Metformin attenuates the production and proliferative effects of prolactin induced by medroxyprogesterone acetate during fertility-sparing treatment for endometrial cancer
Abstract Background Progestin is used for fertility-sparing treatment in cases of endometrial cancer (EC). Progestin can induce hyperprolactinemia by increasing pituitary secretion and endometrial decidualization. However, progestin induces prolactin (PRL) secretion, which stimulates cell proliferat...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-07-01
|
| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-022-09858-w |
| _version_ | 1828747165978066944 |
|---|---|
| author | Wenjing Gu Akira Mitsuhashi Tatsuya Kobayashi Makio Shozu |
| author_facet | Wenjing Gu Akira Mitsuhashi Tatsuya Kobayashi Makio Shozu |
| author_sort | Wenjing Gu |
| collection | DOAJ |
| description | Abstract Background Progestin is used for fertility-sparing treatment in cases of endometrial cancer (EC). Progestin can induce hyperprolactinemia by increasing pituitary secretion and endometrial decidualization. However, progestin induces prolactin (PRL) secretion, which stimulates cell proliferation and deleteriously affects treatment. To date, the detrimental effect of PRL, the secretion of which is induced by medroxyprogesterone acetate (MPA) during fertility-sparing treatment, has not yet been fully elucidated. Therefore, we aimed to assess the effects of PRL on EC cells during combined treatment with progestin and metformin. Methods In total, 71 patients with EC/endometrial atypical hyperplasia who underwent fertility-sparing treatment at our institution from 2009–2019 were enrolled. Serum PRL levels were determined using enzyme immunoassays; mRNA levels in endometrial tissues were determined using quantitative reverse-transcription PCR. To evaluate MPA-induced decidualization, cancer-associated stromal cells were enzymatically released from surgically removed specimens of six patients with EC. To examine PRL-induced cell proliferation, the EC cell lines Ishikawa, HEC1B, and HEC265 were used. In vitro cell proliferation was evaluated using the WST assay; protein levels of signaling molecules were determined using western blotting. Results MPA administration significantly increased serum PRL levels at 3 and 6 months and upregulated IGFBP-1 and PRL mRNA expression in tissues at 3 months of fertility-sparing treatment. Metformin significantly reduced MPA-induced IGFBP-1 and PRL mRNA expression during fertility-sparing treatment and significantly inhibited the upregulation of IGFBP-1 and PRL mRNA and PRL levels due to decidualization induced by MPA and cAMP treatment in primary cultured EC stromal cells. In vitro, PRL increased cell proliferation and ERK1/2 phosphorylation levels, whereas metformin attenuated these increases. Conclusions MPA upregulated PRL levels in serum and endometrial tissues during fertility-sparing treatment. Metformin co-administration reduced PRL production and attenuated PRL-induced cell-proliferation activity. This study may provide valuable insights on the application of metformin to improve the outcomes of fertility-sparing treatment. |
| first_indexed | 2024-04-14T04:37:35Z |
| format | Article |
| id | doaj.art-f41eaf6211404c91b0b1b298b9d3b333 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-14T04:37:35Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-f41eaf6211404c91b0b1b298b9d3b3332022-12-22T02:11:49ZengBMCBMC Cancer1471-24072022-07-0122111010.1186/s12885-022-09858-wMetformin attenuates the production and proliferative effects of prolactin induced by medroxyprogesterone acetate during fertility-sparing treatment for endometrial cancerWenjing Gu0Akira Mitsuhashi1Tatsuya Kobayashi2Makio Shozu3Department of Reproductive Medicine, Graduate School of Medicine, Chiba UniversityDepartment of Reproductive Medicine, Graduate School of Medicine, Chiba UniversityDepartment of Reproductive Medicine, Graduate School of Medicine, Chiba UniversityDepartment of Reproductive Medicine, Graduate School of Medicine, Chiba UniversityAbstract Background Progestin is used for fertility-sparing treatment in cases of endometrial cancer (EC). Progestin can induce hyperprolactinemia by increasing pituitary secretion and endometrial decidualization. However, progestin induces prolactin (PRL) secretion, which stimulates cell proliferation and deleteriously affects treatment. To date, the detrimental effect of PRL, the secretion of which is induced by medroxyprogesterone acetate (MPA) during fertility-sparing treatment, has not yet been fully elucidated. Therefore, we aimed to assess the effects of PRL on EC cells during combined treatment with progestin and metformin. Methods In total, 71 patients with EC/endometrial atypical hyperplasia who underwent fertility-sparing treatment at our institution from 2009–2019 were enrolled. Serum PRL levels were determined using enzyme immunoassays; mRNA levels in endometrial tissues were determined using quantitative reverse-transcription PCR. To evaluate MPA-induced decidualization, cancer-associated stromal cells were enzymatically released from surgically removed specimens of six patients with EC. To examine PRL-induced cell proliferation, the EC cell lines Ishikawa, HEC1B, and HEC265 were used. In vitro cell proliferation was evaluated using the WST assay; protein levels of signaling molecules were determined using western blotting. Results MPA administration significantly increased serum PRL levels at 3 and 6 months and upregulated IGFBP-1 and PRL mRNA expression in tissues at 3 months of fertility-sparing treatment. Metformin significantly reduced MPA-induced IGFBP-1 and PRL mRNA expression during fertility-sparing treatment and significantly inhibited the upregulation of IGFBP-1 and PRL mRNA and PRL levels due to decidualization induced by MPA and cAMP treatment in primary cultured EC stromal cells. In vitro, PRL increased cell proliferation and ERK1/2 phosphorylation levels, whereas metformin attenuated these increases. Conclusions MPA upregulated PRL levels in serum and endometrial tissues during fertility-sparing treatment. Metformin co-administration reduced PRL production and attenuated PRL-induced cell-proliferation activity. This study may provide valuable insights on the application of metformin to improve the outcomes of fertility-sparing treatment.https://doi.org/10.1186/s12885-022-09858-wProlactinMetforminMedroxyprogesterone acetateFertility preservationEndometrial neoplasms |
| spellingShingle | Wenjing Gu Akira Mitsuhashi Tatsuya Kobayashi Makio Shozu Metformin attenuates the production and proliferative effects of prolactin induced by medroxyprogesterone acetate during fertility-sparing treatment for endometrial cancer BMC Cancer Prolactin Metformin Medroxyprogesterone acetate Fertility preservation Endometrial neoplasms |
| title | Metformin attenuates the production and proliferative effects of prolactin induced by medroxyprogesterone acetate during fertility-sparing treatment for endometrial cancer |
| title_full | Metformin attenuates the production and proliferative effects of prolactin induced by medroxyprogesterone acetate during fertility-sparing treatment for endometrial cancer |
| title_fullStr | Metformin attenuates the production and proliferative effects of prolactin induced by medroxyprogesterone acetate during fertility-sparing treatment for endometrial cancer |
| title_full_unstemmed | Metformin attenuates the production and proliferative effects of prolactin induced by medroxyprogesterone acetate during fertility-sparing treatment for endometrial cancer |
| title_short | Metformin attenuates the production and proliferative effects of prolactin induced by medroxyprogesterone acetate during fertility-sparing treatment for endometrial cancer |
| title_sort | metformin attenuates the production and proliferative effects of prolactin induced by medroxyprogesterone acetate during fertility sparing treatment for endometrial cancer |
| topic | Prolactin Metformin Medroxyprogesterone acetate Fertility preservation Endometrial neoplasms |
| url | https://doi.org/10.1186/s12885-022-09858-w |
| work_keys_str_mv | AT wenjinggu metforminattenuatestheproductionandproliferativeeffectsofprolactininducedbymedroxyprogesteroneacetateduringfertilitysparingtreatmentforendometrialcancer AT akiramitsuhashi metforminattenuatestheproductionandproliferativeeffectsofprolactininducedbymedroxyprogesteroneacetateduringfertilitysparingtreatmentforendometrialcancer AT tatsuyakobayashi metforminattenuatestheproductionandproliferativeeffectsofprolactininducedbymedroxyprogesteroneacetateduringfertilitysparingtreatmentforendometrialcancer AT makioshozu metforminattenuatestheproductionandproliferativeeffectsofprolactininducedbymedroxyprogesteroneacetateduringfertilitysparingtreatmentforendometrialcancer |