DNA into multiples of oligonucleosomal fragments. After 24 hours of exposure to either 1 microM or 10 microM progesterone, the expression by T47-D cancer cells of bcl-2 was down-regulated, and that of p53 was up-regulated as detected by semiquantitative RT-PCR analysis. These results demonstrate that progesterone at a concentration similar to that seen during the third trimester of pregnancy exhibited a strong antiproliferative effect on at least two breast cancer cell lines. Apoptosis was induced in the progesterone receptor expressing T47-D breast cancer cells.

Apoptosis↗
PubMed2026

Progesterone Is Associated With Increased Vasohibin-2 Expression, Tubulin Detyrosination, and Paclitaxel Sensitivity in PR-Negative Ovarian Cancer Cells.

BACKGROUND: Progesterone induces rapid cellular responses in progesterone receptor (PR)-negative ovarian cancer cells that are consistent with non-genomic progesterone signaling. Vasohibin-2 (VASH2), originally identified as a pro-angiogenic factor, has recently been recognized as a tubulin carboxypeptidase involved in microtubule regulation. AIMS: This study investigated the association of progesterone treatment with VASH2-related molecular changes and paclitaxel sensitivity in ovarian cancer cells. METHODS: Two PR-negative ovarian cancer cell lines expressing membrane progesterone receptors (mPRs) were treated with progesterone. VASH2 mRNA expression was evaluated by RT-qPCR, whereas detyrosinated tubulin and cyclin B1 expression were assessed by western blotting. Paclitaxel and gemcitabine sensitivities were determined using WST-1 cell viability assays. RESULTS: Progesterone treatment was associated with increased VASH2 mRNA expression, enhanced tubulin detyrosination, cyclin B1 accumulation, and significantly reduced paclitaxel IC50 values in both cell lines. In contrast, progesterone had no significant effect on gemcitabine sensitivity. CONCLUSION: Progesterone treatment was associated with increased VASH2 expression, enhanced tubulin detyrosination, and increased paclitaxel sensitivity in PR-negative ovarian cancer cells. These findings provide in&#xa0;vitro evidence supporting further mechanistic and preclinical investigation of progesterone as a potential adjunct to paclitaxel therapy.

Humans↗