Статті в журналах: "Synthetic progestin"

1

Hyder, Salman M., Yayun Liang, Jianbo Wu, and Vanessa Welbern. "Regulation of thrombospondin-1 by natural and synthetic progestins in human breast cancer cells." Endocrine-Related Cancer 16, no. 3 (September 2009): 809–17. http://dx.doi.org/10.1677/erc-08-0311.

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Our recent studies show that progestins induce vascular endothelial growth factor (VEGF) in breast cancer cells that express mutant p53 protein. Here, we show that natural and synthetic progestins also induce thrombospondin-1 (TSP-1) mRNA and protein in T47-D and BT-474 breast cancer cells. Antiprogestin RU-486 inhibits the induction of VEGF and TSP-1 by progestins, suggesting that this effect of progestin is mediated by the progesterone receptor (PR). Actinomycin-D, but not puromycin, also blocks progestin-dependent induction of TSP-1. A putative progestin-response element was identified in the human TSP-1 promoter, which is consistent with the hypothesis that a progestin–PR complex might directly regulate transcription of the TSP-1 gene in human cells. Conditioned medium from progestin-treated breast cancer cells stimulates endothelial cell proliferation in the absence though not in the presence of antibody to TSP-1, indicating that TSP-1 secreted by breast cancer cells could be pro-angiogenic. Since tumor cell-derived TSP-1 has the potential to promote angiogenesis in the tumor microenvironment, it could be a potential target for breast cancer therapy.

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2

Otto, Christiane, Iris Fuchs, Helga Altmann, Mario Klewer, Alexander Walter, Katja Prelle, Richardus Vonk, and Karl-Heinrich Fritzemeier. "Comparative Analysis of the Uterine and Mammary Gland Effects of Drospirenone and Medroxyprogesterone Acetate." Endocrinology 149, no. 8 (April 17, 2008): 3952–59. http://dx.doi.org/10.1210/en.2007-1612.

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The role of progestins in combined hormone therapy is the inhibition of uterine epithelial cell proliferation. The Women’s Health Initiative study provided evidence for an increased risk of breast cancer in women treated with conjugated equine estrogens plus the synthetic progestin medroxyprogesterone acetate (MPA), compared with conjugated equine estrogens-only treatment. These findings continue to be discussed, and it remains to be clarified whether the results obtained for MPA in the Women’s Health Initiative study are directly applicable to other progestins used in hormone therapy. In this study we compared in a mouse model the effects of the synthetic progestins, MPA, and drospirenone in two major target organs: the uterus and mammary gland. As quantitative measures of progestin activity, we analyzed maintenance of pregnancy, ductal side branching in the mammary gland, and proliferation of mammary and uterine epithelial cells as well as target gene induction in both organs. The outcome of this study is that not all synthetic progestins exhibit the same effects. MPA demonstrated uterine activity and mitogenic activity in the mammary gland at the same doses. In contrast, drospirenone behaved similarly to the natural hormone, progesterone, and exhibited uterine activity at doses lower than those leading to considerable proliferative effects in the mammary gland. We hypothesize that the safety of combined hormone therapy in postmenopausal women may be associated with a dissociation between the uterine and mammary gland activities of the progestin component.

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3

Musgrove, E. A., C. S. Lee, and R. L. Sutherland. "Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos, and c-myc genes." Molecular and Cellular Biology 11, no. 10 (October 1991): 5032–43. http://dx.doi.org/10.1128/mcb.11.10.5032-5043.1991.

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This study documents a biphasic change in the rate of cell cycle progression and proliferation of T-47D human breast cancer cells treated with synthetic progestins, consisting of an initial transient acceleration in transit through G1, followed by cell cycle arrest and growth inhibition. Both components of the response were mediated via the progesterone receptor. The data are consistent with a model in which the action of progestins is to accelerate cells already progressing through G1, which are then arrested early in G1 after completing a round of replication, as are cells initially in other phases of the cell cycle. Such acceleration implies that progestins act on genes or gene products which are rate limiting for cell cycle progression. Increased production of epidermal growth factor and transforming growth factor alpha, putative autocrine growth factors in breast cancer cells, does not appear to account for the initial response to progestins, since although the mRNA abundance for these growth factors is rapidly induced by progestins, cells treated with epidermal growth factor or transforming growth factor alpha did not enter S phase until 5 to 6 h later than those stimulated by progestin. The proto-oncogenes c-fos and c-myc were rapidly but transiently induced by progestin treatment, paralleling the well-known response of these genes to mitogenic signals in other cell types. The progestin antagonist RU 486 inhibited progestin regulation of both cell cycle progression and c-myc expression, suggesting that this proto-oncogene may participate in growth modulation by progestins.

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4

Musgrove, E. A., C. S. Lee, and R. L. Sutherland. "Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos, and c-myc genes." Molecular and Cellular Biology 11, no. 10 (October 1991): 5032–43. http://dx.doi.org/10.1128/mcb.11.10.5032.

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This study documents a biphasic change in the rate of cell cycle progression and proliferation of T-47D human breast cancer cells treated with synthetic progestins, consisting of an initial transient acceleration in transit through G1, followed by cell cycle arrest and growth inhibition. Both components of the response were mediated via the progesterone receptor. The data are consistent with a model in which the action of progestins is to accelerate cells already progressing through G1, which are then arrested early in G1 after completing a round of replication, as are cells initially in other phases of the cell cycle. Such acceleration implies that progestins act on genes or gene products which are rate limiting for cell cycle progression. Increased production of epidermal growth factor and transforming growth factor alpha, putative autocrine growth factors in breast cancer cells, does not appear to account for the initial response to progestins, since although the mRNA abundance for these growth factors is rapidly induced by progestins, cells treated with epidermal growth factor or transforming growth factor alpha did not enter S phase until 5 to 6 h later than those stimulated by progestin. The proto-oncogenes c-fos and c-myc were rapidly but transiently induced by progestin treatment, paralleling the well-known response of these genes to mitogenic signals in other cell types. The progestin antagonist RU 486 inhibited progestin regulation of both cell cycle progression and c-myc expression, suggesting that this proto-oncogene may participate in growth modulation by progestins.

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5

Bigsby, Robert M. "Progestins and Antiprogestins: A Review of Their Role in Medicine and Bioassays Used in Their Development." Alternatives to Laboratory Animals 18, no. 1_part_1 (November 1990): 301–11. http://dx.doi.org/10.1177/026119299001800130.1.

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The physiological role of ovarian progesterone in reproduction and the medical uses of synthetic progestins and antiprogestins are briefly reviewed. Although a number of progestins are in wide use, the search continues for better analogues that display fewer of the unwanted effects of the present compounds. The one antiprogestin approved for human use to date, RU486, exhibits considerable antiglucocortoid activity The classical bioassays currently in use for the development of these steroid analogues depend upon in vivo progestin effects. However, progestins induce measurable responses in several cell culture systems that could be used as alternative bioassays. Rabbit uterine stromal cells in primary culture are especially suitable for such use. Addition of progesterone to these cultures stimulates synthesis of a 42 kilodalton (42kD) protein that appears in the medium. The 42kD protein response is specific for a progesterone receptor-mediated event and it can be blocked by known progestins. Using this culture system as a bioassay, one rabbit yields enough cells to measure the effect of 30 test doses in triplicate. Thus, a culture system is described that could substitute for current in vivo bioassays. This culture bioassay would allow large scale screening for potential progestin or antiprogestin activity.

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6

Houshdaran, Sahar, Joseph C. Chen, Júlia Vallvé-Juanico, Shayna Balayan, Kim Chi Vo, Karen Smith-McCune, Ruth M. Greenblatt, Juan C. Irwin, and Linda C. Giudice. "Progestins Related to Progesterone and Testosterone Elicit Divergent Human Endometrial Transcriptomes and Biofunctions." International Journal of Molecular Sciences 21, no. 7 (April 9, 2020): 2625. http://dx.doi.org/10.3390/ijms21072625.

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Progestins are widely used for the treatment of gynecologic disorders and alone, or combined with an estrogen, are used as contraceptives. While their potencies, efficacies and side effects vary due to differences in structures, doses and routes of administration, little is known about their effects on the endometrial transcriptome in the presence or absence of estrogen. Herein, we assessed the transcriptome and pathways induced by progesterone (P4) and the three most commonly used synthetic progestins, medroxyprogesterone acetate (MPA), levonorgestrel (LNG), and norethindrone acetate (NETA), on human endometrial stromal fibroblasts (eSF), key players in endometrial physiology and reproductive success. While there were similar transcriptional responses, each progestin induced unique genes and biofunctions, consistent with their structural similarities to progesterone (P4 and MPA) or testosterone (LNG and NETA), involving cellular proliferation, migration and invasion. Addition of estradiol (E2) to each progestin influenced the number of differentially expressed genes and biofunctions in P4 and MPA, while LNG and NETA signatures were more independent of E2. Together, these data suggest different mechanisms of action for different progestins, with progestin-specific altered signatures when combined with E2. Further investigation is warranted for a personalized approach in different gynecologic disorders, for contraception, and minimizing side effects associated with their use.

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7

Liang, Yayun, and Salman M. Hyder. "Proliferation of Endothelial and Tumor Epithelial Cells by Progestin-Induced Vascular Endothelial Growth Factor from Human Breast Cancer Cells: Paracrine and Autocrine Effects." Endocrinology 146, no. 8 (August 1, 2005): 3632–41. http://dx.doi.org/10.1210/en.2005-0103.

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Abstract Angiogenesis, the formation of new blood vessels, is essential for tumor expansion, and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic growth factors known. We have previously shown that natural and synthetic progestins, including those used in hormone replacement therapy and oral contraception, induce the synthesis and secretion of VEGF in a subset of human breast cancer cells in a progesterone receptor-dependent manner. We now report that conditioned medium from progestin-treated breast tumor cells can induce the proliferation of endothelial cells in a paracrine manner and induce the proliferation of tumor epithelial cells in a paracrine and an autocrine manner. The use of an anti-VEGF antibody and SU-1498, an inhibitor of VEGF receptor-2 (VEGFR-2 or flk/kdr) tyrosine kinase activity, demonstrated that these effects involve interactions between VEGF and VEGFR-2. Also, blockage of progestin-induced VEGF by the antiprogestin RU-486 (mifepristone) eliminated VEGF-induced proliferative effects. The ability of VEGF to increase the proliferation of endothelial cells and tumor cells, including those that do not release VEGF in response to progestins, suggests that these effects are mediated by amplification of the progestin signal, which culminates in angiogenesis and tumor growth. These novel findings suggest that targeting the release of VEGF from tumor epithelial cells as well as blocking interactions between VEGF and VEGFR-2 on both endothelial and tumor epithelial cells may facilitate the development of new antiangiogenic therapies for progestin-dependent breast tumors. Furthermore, these data indicate that it would be useful to develop selective progesterone receptor modulators that prevent the release of angiogenic growth factors from breast cancer cells.

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8

Selman, PJ, JA Mol, GR Rutteman, and A. Rijnberk. "Progestin treatment in the dog I. Effects on growth hormone, insulin-like growth factor I and glucose homeostasis." European Journal of Endocrinology 131, no. 4 (October 1994): 413–21. http://dx.doi.org/10.1530/eje.0.1310413.

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Selman PJ, Mol JA, Rutteman GR, Rijnberk A. Progestin treatment in the dog. I. Effects on growth hormone, insulin-like growth factor I and glucose homeostasis. Eur J Endocrinol 1994;131:413–21. ISSN 0804–4643 The effects of two synthetic progestins, medroxyprogesterone acetate (MPA) and proligestone (PROL), on the release of growth hormone (GH) and glucose metabolism were studied in two groups of eight ovariohysterectomized dogs. Eight injections of long-acting progestins were administered at 3-week intervals. Recovery was studied in four dogs of each treatment group in the 6 months following cessation of progestin administration. Treatment with both MPA and PROL resulted in similar increases in plasma levels of GH and insulin-like growth factor I (IGF-I). The GH responses to both clonidine and growth hormone-releasing hormone became impaired. In neither treatment group did the elevated plasma GH levels decrease after administration of the synthetic somatostatin analogue SMS 201-995. The size and shape of the pituitary gland were not changed by progestin treatment. After cessation of progestin administration, basal plasma levels of GH and IGF-I did not return to pretreatment values. The GH response to growth hormone-releasing hormone remained impaired for at least 6 months after the last progestin administration. In both treatment groups, glucose homeostasis was sustained initially by increased insulin production. Prolonged treatment with MPA and PROL resulted in glucose intolerance. No amelioration was observed during the recovery period in either group. A small number of dogs developed diabetes mellitus. In more than 50% of the dogs in both treatment groups small mammary tumours developed. The recently discovered local production of GH probably played a role in mammary tumorigenesis. It is concluded that treatment with MPA and PROL results in similar increases in plasma levels of GH and IGF-I and leads to a similar degree of insulin resistance. The elevated GH levels can be neither stimulated nor inhibited, which is a feature compatible with autonomous secretion. These results are consistent with the recent finding of a progestin-induced ectopic production of GH in the mammary gland of the dog. JA Mol, Department of Clinical Sciences of Companion Animals, Utrecht University, PO Box 80. 154, 3508 TD Utrecht, The Netherlands

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9

Jordan, V. Craig, Philipp Y. Maximov, and Ping Fan. "Progesterone and Synthetic Progestin Controversies." JAMA Oncology 1, no. 7 (October 1, 2015): 986. http://dx.doi.org/10.1001/jamaoncol.2015.2280.

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10

Gompel, Anne, and Geneviève Plu-Bureau. "Progesterone and Synthetic Progestin Controversies." JAMA Oncology 1, no. 7 (October 1, 2015): 987. http://dx.doi.org/10.1001/jamaoncol.2015.2283.

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11

Jaffe, Randal C., Susan D. Ferguson-Gottschall, Weihua Gao, Craig Beam, and Asgerally T. Fazleabas. "Histone deacetylase inhibition and progesterone act synergistically to stimulate baboon glycodelin gene expression." Journal of Molecular Endocrinology 38, no. 3 (March 2007): 401–7. http://dx.doi.org/10.1677/jme-06-0030.

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During the late luteal phase of the menstrual cycle and early pregnancy, the major secretory product of the uterine glandular epithelial cells in humans and non-human primates is glycodelin. Previous studies using Ishikawa cells, a human endometrial cell line, have shown that a chimeric plasmid containing the baboon glycodelin promoter responds to progestins but the response is modest compared with the induction of glycodelin seen in vivo and in gene array analysis. A recent report indicating that the histone deacetylase inhibitor trichostatin A (TSA) promoted glycodelin expression prompted us to examine its mechanism of action. In Ishikawa cells transfected with the baboon glycodelin promoter, TSA and the synthetic progestin medroxyprogesterone acetate both stimulated expression of the reporter and the combined treatment produced a synergistic effect. The effect of TSA and progestin was absent when the same promoter constructs were transfected into COS-1 cells, a kidney cell line, and a TSA effect but no progestin effect was observed in T47D cells, a mammary cell line. Through deletion analysis, the TSA action was localized to the −67/−52 region of the baboon glycodelin promoter, a region which contains the proximal Sp1 site. Deletions of this same region had no effect on progestin responsiveness. Our findings indicate that at least two regions of the glycodelin promoter are important for the normal induction of glycodelin expression. Non-target cells may lack factors which act on the response elements resulting in the restriction of expression to the appropriate target tissue.

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12

Piña, B., R. J. Haché, J. Arnemann, G. Chalepakis, E. P. Slater, and M. Beato. "Hormonal induction of transfected genes depends on DNA topology." Molecular and Cellular Biology 10, no. 2 (February 1990): 625–33. http://dx.doi.org/10.1128/mcb.10.2.625-633.1990.

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Plasmids containing the hormone regulatory element of mouse mammary tumor virus linked to the thymidine kinase promoter of herpes simplex virus and the reporter gene chloramphenicol acetyltransferase of Escherichia coli respond to glucocorticoids and progestins when transfected into appropriate cells. In the human mammary tumor cell line T47D, the response to progestins, but not to glucocorticoids, is highly dependent on the topology of the transfected DNA. Although negatively supercoiled plasmids respond optimally to the synthetic progestin R5020, their linearized counterparts exhibit markedly reduced progestin inducibility. This is not due to changes in the efficiency of DNA transfection, since the amount of DNA incorporated into the cell nucleus is not significantly dependent on the initial topology of the plasmids. In contrast, cotransfection experiments with glucocorticoid receptor cDNA in the same cell line show no significant influence of DNA topology on induction by dexamethasone. A similar result was obtained with fibroblasts that contain endogenous glucocorticoid receptors. When the distance between receptor-binding sites or between the binding sites and the promoter was increased, the dependence of progestin induction on DNA topology was more pronounced. In contrast to the original plasmid, these constructs also revealed a similar topological dependence for induction by glucocorticoids. The differential influence of DNA topology is not due to differences in the affinity of the two hormone receptors for DNA of various topologies, but probably reflects an influence of DNA topology on the interaction between different DNA-bound receptor molecules and between receptors and other transcription factors.

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13

Selman, PJ, JA Mol, GR Rutteman, and A. Rijnberk. "Progestin treatment in the dog II. Effects on the hypothalamic–pituitary–adrenocortical axis." European Journal of Endocrinology 131, no. 4 (October 1994): 422–30. http://dx.doi.org/10.1530/eje.0.1310422.

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Selman PJ, Mol JA, Rutteman GR, Rijnberk A. Progestin treatment in the dog. II. Effects on the hypothalamic–pituitary–adrenocortical axis. Eur J Endocrinol 1994;131:422–30. ISSN 0804–4643 The effects of two synthetic progestins, medroxyprogesterone acetate (MPA) and proligestone (PROL), on the hypothalamic–pituitary–adrenocortical (HPA) axis were studied in two groups of eight ovariohysterectomized dogs each. Eight injections of long-acting progestins were administered at 3-week intervals. Recovery of the HPA axis was studied in four dogs of each group in the following 6 months. Basal levels of adrenocorticotrophin (ACTH) and cortisol in plasma and the urinary corticoid/creatinine ratio were measured. The responsiveness of the HPA axis was investigated by stimulation with ovine corticotrophin-releasing hormone. Both MPA and PROL caused sawtooth patterns of supression of basal ACTH and cortisol levels in plasma, synchronous with the time of administration. The suppression of the adrenocortical component of the HPA axis was most pronounced. Adrenocorticotrophin production also was affected but to a lesser extent and occurred especially in PROL-treated dogs. Soon after the cessation of progestin administration ACTH levels increased, sometimes with a rebound. In both groups basal cortisol levels and urinary corticoid/creatinine ratios did not return to pretreatment levels until 6 months after the last progestin injection. It is concluded that MPA and PROL act as glucocorticoid agonists and suppress the HPA axis. The suppression at the adrenocortical level may last for 6 months. JA Mol, Department of Clinical Sciences of Companion Animals, Utrecht University, PO Box 80.154, 3508 TD Utrecht, The Netherlands

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14

Piña, B., R. J. Haché, J. Arnemann, G. Chalepakis, E. P. Slater, and M. Beato. "Hormonal induction of transfected genes depends on DNA topology." Molecular and Cellular Biology 10, no. 2 (February 1990): 625–33. http://dx.doi.org/10.1128/mcb.10.2.625.

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Plasmids containing the hormone regulatory element of mouse mammary tumor virus linked to the thymidine kinase promoter of herpes simplex virus and the reporter gene chloramphenicol acetyltransferase of Escherichia coli respond to glucocorticoids and progestins when transfected into appropriate cells. In the human mammary tumor cell line T47D, the response to progestins, but not to glucocorticoids, is highly dependent on the topology of the transfected DNA. Although negatively supercoiled plasmids respond optimally to the synthetic progestin R5020, their linearized counterparts exhibit markedly reduced progestin inducibility. This is not due to changes in the efficiency of DNA transfection, since the amount of DNA incorporated into the cell nucleus is not significantly dependent on the initial topology of the plasmids. In contrast, cotransfection experiments with glucocorticoid receptor cDNA in the same cell line show no significant influence of DNA topology on induction by dexamethasone. A similar result was obtained with fibroblasts that contain endogenous glucocorticoid receptors. When the distance between receptor-binding sites or between the binding sites and the promoter was increased, the dependence of progestin induction on DNA topology was more pronounced. In contrast to the original plasmid, these constructs also revealed a similar topological dependence for induction by glucocorticoids. The differential influence of DNA topology is not due to differences in the affinity of the two hormone receptors for DNA of various topologies, but probably reflects an influence of DNA topology on the interaction between different DNA-bound receptor molecules and between receptors and other transcription factors.

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15

Willing, Jari, та Christine K. Wagner. "Exposure to the Synthetic Progestin, 17α-Hydroxyprogesterone Caproate During Development Impairs Cognitive Flexibility in Adulthood". Endocrinology 157, № 1 (1 січня 2016): 77–82. http://dx.doi.org/10.1210/en.2015-1775.

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Abstract The synthetic progestin, 17α-hydroxyprogesterone caproate, is increasingly used for the prevention of premature birth in at-risk women, despite little understanding of the potential effects on the developing brain. Rodent models suggest that many regions of the developing brain are sensitive to progestins, including the mesocortical dopamine pathway, a neural circuit important for complex cognitive behaviors later in life. Nuclear progesterone receptor is expressed during perinatal development in dopaminergic cells of the ventral tegmental area that project to the medial prefrontal cortex. Progesterone receptor is also expressed in the subplate and in pyramidal cell layers II/III of medial prefrontal cortex during periods of dopaminergic synaptogenesis. In the present study, exposure to 17α-hydroxyprogesterone caproate during development of the mesocortical dopamine pathway in rats altered dopaminergic innervation of the prelimbic prefrontal cortex and impaired cognitive flexibility with increased perseveration later in life, perhaps to a greater extent in males. These studies provide evidence for developmental neurobehavioral effects of a drug in widespread clinical use and highlight the need for a reevaluation of the benefits and potential outcomes of prophylactic progestin administration for the prevention of premature delivery.

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16

Bodean, Oana, Ovidiu Bratu, Roxana Bohiltea, Octavian Munteanu, Dragos Marcu, Dan Arsenie Spinu, Ileana Adela Vacaroiu, et al. "The Efficacy of Synthetic Oral Progestin Pills in Patients with Severe Endometriosis." Revista de Chimie 69, no. 6 (July 15, 2018): 1411–15. http://dx.doi.org/10.37358/rc.18.6.6335.

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Endometriosis is an important public health issues concerning women of reproductive age due to its debilitating painful symptoms. Deep infiltrating endometriosis is the severe form, involving uterosacral ligaments, rectum, bowel and bladder. There is no optimal treatment for this disease, but there are 3 main therapeutic options: medical, surgical and a combination of both. A modern approach for the treatment of endometriosis pain uses dienogest, a progestin, as a long-term solution for women who do not wish to procreate or to whom surgery is not an option. Dienogest 2mg daily has a positive effect on the reduction of pain and endometrial lesions when used perioperatively or as a long-term postoperative treatment. This article focuses on the literature evidence on the efficacy of newly approved oral synthetic progestins in the treatment of severe endometriosis.

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17

Joshi, Purna A., Pamela J. Goodwin, and Rama Khokha. "Progesterone and Synthetic Progestin Controversies—Reply." JAMA Oncology 1, no. 7 (October 1, 2015): 987. http://dx.doi.org/10.1001/jamaoncol.2015.2294.

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18

Musgrove, Elizabeth A., Alexander Swarbrick, Christine S. L. Lee, Ann L. Cornish, and Robert L. Sutherland. "Mechanisms of Cyclin-Dependent Kinase Inactivation by Progestins." Molecular and Cellular Biology 18, no. 4 (April 1, 1998): 1812–25. http://dx.doi.org/10.1128/mcb.18.4.1812.

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ABSTRACT The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. In breast cancer cells the predominant effect of synthetic progestins is long-term growth inhibition and arrest in G1 phase. Progestin-mediated growth arrest of T-47D breast cancer cells was preceded by inhibition of cyclin D1-Cdk4, cyclin D3-Cdk4, and cyclin E-Cdk2 kinase activities in vitro and reduced phosphorylation of pRB and p107. This was accompanied by decreases in the expression of cyclins D1, D3, and E, decreased abundance of cyclin D1- and cyclin D3-Cdk4 complexes, increased association of the cyclin-dependent kinase (CDK) inhibitor p27 with the remaining Cdk4 complexes, and changes in the molecular masses and compositions of cyclin E complexes. In control cells cyclin E eluted from Superdex 200 as two peaks of ∼120 and ∼200 kDa, with the 120-kDa peak displaying greater cyclin E-associated kinase activity. Following progestin treatment, almost all of the cyclin E was in the 200-kDa, low-activity form, which was associated with the CDK inhibitors p21 and p27; this change preceded the inhibition of cell cycle progression. These data suggest preferential formation of this higher-molecular-weight, CDK inhibitor-bound form and a reduced number of cyclin E-Cdk2 complexes as mechanisms for the decreased cyclin E-associated kinase activity following progestin treatment. Ectopic expression of cyclin D1 in progestin-inhibited cells led to the reappearance of the 120-kDa active form of cyclin E-Cdk2 preceding the resumption of cell cycle progression. Thus, decreased cyclin expression and consequent increased CDK inhibitor association are likely to mediate the decreases in CDK activity accompanying progestin-mediated growth inhibition.

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19

Wang, Siqi, Zhuhao Huo, Jianzhong Gu, and Gang Xu. "Benzophenones and synthetic progestin in wastewater and sediment from farms, WWTPs and receiving surface water: distribution, sources, and ecological risks." RSC Advances 11, no. 50 (2021): 31766–75. http://dx.doi.org/10.1039/d1ra05333g.

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20

Swanepoel, Albe C., Odette Emmerson, and Etheresia Pretorius. "Effect of Progesterone and Synthetic Progestins on Whole Blood Clot Formation and Erythrocyte Structure." Microscopy and Microanalysis 23, no. 3 (May 8, 2017): 607–17. http://dx.doi.org/10.1017/s1431927617000484.

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AbstractCombined oral contraceptive (COC) use is a risk factor for venous thrombosis (VT) and related to the specific type of progestin used. VT is accompanied by inflammation and pathophysiological clot formation, that includes aberrant erythrocytes and fibrin(ogen) interactions. In this paper, we aim to determine the influence of progesterone and different synthetic progestins found in COCs on the viscoelasticity of whole blood clots, as well as erythrocyte morphology and membrane ultrastructure, in an in vitro laboratory study. Thromboelastography (TEG), light microscopy, and scanning electron microscopy were our chosen methods. Our results point out that progestins influence the rate of whole blood clot formation. Alterations to erythrocyte morphology and membrane ultrastructure suggest the presence of eryptosis. We also note increased rouleaux formation, erythrocyte aggregation, and spontaneous fibrin formation in whole blood which may explain the increased risk of VT associated with COC use. Although not all COC users will experience a thrombotic event, individuals with a thrombotic predisposition, due to inflammatory or hematological illness, should be closely monitored to prevent pathological thrombosis.

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21

Fujii-Hanamoto, H., K. Seiki, K. Sakabe, and H. Ogawa. "Progestin receptor in the thymus of ovariectomized immature rats." Journal of Endocrinology 107, no. 2 (November 1985): 223–29. http://dx.doi.org/10.1677/joe.0.1070223.

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ABSTRACT By using the synthetic progestin promegestone (R5020), the location and characteristics of progestin receptors in the thymic cytosols from immature ovariectomized oestrogen-treated rats were determined. Tritiated promegestone bound to the cytosol with high affinity (dissociation constant (Kd) = 2·0± 0·3 nmol/l; promegestone > progesterone > oestradiol > corticosterone ≃testosterone) and low capacity (number of binding sites (Bmax) = 143·0 ±13·5fmol/mg protein). These values were appropriate for progestin receptors. However, an extremely high dose of dexamethasone (10 μmol/l; 1000-fold excess over [3H]promegestone) slightly inhibited the specific binding. Progestin receptors were predominantly located in the reticuloepithelial (RE)-cell fraction, with few in the thymocyte T-cell fraction. The receptor level was raised (24·9 ± 11·3 (s.e.m.) to 143·0 ± 13·5 fmol/mg protein) with increased doses of oestrogen (0–30 μg) administered in vivo. Using sucrose density gradient ultra-centrifugation it was found that the thymic progestin receptor had a sedimentation coefficient of 9 S under low-salt conditions. These results clearly suggest that the thymus of the immature female rat contains a specific progestin receptor which is mainly located in the RE cells. J. Endocr. (1985) 107, 223–229

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Kim, Yoon Young, Hoon Kim, Chang Suk Suh, Hung-Ching Liu, Zev Rosenwaks, and Seung-Yup Ku. "Effects of Natural Progesterone and Synthetic Progestin on Germ Layer Gene Expression in a Human Embryoid Body Model." International Journal of Molecular Sciences 21, no. 3 (January 24, 2020): 769. http://dx.doi.org/10.3390/ijms21030769.

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Natural progesterone and synthetic progestin are widely used for the treatment of threatened abortion or in in vitro fertilization (IVF) cycles. This in vitro study aimed to assess whether the treatment with natural progesterone or synthetic progestin influences the germ layer gene expression on the early human embryonic development using human embryonic stem cells (hESCs)-derived embryoid bodies (hEBs) as a surrogate of early stage human embryonic development. Human EBs derived from hESCs were cultured for nine days, and were treated with natural progesterone (P4) or synthetic progestin, medroxyprogesterone acetate (MPA) at 10–7 M for five days. To reverse the effects of treatment, mifepristone (RU486) as progesterone antagonist was added to the hEBs for four days starting one day after the initiation of treatment. Mouse blastocysts (mBLs) were cultured in vitro for 24 h, and P4 or MPA at 10−7 M was treated for an additional 24 h. The treated embryos were further transferred onto in vitro cultured endometrial cells to evaluate chorionic gonadotropin (CG) expression. To analyze the effects of P4 or MPA, the expression of differentiation genes representing the three germ layers was investigated, GATA-binding factor 4 (GATA4), α-fetoprotein (AFP), hepatocyte nuclear factor (HNF)-3β, hepatocyte nuclear factor (HNF)-4α (endoderm), Brachyury, cardiac actin (cACT) (mesoderm), and Nestin (ectoderm), using quantitative reverse transcription PCR (qRT-PCR) and immunostaining. Significantly lower expressions of HNF-3β, HNF-4α, Brachyury, and Nestin were observed in MPA-treated hEBs (all p < 0.05), which was negated by RU486 treatment. This inhibitory effect of MPA was also observed in mouse embryos. Conclusively, the effects of natural progesterone and synthetic progestin may differ in the germ layer gene expression in the hEB model, which suggests that caution is necessary in the use of progestogen.

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Tatsumi, K., M. Mikami, T. Kuriyama, and Y. Fukuda. "Respiratory stimulation by female hormones in awake male rats." Journal of Applied Physiology 71, no. 1 (July 1, 1991): 37–42. http://dx.doi.org/10.1152/jappl.1991.71.1.37.

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The respiratory effect of progestin differs among various animal species and humans. The rat does not hyperventilate in response to exogenous progestin. The present study was conducted to determine whether administration of combined progestin and estrogen prompts ventilatory stimulation in the male rat. Ventilation, blood gases, and metabolic rates (O2 consumption and CO2 production) were measured in the awake and unrestrained male Wistar rat. The combined administration of a synthetic potent progestin (TZP4238) and estradiol for 5 days significantly increased tidal volume and minute expiratory ventilation (VE), reduced arterial PCO2, and enhanced the ventilatory response to CO2 inhalation (delta VE/delta PCO2). On the other hand, respiratory frequency, O2 consumption, CO2 production, and body temperature were not affected. The arterial pH increased slightly, with a concomitant decrease in plasma [HCO3-]. Administration of either TZP4238 or estradiol alone or vehicle (Tween 80) had no effect on respiration, blood gases, and ventilatory response to CO2. The results indicated that respiratory stimulation following combined progestin plus estradiol treatment in the male rat involves activation of process(es) that regulate tidal volume and its augmentation during CO2 stimulus.

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24

Shukla, Akshara, Rohitash Jamwal, and Kumud Bala. "ADVERSE EFFECT OF COMBINED ORAL CONTRACEPTIVE PILLS." Asian Journal of Pharmaceutical and Clinical Research 10, no. 1 (January 1, 2016): 17. http://dx.doi.org/10.22159/ajpcr.2017.v10i1.14565.

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ABSTRACTOral contraceptive (OC) pills contain estrogen and progestin that are synthetic analogs of natural hormones. These synthetic hormones affectthe hypothalamus-pituitary-gonadal axis of the female reproductive system. There are many types of contraceptives; most of the OC pills preventpregnancy by inhibiting ovulation. Estrogen and progestin are two female reproductive hormones that are critical. Typically, estradiol is producedby growing follicle (ovaries) which stimulates the hypothalamus to produce the gonadotropin-releasing hormone, which further stimulates theanterior pituitary to produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH). LH production triggers the ovulation. Similarly, theprogesterone is produced by corpus luteum (ovaries), which triggers the production of FSH and LH. There are many types of progesterone available.Long-term usage of synthetic estrogen and progesterone can disturb the balance between the level of these hormones in the body. This imbalance maylead to severe side effects such as breast cancer, cervical cancer, thrombosis, direct impact on the brain, and infertility.Keywords: Estrogen, Progesterone, Contraceptives, Herbal contraceptives.

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Proietti, Cecilia, Mariana Salatino, Cinthia Rosemblit, Romina Carnevale, Adalí Pecci, Alberto R. Kornblihtt, Alfredo A. Molinolo, et al. "Progestins Induce Transcriptional Activation of Signal Transducer and Activator of Transcription 3 (Stat3) via a Jak- and Src-Dependent Mechanism in Breast Cancer Cells." Molecular and Cellular Biology 25, no. 12 (June 15, 2005): 4826–40. http://dx.doi.org/10.1128/mcb.25.12.4826-4840.2005.

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ABSTRACT 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.

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Graham, JD, SM Hunt, N. Tran, and CL Clarke. "Regulation of the expression and activity by progestins of a member of the SOX gene family of transcriptional modulators." Journal of Molecular Endocrinology 22, no. 3 (June 1, 1999): 295–304. http://dx.doi.org/10.1677/jme.0.0220295.

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The mammalian testis-determining gene Sry and the related Sox genes define a family of transcriptional regulators widely expressed during embryogenesis. Tightly controlled temporal profiles of expression are a feature of the Sox gene family and may be required for initiation of a cascade of gene expression, yet the molecular mechanisms that control Sox gene expression are unknown. We now show that human SOX4 is expressed in the normal breast and in breast cancer cells. In these cells SOX4 is a progesterone-regulated gene, the expression of which is increased by progestins, leading to a marked increase in SOX-mediated transcriptional activity. Treatment of T-47D breast cancer cells with the synthetic progestin ORG 2058 directly increased SOX4 transcription, resulting in a 4-fold increase in SOX4 mRNA levels within 4 h of treatment. No effect of ORG 2058 was noted on other SOX genes measured, nor were other hormone-regulated HMG box proteins detected in this system, suggesting that the observed ability of progestin to increase SOX mRNA expression was confined to SOX4. The increase in SOX4 transcription was reflected in increased SOX4 protein expression, as progestin treatment of T-47D cells transfected with a SOX-responsive reporter resulted in a marked increase in reporter gene expression. Progesterone is essential for normal development and differentiation of the female reproductive system, plays an essential role in regulating growth and differentiation of the mammary gland and is required for opposing the proliferative effects of estrogen in specific cell types. The detection of SOX4 expression in the normal and malignant breast and the demonstration that SOX4 expression is under progesterone control suggests that changes in SOX4 gene expression may play a role in commitment to the differentiated phenotype in the normal and malignant mammary gland.

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27

Tempfer, Clemens B., Ziad Hilal, Peter Kern, Ingolf Juhasz-Boess, and Günther A. Rezniczek. "Menopausal Hormone Therapy and Risk of Endometrial Cancer: A Systematic Review." Cancers 12, no. 8 (August 6, 2020): 2195. http://dx.doi.org/10.3390/cancers12082195.

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Background: Menopausal hormone therapy (MHT) is an appropriate treatment for women with the climacteric syndrome. The estrogen component of MHT effectively alleviates climacteric symptoms but also stimulates the endometrium and thus may increase the risk of endometrial cancer (EC). Materials and Methods: We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify controlled and uncontrolled clinical trials reporting on the prevalence and/or incidence of EC among women using MHT. Results: 31 publications reporting on 21,306 women with EC diagnosed during or after MHT were identified. A significantly reduced risk of EC among continuous-combined (cc)MHT users with synthetic progestins (SPs) was demonstrated in 10/19 studies with odds ratios (ORs)/hazard ratios (HRs) between 0.24 and 0.71. Only one study documented an increased risk of EC among long-term users (≥10 years), not confirmed in three other sub-group analyses of women with ≥6, ≥5, and >10 years of ccMHT use. A significantly increased risk of EC among users of sequential-combined (sc)MHT with SPs was demonstrated in 6/12 studies with ORs/HRs between 1.38 and 4.35. Number of days of progestin per month was a significant modulator of EC risk. A decreased risk of EC was seen in obese women. Two studies documented an increased risk of EC among users of cc/scMHT with micronized progesterone. A significantly increased risk of EC among estrogen-only MHT users was demonstrated in 9/12 studies with ORs/HRs between 1.45 and 4.46. The adverse effect of estrogen-only MHT was greatest among obese women. Conclusion: ccMHT with SPs reduces the risk of EC, whereas estrogen-only MHT increases the risk. scMHT with SPs and cc/scMHT with micronized progesterone increase the risk of EC depending on type of progestin, progestin dosage, and duration of MHT use.

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Wu, Jianbo, Sandra Brandt, and Salman M. Hyder. "Ligand- and Cell-Specific Effects of Signal Transduction Pathway Inhibitors on Progestin-Induced Vascular Endothelial Growth Factor Levels in Human Breast Cancer Cells." Molecular Endocrinology 19, no. 2 (February 1, 2005): 312–26. http://dx.doi.org/10.1210/me.2004-0252.

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Abstract We evaluated the signaling pathways involved in regulating vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, in response to natural and synthetic progestins in breast cancer cells. Inhibition of the phosphoinositide-3′-kinase (PI3-kinase) signaling pathway or the specificity protein-1 (SP-1) transcription factor abolished both progesterone- and medroxyprogesterone acetate (MPA)-induced VEGF secretion from BT-474 and T47-DCO cells. Inhibitors of the MAPK kinase 1/2/MAPK and N-terminal jun kinase/MAPK signaling pathways blocked both progesterone- and MPA-induced VEGF secretion in BT-474 cells. However, these inhibitors blocked only progesterone-, but not MPA-induced VEGF secretion in T47-DCO cells. Inhibitors of PI3-kinase or SP-1 blocked both progesterone- and MPA-induced increases in VEGF mRNA levels in T47-DCO cells. The proximal SP-1 sites within the VEGF promoter were critical for progestin-dependent induction of VEGF. In contrast, MAPK inhibitors did not block the progesterone- or MPA-induced increases in VEGF mRNA in T47-DCO cells, suggesting that MAPK inhibitors decreased progesterone-induced VEGF secretion in T47-DCO cells by blocking posttranscriptional mechanisms. The MAPK kinase/ERK/MAPK-independent induction of VEGF mediated by MPA was associated with the PRB [progesterone receptor (PR) B] isoform of the PR in T47-DCO cells. None of the inhibitors tested reduced basal PR levels or abrogated PR-dependent gene expression from a reporter plasmid, indicating that loss of PR function cannot explain any of the observed effects. Because the PI3-kinase signaling pathway and SP-1 transcription factor play critical roles in progestin-dependent VEGF induction, these may be useful targets for developing antiangiogenic therapies to prevent progression of progestin-dependent human breast cancers.

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29

Fedotcheva, Tatiana A., Nadezhda I. Fedotcheva, and Nikolai L. Shimanovsky. "Progestins as Anticancer Drugs and Chemosensitizers, New Targets and Applications." Pharmaceutics 13, no. 10 (October 4, 2021): 1616. http://dx.doi.org/10.3390/pharmaceutics13101616.

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Progesterone and its synthetic analogues, progestins, participate in the regulation of cell differentiation, proliferation and cell cycle progression. Progestins are usually applied for contraception, maintenance of pregnancy, and hormone replacement therapy. Recently, their effectiveness in the treatment of hormone-sensitive tumors was revealed. According to current data, the anticancer activity of progestins is mainly mediated by their cytotoxic and chemosensitizing influence on different cancer cells. In connection with the detection of previously unknown targets of the progestin action, which include the membrane-associated progesterone receptor (PR), non-specific transporters related to the multidrug resistance (MDR) and mitochondrial permeability transition pore (MPTP), and checkpoints of different signaling pathways, new aspects of their application have emerged. It is likely that the favorable influence of progestins is predominantly associated with the modulation of expression and activity of MDR-related proteins, the inhibition of survival signaling pathways, especially TGF-β and Wnt/β-catenin pathways, which activate the proliferation and promote MDR in cancer cells, and the facilitation of mitochondrial-dependent apoptosis. Biological effects of progestins are mediated by the inhibition of these signaling pathways, as well as the direct interaction with the nucleotide-binding domain of ABC-transporters and mitochondrial adenylate translocase as an MPTP component. In these ways, progestins can restore the proliferative balance, the ability for apoptosis, and chemosensitivity to drugs, which is especially important for hormone-dependent tumors associated with estrogen stress, epithelial-to-mesenchymal transition, and drug resistance.

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30

Siddique, Yasir Hasan, and Mohammad Afzal. "Evaluation of genotoxic potential of synthetic progestin chlormadinone acetate." Toxicology Letters 153, no. 2 (November 2004): 221–25. http://dx.doi.org/10.1016/j.toxlet.2004.03.026.

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31

Han, Jian, Qiangwei Wang, Xianfeng Wang, Yonggang Li, Sheng Wen, Shan Liu, Guangguo Ying, Yongyong Guo, and Bingsheng Zhou. "The synthetic progestin megestrol acetate adversely affects zebrafish reproduction." Aquatic Toxicology 150 (May 2014): 66–72. http://dx.doi.org/10.1016/j.aquatox.2014.02.020.

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32

Brodeur, P., M. Mockus, R. McCullough, and L. G. Moore. "Progesterone receptors and ventilatory stimulation by progestin." Journal of Applied Physiology 60, no. 2 (February 1, 1986): 590–95. http://dx.doi.org/10.1152/jappl.1986.60.2.590.

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Progestin is thought to be a ventilatory stimulant but its effectiveness in raising ventilation is variable in humans and other species. We hypothesized that the level of progesterone receptors was an important determinant of the ventilatory response to progestin. Since estradiol induces progesterone receptor formation, we compared the ventilatory effect of the synthetic progestin medroxyprogesterone acetate (MPA) given in combination with estradiol with the effects of estradiol alone, MPA alone, or vehicle (saline) in ovariectomized rats. Animals receiving MPA alone had low numbers of progesterone receptors (2.43 pmol/g uterine wt) and had no change in ventilation, arterial Pco2, or Po2. MPA administration raised ventilation 23 +/- 5%, lowered arterial Pco2 3.2 +/- 0.9 Torr (both P less than 0.01) and tended to raise arterial Po2 when given in combination with estradiol to animals with increased numbers of progesterone receptors (4.85 pmol/g uterine wt). Estradiol alone produced the highest number of progesterone receptors (12.3 pmol/g uterine wt) but had no effect on ventilation or arterial Pco2 and decreased arterial Po2. Combined estradiol plus MPA treatment produced a greater fall in arterial Pco2 than did treatment with MPA alone, estradiol, or saline (all P less than 0.05). These results suggest that both an elevation in progestin levels and progesterone receptor numbers are required to stimulate ventilation.

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33

Gogoi, R., M. Kudla, O. Gill, K. Horwitz, and D. Fishman. "The activity of the synthetic progestin medroxyprogesterone acetate on the invasive phenotype of ovarian cancer cells." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 16003. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.16003.

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16003 Background: Androgens play an integral role in the physiologic and pathologic processes of the ovary. Yet it has been difficult to study the role of the androgen recptors (AR) separately from the other steroid receptors such as the progesterone receptor (PR) in ovarian cancer. This has been made more complicated because most synthetic progestins such as Medroxyprogesterone acetate (MPA) bind both PR and AR. The objectives of our study were: 1. To create an ovarian cancer cell line constitutively expressing only AR. 2. To compare the role of AR activated by the synthetic progestin MPA vs. the pure androgen dihydrotestosterone (DHT) on the invasiveness of human breast and ovarian cancer cells. 3. To investigate the role of matrix metalloproteases (MMP's) associated with invasion. Methods: ER- and PR- human breast (T47D-Y) and ovarian (OvCa 429) cancer cells were engineered to stably express AR. Immunocytochemistry and western blot analyses confirmed that these breast and ovarian cancer cell lines (called Y-AR and OvCa-AR respectively) are PR-, but AR+. Boyden chamber invasion assays were performed using Y-AR and OvCa-AR cells treated with either vehicle, MPA or DHT. The MMP's associated with invasion were further investigated using zymographic assays. Results: AR activation by either MPA or DHT increased the invasive potential of both breast (p<0.05) and ovarian cancer cells with MPA being significantly more effective than DHT at stimulating invasion. However, regardless of the ligand, activation of AR increases tumor cell invasion. To elucidate the MMP's associated with this activation in OvCa-AR cells, we used zymographic analysis. Interestingly, we found that MPA activation of AR decreases both the total level and activation of MMP-9 compared to DHT and vehicle control. Conclusions: Using our model system we are able to study the role of AR independent of PR on the biology of breast and ovarian cancer cells. Our studies suggest that the use of pharmacological doses of synthetic progestins may actually increase the invasive potential of ovarian cancer cells through AR. We hypothesize that blockade of downstream AR targets or the use of selective AR modulators (SARMS) may be of therapeutic value in the treatment of ovarian cancer. No significant financial relationships to disclose.

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Lamb, Caroline A., Victoria T. Fabris, Britta M. Jacobsen, Alfredo Molinolo, and Claudia Lanari. "Biological and clinical impact of imbalanced progesterone receptor isoform ratios in breast cancer." Endocrine-Related Cancer 25, no. 12 (December 2018): R605—R624. http://dx.doi.org/10.1530/erc-18-0179.

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There is a consensus that progestins and thus their cognate receptor molecules, the progesterone receptors (PRs), are essential in the development of the adult mammary gland and regulators of proliferation and lactation. However, a role for natural progestins in breast carcinogenesis remains poorly understood. A hint to that possible role came from studies in which the synthetic progestin medroxyprogesterone acetate was associated with an increased breast cancer risk in women under hormone replacement therapy. However, progestins have also been used for breast cancer treatment and to inhibit the growth of several experimental breast cancer models. More recently, PRs have been shown to be regulators of estrogen receptor signaling. With all this information, the question is how can we target PR, and if so, which patients may benefit from such an approach? PRs are not single unique molecules. Two main PR isoforms have been characterized, PRA and PRB, which exert different functions and the relative abundance of one isoform with respect to the other determines the response of PR agonists and antagonists. Immunohistochemistry with standard antibodies against PR do not discriminate between isoforms. In this review, we summarize the current knowledge on the expression of both PR isoforms in mammary glands, in experimental models of breast cancer and in breast cancer patients, to better understand how the PRA/PRB ratio can be exploited therapeutically to design personalized therapeutic strategies.

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Kimura, H., M. Mikami, T. Kuriyama, and Y. Fukuda. "Effect of a synthetic progestin on ventilatory response to hypoxia in anesthetized rats." Journal of Applied Physiology 67, no. 5 (November 1, 1989): 1754–58. http://dx.doi.org/10.1152/jappl.1989.67.5.1754.

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Effects on ventilatory responses to progressive isocapnic hypoxia of a synthetic potent progestin, chlormadinone acetate (CMA), were determined in the halothane-anesthetized male rat. Ventilation during the breathing of hyperoxic gas was largely unaffected by treatment with CMA when carotid chemoreceptor afferents were kept intact. The sensitivity to hypoxia evaluated by hyperbolic regression analysis of the response curve did not differ between the control and CMA groups. The reduction of ventilation after bilateral section of the carotid sinus nerve (CSN) in hyperoxia was less severe in CMA-treated than in untreated animals. Furthermore, the CMA-treated rats showed a larger increase in ventilation during the hypoxia test and a lower PO2 break point for ventilatory depression. Inhibition of hypoxic ventilatory depression by CMA persisted even after the denervation of CSN. We conclude that exogenous progestin likely protects regulatory mechanism(s) for respiration against hypoxic depression through a stimulating action independent of carotid chemoreceptor afferents and without a change in the sensitivity of the ventilatory response to hypoxia.

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36

Liang, Yan-Qiu, Guo-Yong Huang, Zhong Lin, Jin Li, Jie-Wen Yang, Lai-Yuan Zhong, and Guang-Guo Ying. "Reproductive effects of synthetic progestin norgestrel in zebrafish (Danio rerio)." Chemosphere 190 (January 2018): 17–24. http://dx.doi.org/10.1016/j.chemosphere.2017.09.127.

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37

Blanchon, Sylvene, Guy Couarraze, Françoise Rieg-Falson, Gerard Cohen, and Francis Puisieux. "Permeability of progesterone and a synthetic progestin through methacrylic films." International Journal of Pharmaceutics 72, no. 1 (May 1991): 1–10. http://dx.doi.org/10.1016/0378-5173(91)90374-w.

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38

Death, A. K., K. C. Y. McGrath, T. Tsatralis, R. Kazlauskas, and D. J. Handelsman. "124.Tetrahydrogestrinone (THG) is a potent androgen and progestin." Reproduction, Fertility and Development 16, no. 9 (2004): 124. http://dx.doi.org/10.1071/srb04abs124.

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Tetrahydrogestrinone (THG) is a novel steroid recently identified by a sports doping laboratory as an illicit agent sold to improve elite athletic performance. While its structure is closely related to gestrinone, a 19-nor progestin, and resembles that of trenbolone, a potent banned synthetic androgen, THG was never marketed, so no information on its hormonal properties are known. We therefore examined THG for steroidal bioactivity using yeast transformed with a steroid receptor-reporter system, comparing its bioactivity to other known androgens, nandrolone, 7α nandrolone (MENT), norbolethone, 5α-norbolethone, norethandrolone and trenbolone, as well as THG's parent compound, gestrinone. Yeast were stably transformed with human androgen receptor (AR) or progesterone receptor A (PR) cDNA, together with a reporter plasmid containing a β-galactosidase gene under the transcriptional control of an androgen (ARE) or progestin (PRE) reporter element. Bioassays were established by culturing transformed yeast in the presence of the steroids over the range of 1.2�×�10–6 to 5.9�–�10–10�M.The bioassay end-point was β-galactosidase activity in yeast cell lysates. THG showed dose-dependent highly potent activation of AR activity with an EC50 of 0.29�nM compared with other steroids nandrolone (0.12�nM), norbolethone (0.3�nM), 5α-norbolethone (0.026�nM), gestrinone (0.59�nM), trenbolone (0.78�nM), norethandrolone (0.19�nM) and MENT (0.01�nM). THG also activated PR (EC50 0.7�nM) with much higher potency than its parent steroid, gestrinone (EC50 30�nM). We conclude that THG is a potent androgen and progestin. It shows similar potency to the comparator androgens, nandrolone, norbolethone, 5α-norbolethone and trenbolone. The discovery of this illicit designer androgen raises concern about the possibility of other novel androgens being produced from other marketed synthetic sex steroids.

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39

White, Nicole D. "Hormonal Contraception and Breast Cancer Risk." American Journal of Lifestyle Medicine 12, no. 3 (January 31, 2018): 224–26. http://dx.doi.org/10.1177/1559827618754833.

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Contemporary hormonal contraception formulations contain lower doses of estrogen, have new synthetic progestin components, and provide novel methods of delivery that have not been studied extensively in relation to breast cancer risk. Given that hormonal contraception is the leading method of birth control in the United States, it is important to reevaluate risk using current formulations. Recent studies including contemporary hormonal contraception formulations will be described.

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40

Davoren, J. B., J. W. Hsueh, and C. H. Li. "Somatomedin C augments FSH-induced differentiation of cultured rat granulosa cells." American Journal of Physiology-Endocrinology and Metabolism 249, no. 1 (July 1, 1985): E26—E33. http://dx.doi.org/10.1152/ajpendo.1985.249.1.e26.

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Growth hormone (GH) deficiency in rats is associated with decreased ovarian steroidal responsiveness to gonadotropins, possibly through a reduction in the production of the GH-dependent Somatomedin C/insulinlike growth factor I (SM C/IGF I). We have investigated the direct effects of synthetic SM C/IGF I on gonadotropin-stimulated ovarian steroidogenesis in vitro. Granulosa cells were cultured in a serum-free medium for 48 h in the presence of follicle-stimulating hormone (FSH), with or without SM C/IGF I. FSH dose-dependently increased both estrogen and progestin production. Concomitant treatment with SM C/IGF I led to a dose-dependent augmentation of progestin secretion over the full range of FSH doses tested, by a maximum of 2.3- to 2.6-fold. FSH-stimulated estrogen was enhanced by up to 2.4-fold but only at low doses of FSH. SM C/IGF I-enhanced progestin production was associated with increased pregnenolone production and 3 beta-hydroxysteroid dehydrogenase activity, whereas augmented estrogen production appeared to be due to enhanced aromatase activity. The actions of SM C/IGF I, at physiologically relevant concentrations were correlated with increased extracellular cAMP accumulation and cellular protein content but were independent of any change in cell number or viability. In contrast to SM C/IGF I, the closely related peptide multiplication-stimulating activity decreased estrogen production while increasing progestin metabolite accumulation. The present results indicate that the GH-dependent peptide SM C/IGF I may play a role in ovarian development by enhancing gonadotropin-stimulated granulosa cell steroidogenesis.

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41

Mikami, Makoto, Koichiro Tatsumi, Hiroshi Kimura, Yoshiyuki Honda, and Takayuki Kuriyama. "Respiration Effect of Synthetic Progestin in Small Doses in Normal Men." Chest 96, no. 5 (November 1989): 1073–75. http://dx.doi.org/10.1378/chest.96.5.1073.

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42

Nagle, Carlos A., Monica M. Lahoz, Maria M. Porta, Marta Torres, Teresita Manzur, and Zulema Farinati. "Suppression of ovulation by a synthetic progestin in the capuchin monkey." Journal of Medical Primatology 38, no. 5 (October 2009): 340–46. http://dx.doi.org/10.1111/j.1600-0684.2009.00357.x.

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43

Kekkonen, Raimo, Pekka Lähteenmäki, Tapani Luukkainen, and Juhani Tuominen. "Sequential regimen of the antiprogesterone RU486 and synthetic progestin for contraception * †." Fertility and Sterility 60, no. 4 (October 1993): 610–15. http://dx.doi.org/10.1016/s0015-0282(16)56209-8.

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44

Liang, Yan-Qiu, Wenqiang Xu, Xingyi Liang, Zhanxin Jing, Chang-Gui Pan, and Fei Tian. "The synthetic progestin norethindrone causes thyroid endocrine disruption in adult zebrafish." Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 236 (October 2020): 108819. http://dx.doi.org/10.1016/j.cbpc.2020.108819.

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45

Van Der Walt, L. A., and J. L. Wittliff. "Assessment of progestin receptor polymorphism by various synthetic ligands using HPLC." Journal of Steroid Biochemistry 24, no. 1 (January 1986): 377–82. http://dx.doi.org/10.1016/0022-4731(86)90086-5.

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46

Fedorka, C. E., B. A. Ball, K. J. Lu, J. M. Hanneman, and A. A. Adams. "Alteration of the Mare’s Immune System by the Synthetic Progestin, Altrenogest." Journal of Equine Veterinary Science 66 (July 2018): 113. http://dx.doi.org/10.1016/j.jevs.2018.05.158.

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47

Cutini, Pablo H., Adrián E. Campelo, and Virginia L. Massheimer. "Differential regulation of endothelium behavior by progesterone and medroxyprogesterone acetate." Journal of Endocrinology 220, no. 3 (December 3, 2013): 179–93. http://dx.doi.org/10.1530/joe-13-0263.

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Анотація:

Medroxyprogesterone acetate (MPA) is a synthetic progestin commonly used in hormone replacement therapy (HRT). The aim of this research was to study and compare the effect of progesterone (Pg) and MPA on the regulation of cellular events associated with vascular homeostasis and disease. Platelet adhesion to endothelial cells (ECs), nitric oxide (NO) production, and cell migration were studied using murine ECs in vitro exposed to the progestins. After 7 min of treatment, MPA significantly inhibited NO synthesis with respect to control values; meanwhile, Pg markedly increased vasoactive production. In senile ECs, the stimulatory action of Pg decreases; meanwhile, MPA maintained its ability to inhibit NO synthesis. The presence of RU486 antagonized the action of each steroid. When ECs were preincubated with PD98059 (MAPK inhibitor) or chelerythrine (protein kinase C (PKC) inhibitor) before Pg or MPA treatment, the former totally suppressed the steroid action, but the PKC antagonist did not affect NO production. In the presence of a PI3K inhibitor (LY294002), a partial reduction in Pg effect and a reversal of MPA action were detected. Using indomethacin, the contribution of the cyclooxygenase (COX) pathway was also detected. On platelet adhesion assays, Pg inhibited and MPA stimulated platelet adhesion to ECs. Under inflammatory conditions, Pg prevented platelet adhesion induced by lipopolysaccharide (LPS); meanwhile, MPA potentiated the stimulatory action of LPS. Finally, although both steroids enhanced migration of ECs, MPA exhibited a greater effect. In conclusion, the data presented in this research provide evidence of a differential regulation of vascular function by Pg and MPA.

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48

COLLETTA, A. A., L. M. WAKEFIELD, M. BAUM, and M. SPORN. "Autocrine TGF? Synthesis by T47D Breast Cancer Cells in Response to a Novel Synthetic Progestin." Annals of the New York Academy of Sciences 593, no. 1 Transforming (June 1990): 298. http://dx.doi.org/10.1111/j.1749-6632.1990.tb16123.x.

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49

LAURIKKA-ROUTTI, MARJUT, MAIJA HAUKKAMAA, and PEKKA LÄHTEENMÄKI. "Suppression of Ovarian Function With the Transdermally Given Synthetic Progestin ST 1435." Obstetrical & Gynecological Survey 48, no. 3 (March 1993): 207–8. http://dx.doi.org/10.1097/00006254-199303000-00026.

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50

Doonan, Francesca, Carolyn O’Driscoll, Paul Kenna, and Thomas G. Cotter. "Enhancing survival of photoreceptor cells in vivo using the synthetic progestin Norgestrel." Journal of Neurochemistry 118, no. 5 (July 18, 2011): 915–27. http://dx.doi.org/10.1111/j.1471-4159.2011.07354.x.

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