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PubMed2003

Progestins and breast cancer.

The relationship between the use of menopausal hormone therapy (ERT, unopposed estrogen therapy; HRT, combined estrogen and progestin therapy) and the development of breast cancer remains controversial. Mechanistic studies examining progestins in human breast cancer cell lines have demonstrated a biphasic cellular response to progesterone; initial exposure to hormone results in a proliferative burst with sustained exposure resulting in growth inhibition. To date, there is no definitive evidence that progestins act in the pathogenesis of breast cancer. Epidemiologic studies have produced inconsistent results, and data from randomized, placebo-controlled trials are limited. Although recent results from the continuous combined therapy arm of the Women's Health Initiative trial showed a small increase in the risk of invasive breast cancer in women on therapy for 5 years or more, a clear consensus regarding the relationship between HRT and breast cancer risk cannot yet be drawn from existing data. Studies have consistently documented that HRT use is associated with improved mortality and survival rates for women with breast cancer. Large-scale, randomized studies on different progestin regimens are needed to critically assess the effect of progestin on breast cancer.

Animals↗

PubMed1990

Modulation of steroid production in goat ovarian cells: effect of progestins and antiprogestins.

Effect of various synthetic progestins and antiprogestational compounds on progesterone (P) and estradiol (E) production by isolated goat ovarian granulosa (G) and corpus luteum (CL) cell types was studied in vitro. Steroid production was studied either under basal conditions or after stimulation with follicle stimulating hormone (FSH) in the presence of aromatase substrate, androstenedione (A). None of the progestins had any significant effect on basal P and E production by either cell types during 48 hour of culture. The FSH and A - induced increase in P and E production was significantly inhibited following concommitant treatment with synthetic progestins at concentrations higher than 10(-7) M. The added progestins had no effect on G and CL cell viability. None of the antiprogestational compounds had any significant effect on basal steroid production in either of the cell types. Furthermore, the higher concentrations of three antiprogestins namely RMI 14156, STS 557 and isomer 201 of RMI 12936, were found to stimulate significantly the basal as well as FSH + A - induced production of estradiol in both the cell types. In contrast, the other two antiprogestins tested were found to stimulate the gonadotropin + A - induced production of P. These results indicate that exogeneous progestins directly inhibit the gonadotropin + androstenedione - induced steroid production by G and CL cells in vitro. Moreover, different antiprogestin had different effect on the modulation of steroid production.

Androstenedione↗

PubMed2001

Progestins and endometrial cancer.

Premenopausal women--especially young women--with endometrial cancer stage I may be treated successfully with progestins alone as primary therapy to preserve their child-bearing potential. There is some indication that progestins could be used in neoadjuvant fashion. Individualization of adjuvant treatment with radiation or progestins and in combination seems possible. Progestins have an established place in the palliative treatment of women with advanced cancer. In addition, progestins can be used in advanced and/or recurrent endometrial cancer in combination with chemotherapy and tamoxifen.

Adult↗

PubMed2000

The role of matrix metalloproteinases and leukocytes in abnormal uterine bleeding associated with progestin-only contraceptives.

Progestin-only contraceptives are associated with menstrual bleeding disturbances; a major reason why these agents are discontinued. The pathogenesis of abnormal uterine bleeding associated with progestin-only contraceptives remains ill-defined. Matrix metalloproteinases (MMPs) and leukocytes are postulated to be involved in the process of normal menstruation. Immunolocalization of MMPs and leukocytes in (Norplant), and injectable depot medroxyprogesendometrium from women using the progestinterone acetate (DMPA), are widely used, safe and only contraceptives, Norplant or depot medroxyprogesterone acetate (DMPA) compared with normal controls, revealed foci of positive MMP-1 and -3 immunostaining in stromal cells and adjacent extracellular matrix, the presence of MMP-9 in various subtypes of leukocytes and alterations in mast cell phenotype. In women using progestin-only contraceptives, extent of endometrial MMP, neutrophil and eosinophil immunolocalization and the mast cell activation state was similar to or greater than that observed in perimenstrual control women. However, differences in MMP immunostaining were observed in endometrial samples from women using different progestin-only contraceptive agents; in particular, significantly higher MMP-1 immunostaining was observed associated with the use of Norplant compared with DMPA. No correlation was observed with the number of bleeding days recorded. These results suggest that MMP and leukocytes may be involved in endometrial breakdown in women using progestin-only contraceptives.

Biopsy↗

PubMed2002

Effects of different progestin regimens in hormone replacement therapy on blood coagulation factor VII and tissue factor pathway inhibitor.

BACKGROUND: Long-term hormone replacement therapy (HRT) reduces cardiovascular risk, but an early increased risk was reported in women with coronary heart disease. In such women the arterial intima can express tissue factor, and changes in coagulation factor VII (factor VII) and tissue factor pathway inhibitor (TFPI) may be deleterious. METHODS: We measured factor VII clotting activity, activated factor VII, and concentrations of factor VII and TFPI during 12 months in healthy post-menopausal women randomized to: (i). cyclic oral estrogen/progestin (n = 25); (ii). long-cycle oral estrogen/quarterly progestin (n = 32); (iii). continuous oral estrogen/progestin (n = 21); (iv). continuous oral estrogen/intrauterine progestin (n = 22); (v). no HRT (n = 26). Blood was collected at baseline, 3, 6 and 12 months. Additional sampling was done before progestin intake in the long cycle group. RESULTS: No variations were observed in the reference group. There was a substantial decrease in TFPI concentrations in the HRT groups irrespective of the type of progestin. In women receiving long-cycle treatment, all factor VII measures increased during the unopposed estrogen periods, and the increase was reversed after progestin intake. The integrated response, AUC, for TFPI was significantly lower in the HRT groups compared with the reference group. CONCLUSION: The observed changes may increase the early thrombotic risk associated with HRT use.

Cholesterol, LDL↗

PubMed2003

Lack of difference among progestins on the anti-atherogenic effect of ethinyl estradiol: a rabbit study.

BACKGROUND: Progestins in combination with estrogen are believed to have different effects on the cardiovascular system. The aim of this study was to investigate the influence of different oral contraceptive formulations on the development of experimental atherosclerosis and vascular reactivity. METHODS: A total of 160 sexually mature rabbits were ovariectomized and randomly assigned to equally large groups: (i) a cholesterol-rich diet (320 mg/day), either given alone (placebo), or together with (ii) ethinyl estradiol (EE 70 micro g/day, oral), (iii) desogestrel (DSG 525 micro g/day, oral), (iv) gestodene (GSD 262.5 micro g/day, oral), (v) levonorgestrel (LNG 525 micro g/day, oral), (vi) EE + DSG, (vii) EE + LNG, or (viii) EE + GSD. After 31 weeks of treatment, aortic accumulation of cholesterol and vascular vasoreactivity (in vitro) were determined. RESULTS: Progestins alone did not reduce the accumulation of cholesterol. EE alone or in combination with a progestin reduced the accumulation of cholesterol relative to placebo (P < 0.0001). Isolated vessels from EE-treated animals relaxed significantly more to physiological concentrations of acetylcholine than did placebo (P < 0.001), whereas vessels treated with EE plus a progestin showed an intermediate response. CONCLUSION: The progestins investigated can be combined with EE without attenuating the anti-atherogenic effect of EE.

Animals↗

PubMed1982

In vivo and in vitro production of progestins by the corpus luteum of pregnancy of the hamster.

Synthesis by hamster corpora lutea (CL) in vitro and serum levels of progesterone (P4), 17 alpha-hydroxyprogesterone (17OHP) and 20 alpha-dihydroprogesterone (20DHP) were assessed for different days of pregnancy (Day 1=day of sperm; Day 16=day of delivery). Highest serum levels of the progestins were observed on Day 14 (P4=33 ng/ml; 17OHP=2 ng/ml; 20DHP=3 ng/ml), followed by precipitous declines on Day 16. The highest in vitro levels of luteal P4 and 17OHP were attained on Days 2-6 (production rates of P4=9-30 ng/mg CL/h; 17OHP=0.6-1.5 ng/mg CL/h), and dropped gradually thereafter. In contrast, the production rate of luteal 20DHP was extremely low on Days 2-8 but abruptly increased on Day 10 and was maintained through Day 14 (4-8 ng/mg CL/h). The in vitro production rates of all 3 progestins dropped abruptly on Day 16. Thus, in the pregnant hamster on the day of parturition (Day 16) there was good agreement between in vivo and in vitro levels of the progestins, contrary to the situation in the rat, where on Day 22 the CL in vitro produce large quantities of P4 and 20DHP while the serum levels are very low (Taya and Greenwald, 1981). Addition of 25 ng/ml of ovine LH to the incubation media containing hamster CL increased production rates of P4 (18-55 ng/mg CL/h) and 17OHP (1.5-2.4 ng/mg CL/h) on Days 2, 4 and 14 of pregnancy but the CL were refractory to this dose of LH from Days 6 to 12. The production rate of luteal 20DHP ws never stimulated by the addition of 25 ng LH. These results indicate that P4 is the principal progestin in the pregnant hamster with 17OHP and 20DHP as minor metabolites. The latter 2 progestins have been measured for the first time in the pregnant hamster and the levels are very low in comparison to the pregnant rat.

Algestone↗

PubMedDate not supplied

The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women.

OBJECTIVE: Women who have ever used estrogen replacement therapy (ERT), even at a low dose, have an increased incidence of endometrial cancer. The addition of a progestin to ERT reduces the incidence of endometrial cancer. The duration of progestin administration is more important than the dose. DESIGN: A MEDLINE review of the literature was performed using the search terms endometrial cancer, epidemiology, and hormone replacement therapy (HRT). RESULTS: Women who have ever used ERT have an increased incidence of endometrial cancer. The use of HRT for more than 5 years, with a progestin use of <10 days per cycle, has a relative risk = 1.8. Continuous combined HRT, or sequential or cyclic HRT with >10 days of progestin per cycle, appears to decrease the incidence of endometrial cancer to that found in nonusers of HRT. CONCLUSIONS: The use of HRT in postmenopausal women with a uterus reduces the incidence of endometrial cancer. The duration of progestin administration should be 14 days or more per cycle based on recent epidemiologic data.

Case-Control Studies↗

PubMed2000

Cooperation of p27(Kip1) and p18(INK4c) in progestin-mediated cell cycle arrest in T-47D breast cancer cells.

The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. The long-term effect of progestins on T-47D breast cancer cells is inhibition of cellular proliferation. This is accompanied by decreased G(1) cyclin-dependent kinase (CDK) activities, redistribution of the CDK inhibitor p27(Kip1) among these CDK complexes, and alterations in the elution profile of cyclin E-Cdk2 upon gel filtration chromatography, such that high-molecular-weight complexes predominate. This study aimed to determine the relative contribution of CDK inhibitors to these events. Following progestin treatment, the majority of cyclin E- and D-CDK complexes were bound to p27(Kip1) and few were bound to p21(Cip1). In vitro, recombinant His(6)-p27 could quantitatively reproduce the effects on cyclin E-Cdk2 kinase activity and the shift in molecular weight observed following progestin treatment. In contrast, cyclin D-Cdk4 was not inhibited by His(6)-p27 in vitro or p27(Kip1) in vivo. However, an increase in the expression of the Cdk4/6 inhibitor p18(INK4c) and its extensive association with Cdk4 and Cdk6 were apparent following progestin treatment. Recombinant p18(INK4c) led to the reassortment of cyclin-CDK-CDK inhibitor complexes in vitro, with consequent decrease in cyclin E-Cdk2 activity. These results suggest a concerted model of progestin action whereby p27(Kip1) and p18(INK4c) cooperate to inhibit cyclin E-Cdk2 and Cdk4. Since similar models have been developed for growth inhibition by transforming growth factor beta and during adipogenesis, interaction between the Cip/Kip and INK4 families of inhibitors may be a common theme in physiological growth arrest and differentiation.

Breast Neoplasms↗

PubMed2005

Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells.

Interactions between steroid hormone receptors and signal transducer and activator of transcription (Stat)-mediated signaling pathways have already been described. In the present study, we explored the capacity of progestins to modulate Stat3 transcriptional activation in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in BALB/c mice and in the human breast cancer cell line T47D. We found that C4HD epithelial cells, from the MPA-induced mammary tumor model, expressed Stat3 and that MPA treatment of C4HD cells up-regulated Stat3 protein expression. In addition, MPA induced rapid, nongenomic Stat3, Jak1, and Jak2 tyrosine phosphorylation in C4HD and T47D cells. MPA treatment of C4HD cells also resulted in rapid c-Src tyrosine phosphorylation. These effects were completely abolished by the progestin antagonist RU486. Abrogation of Jak1 and Jak2 activity by transient transfection of C4HD cells with dominant negative (DN) Jak1 or DN Jak2 vectors, or inhibition of Src activity by preincubation of cells with the Src family kinase inhibitor PP2, blocked the capacity of MPA to induce Stat3 phosphorylation. Treatment of C4HD cells with MPA induced Stat3 binding to DNA. In addition, MPA promoted strong Stat3 transcriptional activation in C4HD and T47D cells that was inhibited by RU486 and by blockage of Jak1, Jak2, and Src activities. To investigate the correlation between MPA-induced Stat3 activation and cell growth, C4HD cells were transiently transfected with a DN Stat3 expression vector, Stat3Y705-F, or with a constitutively activated Stat3 mutant, Stat3-C. While expression of Stat3Y705-F mutant had an inhibitory effect on MPA-induced growth of C4HD cells, transfection with the constitutively activated Stat3-C vector resulted in MPA-independent proliferation. Finally, we addressed the effect of targeting Stat3 in in vivo growth of C4HD breast tumors. Blockage of Stat3 activation by transfection of C4HD cells with the DN Stat3Y705-F expression vector significantly inhibited these cells' ability to form tumors in syngeneic mice. Our results have for the first time demonstrated that progestins are able to induce Stat3 transcriptional activation, which is in turn an obligatory requirement for progestin stimulation of both in vitro and in vivo breast cancer growth.

Active Transport, Cell Nucleus↗

PubMed1988

Progesterone receptor regulation in T47D human breast cancer cells: analysis by density labeling of progesterone receptor synthesis and degradation and their modulation by progestin.

We have examined the effect of progestin on the regulation of cellular progesterone receptor (PR) levels and have used dense amino acid-density shift experiments to determine the mechanism by which progestin markedly decreases PR. We have utilized T47D human breast cancer cells which contain high levels of PR and are progestin responsive. When these cells are exposed to the progestin R5020, there is a time- and concentration-dependent decrease in PR levels. Experiments with different concentrations of R5020 reveal that the rate and extent of PR decrease reflect the time course of receptor occupancy and the fractional saturation of receptor. With a high concentration of ligand (20 nM) that labels all receptors rapidly, reductions in PR levels (processing) occur immediately and proceed rapidly to levels that are 15-20% of the initial; at lower concentrations (5 nM), where it takes several hours to achieve full saturation of receptors, there is a delay before the maximal rate of processing develops and then continues to achieve final receptor levels that are 15-20% of the initial; with a low concentration of ligand (0.5 nM), binding is even slower and never reaches full receptor saturation, with the consequence that processing is not only delayed but also less complete. Immunochemical detection of PR with a monoclonal antibody (B39) reveals a good correspondence between the loss of immunoreactive and hormone binding PR, and analysis of the A (Mr 85,000) and B (Mr 115,000) receptor forms on Western blots demonstrates that both A and B receptor forms are reduced after exposure to R5020. Density labeling of PR by biosynthetic incorporation of 2H, 13C, 15N (dense) amino acids reveals that PR turns over with a half-life of 21 h in control cells. In cells exposed to 20 nM R5020, PR levels decline and receptor half-life is reduced to 6 h. In addition, there is also a time-dependent decrease in the rate constant of PR synthesis, k8, which decreases to less than 10% of its initial value after 24 h of R5020 exposure. Thus, the R5020-evoked reduction in PR levels in this progestin-sensitive cell line is due both to a marked increase in the rate of receptor degradation as well as a dramatic decrease in the rate of receptor synthesis.

Antibodies, Monoclonal↗

PubMed1994

Progestin-induced growth hormone excess in the dog originates in the mammary gland.

In the dog endogenous progesterone and synthetic progestins may incite overproduction of GH, resulting in acromegaly and insulin resistance. This progrestin-induced excessive GH secretion is characterized by disappearance of the pulsatile secretion pattern and insensitivity to both stimulation with GHRH and inhibition with a somatostatin analog. This progestin-induced GH hypersecretion is not associated with neoplastic transformation at the pituitary level. These observations were the impetus for a search of a possible extrapituitary site of GH production. In four ovariohysterectomized dogs elevated plasma GH levels (46.5 +/- 7.7 micrograms/liter; mean +/- SEM) were induced by administration of synthetic progestins. In these dogs hypophysectomy did not led to a significant decrease in plasma GH levels. Analysis of the GH content of various tissue homogenates revealed that the highest GH immunoreactivity was found in extracts of the mammary gland. Ectopic production of GH in the mammary gland was confirmed by lowering of plasma GH concentration to values within the reference range within 2 h after complete mammectomy in two dogs with progestin-induced elevations of plasma GH levels. In one of these dogs the arterial and elevations of plasma GH levels. In one of these dogs the arterial and venous GH concentrations across the mammary gland were measured and an arterio-venous GH gradient was demonstrated. Displacement studies in the RIA and analysis by reversed-phase HPLC revealed that mammary-derived GH is highly similar to pituitary-derived GH. Immuno-histochemical staining revealed that GH immunoreactivity was localized in focal areas of hyperplastic ductular epithelium. In mammary tissue of healthy untreated female dogs no GH immunoreactivity was found. It is concluded that treatment of dogs with synthetic progestins can induce the overproduction of GH in the mammary gland. This GH is biologically active, highly similar to pituitary derived GH, and originates from foci of hyperplastic ductular epithelium of the mammary gland.

Animals↗

PubMed1986

Modulation of lactogenic receptors by progestins in cultured human breast cancer cells.

Progesterone receptors (PgR) are present in many breast cancers, but few specific actions of progestins in breast cancer cells have been reported. We now report that progestins specifically modulate lactogenic receptor expression in cultured T-47D and MCF-7 human mammary carcinoma cells. When T-47D cells were preincubated for 24 h with 1 nM medroxyprogesterone acetate (17 alpha-acetoxy-6 alpha-methyl-4-pregnene-3,20-dione), specific binding of [125I]human GH ([125I]hGH) and [125I]human PRL was increased to 205 +/- 22% (+/- SE) (P less than 0.01) and 175 +/- 32% (P less than 0.05), respectively, of that in control cultures. There was no significant effect on cell number and no significant enhancement of specific binding of [125I]porcine insulin, [125I]salmon calcitonin, [125I]human transferrin, or [3H] Concanavalin A. Lactogenic receptor number was increased from 6,490 +/- 500 (n = 12) to 13,180 +/- 3,270 (n = 7; P less than 0.01) sites/cell, with no significant change in affinity for hGH. Progesterone, which is readily metabolized by these cells, was less potent than the synthetic progestins (medroxyprogesterone acetate, R 5020 (17 alpha, 21-dimethyl-19-norpregn-4,9-diene-3,20-dione), and ORG 2058 (16 alpha-ethyl-21-hydroxy-19-norpregn-4-en-3,20-dione), but physiological concentrations of progesterone (1 nM) significantly enhanced specific binding of [125I]hGH to 153 +/- 23% of the control value (n = 6; P less than 0.05). Physiological concentrations of androgens, estrogens, and glucocorticoids had no significant effect. MCF-7 cells were considerably less sensitive to these effects of progestins than T-47D cells, probably due to the lower PgR concentration in MCF-7 cells. These observations, which indicate that lactogenic receptor expression is controlled, at least in part, by progestins in these mammary carcinoma cell lines, may have important implications in the management of human breast cancer, where high levels of this receptor may reflect a functional PgR and a highly hormone-dependent phenotype.

Breast Neoplasms↗

PubMed1998

Transcriptional regulation of the tissue factor gene by progestins in human endometrial stromal cells.

Decidualization of estradiol (E2)-primed human endometrial cells (HESCs) by progesterone is associated with elevated levels of tissue factor (TF), the primary initiator of hemostasis. Similarly, in cultured human HESCs, the synthetic progestin, medroxyprogesterone acetate (MPA), enhances TF protein and messenger ribonucleic acid (mRNA) levels. Although ineffective alone, E2 potentiates this progestin enhancement of TF expression by HESCs. The current study examines mechanisms underlying MPA enhancement of TF mRNA expression in HESCs. In the presence of the transcription-blocking agent dichlororibofuranosylbenzimidazole, no significant differences were noted in the half-lives of TF mRNA isolated from HESCs treated with E2 alone or with E2 plus MPA. This indicates that MPA-enhanced TF mRNA levels do not reflect changes in the stability of the TF message. To test the effect of progestin on TF promoter activity and to ascertain the mechanism of promoter regulation, primary or first passaged HESCs were transfected with TF promoter constructs spanning the regions -2106 to +121 (TFp(-2106)), -278 to +121 (TFp(-278)), and -111 to +14 (TFp(-111)) bp upstream of the transcription start site. MPA was found to enhance TF transcription by 20-fold in HESCs transfected with TFp(-2106) after correcting for transfection efficiencies with a beta-galactosidase reporter plasmid. Interestingly, levels of E2- plus MPA-stimulated transcription were significantly increased using TFp(-278) compared to TFp(-2106), suggesting that the region between -2106 and -278 bp may contain an inhibitory element. In addition, rates of MPA-stimulated transcription using TFp(-111) were significantly reduced compared to values obtained using TFp(-2106) and were even further reduced compared to values obtained using TFp(-278). This suggests that regulatory elements in the -111 bp region of the TF promoter are necessary for progestin-mediated regulation of the TF gene in HESCs, but are not sufficient to account for maximal rates of TF gene transcription. Our results also demonstrated that induction of steady state TF mRNA by MPA was abolished by treating cells with E2 plus MPA in conjunction with the protein synthesis inhibitor cycloheximide. In light of the absence of a complete progesterone or estrogen response element in the published 5'-sequence of the TF promoter, our results suggest that progestin-enhanced transcription of TF mRNA in stromal cells may be mediated by an uncharacterized protein intermediate(s).

Cells, Cultured↗

PubMed2003

Overlapping but distinct profiles of gene expression elicited by glucocorticoids and progestins.

Glucocorticoids and progestins bind to receptors that share many structural and functional similarities, including virtually identical DNA recognition specificity. Nonetheless, the two hormones mediate very distinct biological functions. For example, progestins are associated with the incidence and progression of breast cancer, whereas glucocorticoids are growth suppressive in mammary cancer cells. To understand the mechanisms that engender biological specificity, we have employed two systematic approaches to identify genes that are differentially regulated by the two hormones. The first strategy is to utilize Affymetrix oligonucleotide arrays to compare glucocorticoid- and progestin-regulated gene expression in a human breast cancer cell line. This global analysis reveals that the two hormones regulate overlapping but distinct sets of genes, including 31 genes that are differentially regulated. Surprisingly, the set of differentially regulated genes was almost as large as the set of genes regulated by both hormones. Examination of the set of differentially regulated genes suggests mechanisms behind the distinct growth effects of the two hormones in breast cancer. The differential regulation of four genes representing different regulatory patterns was confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analyses. Treatment with cycloheximide or mifepristone (RU486) indicates that the regulation is a primary, receptor-mediated event. The second strategy is to employ a retroviral promoter trap and Cre/loxP-mediated, site-specific recombination to identify genes that are differentially regulated by glucocorticoids and progestins. A mouse fibroblast cell line (4F) stably expressing both glucocorticoid receptor (GR) and progesterone receptor (PR) and containing a single copy of a multifunctional selection plasmid was generated. This line was transduced with a self-inactivating retroviral promoter trap vector carrying coding sequences for Cre-recombinase (Cre) in the U3 region. Integration of the provirus places Cre expression under the control of genomic flanking sequence. Activation of Cre expression from integration into active genes results in a permanent switch between the selectable marker genes that convert the cells from neomycin resistant to hygromycin resistant. Selection for hygromycin resistance after hormone treatment yields recombinants in which Cre sequences in the U3 region are expressed from hormone-inducible, upstream cellular promoters. Because Cre-mediated recombination is a permanent event, the expression of the selectable marker genes is independent of ongoing Cre expression. Thus, this system permits the identification of genes that are transiently or weakly induced by hormone. Detailed analyses of genes identified in these studies will furnish a mechanistic understanding of differential regulation by glucocorticoids and progestins.

Animals↗

PubMed1994

Effects of various forms of progestin on the endometrium of the estrogen-primed, ovariectomized rat.

Progestin supplementation has been advocated in estrogen treatment for postmenopausal women to avoid proliferation of the endometrium. In this study we investigated the morphologic and biochemical effects of progestins on the endometrium of estrogen primed, ovariectomized rats. As the progestin derivatives, Allylestenol (AE), Norethisterone (NE), Danazol (DZ), Dydrogesterone (DG), Medroxyprogesterone acetate (MPA) and Cyproterone acetate (CPA), and as a anti-estrogen compound, Tamoxifen (TMX), were applied. To evaluate the effects of these different compounds on the endometrium, histologic studies and measurement of estrogen receptor concentrations were performed. When 19-nortestosterone groups, AE, DZ and NE, were orally administered to the conjugated equine estrogen (CE) treated, ovariectomized rats, the histologic pattern of the endometrium revealed rather a marked inhibition of hyperplasia induced by CE than a progestational response. Two of 3 of 17 alpha-hydroxyprogesterone groups, DG and MPA, provided slightly endometrial protection against the hyperplastic response, but another one, CPA, did not have any inhibitory effect on the estrogenic stimulation of the endometrium. TMX was not capable of suppressing the endometrial hyperplasia caused by CE administration. The average plasma concentrations of estradiol (E2) were 82.0 +/- 27.0 pg/ml (Mean +/- SD) after CE administration and there were no significant differences among these groups. Estrogen receptor concentrations of endometrium of progestins or antiestrogen added groups were not changed, when compared with the CE alone group. There was also no relationship between the estrogen receptor concentrations and the histologic findings in the endometrium. This discrepancy may be chiefly due to the low dose of the progestins as compared with the CE dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Fate of the dominant follicle, embryonal survival, and pregnancy rates in dairy cattle treated with prostaglandin F2 alpha and progestins in the absence or presence of a functional corpus luteum.

Our objective was to examine the role of progestin type on serum concentrations of progesterone (p4) and estradiol-17 beta (E2), ovarian follicular dynamics, and fertility in cattle in the presence or absence of a corpus luteum (CL) in an estrus synchronization scheme using progestin and PGF2 alpha. In Exp. 1, 325 cows and heifers were given one injection of PGF2 alpha (d 0) and then assigned randomly within parity to five treatments: to receive a second PGF2 alpha injection 14 d later (control); to receive norgestomet (NORG) for 7 d beginning on d 8, with a second PGF2 alpha injection given either 1 d (NORG + no CL) or 6 d (NORG + CL) after insertion; or to receive a P4-releasing intravaginal device (PRID) in lieu of norgestomet at comparable times. Presence or absence of a CL was based on concentrations of serum P4 on d 14. Pregnancy rates after insemination were greater (P < .01) with luteal treatments than with nonluteal treatments. Embryonal survival between two stages of pregnancy was 87.6%. In Exp. 2, ovarian structures in 50 cows were examined daily using ultrasonography and the same five treatments. Diameter of the ovulatory follicle was greater (P < .05) with the nonluteal treatments (NORG and PRID + no CL) than with the control and luteal treatments (PRID and NORG + CL). Replacement of the dominant follicle during progestin treatment was altered by treatment (luteal status) and stage of the estrous cycle. Fertility was not enhanced by exogenous progestins when a CL was present. In the absence of a CL, progestin (P4 less than NORG at the doses used) reduced fertility by increasing E2 and the diameter of the ovulatory follicle and decreasing turnover of dominant follicles.

Administration, Intravaginal↗

PubMed1975

Transitory changes in plasma progestins, estradiol, and luteinizing hormone approaching ovulation in the bovine.

Progestins, estradiol, and luteinizing hormone were measured by radioimmunoassay in bovine plasma samples collected from indwelling jugular catheters daily on days minus 6 to minus 4, every 6 h on days minus 3 and minus 2, and every 2 h from day minus 1 to ovulation. Least squares analyses characterized time trends within animals and interrelationships between these hormones. Plasma progestins decreased from 5.7 ng/ml at day minus 6 to .07 ng at the peak of luteinizing hormone. No preovulatory peripheral increase in plasma progestins was detected. Estradiol increased from 2 pg/ml at day minus 4 to 6 pg at minus 12 h and then increased abruptly to 7.4 pg at the peak of luteinizing hormone. This matter increase in estradiol was synchronous with the acute preovulatory surge of luteinizing hormone. Association was positive between estradiol and luteinizing hormone, but negative between progestins and estradiol. Estradiol decreased 50% by 5 h following the peak of luteinizing hormone with a return to base (2 pg) at 14 h. An increase of .1 ng luteinizing hormone/ml plasma per day was linear from day minus 6 to 8 h prior to the luteinizing hormone peak. Luteinizing hormone increased to a peak of 13.5 ng/ml and remained elevated for 10.5 h. These results are consistent with the hypothesis that an increase at proestrus in estradiol rather than progestins triggers the preovulatory surge of luteinizing hormone in the bovine.

Animals↗