Gene expression associated with unfavorable vaginal bleeding in women using the etonogestrel subdermal contraceptive implant: a prospective study.
Contraception
Etonogestrel implant
Genes
Implanon®
Uterine bleeding
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
14 05 2024
14 05 2024
Historique:
received:
13
12
2023
accepted:
09
05
2024
medline:
15
5
2024
pubmed:
15
5
2024
entrez:
14
5
2024
Statut:
epublish
Résumé
To evaluate gene expression associated with unfavorable vaginal bleeding in users of the Etonogestrel (ENG) contraceptive implant. Prospective study involving 100 women who intended to use the ENG implant. Exclusion criteria included abnormal uterine bleeding, inability to attend a 1-year follow-up, and implant removal for reasons unrelated to vaginal bleeding or loss of follow-up. We obtained endometrial biopsies before implant placement and assessed the expression of 20 selected genes. Users maintained a uterine bleeding diary for 12 months post-implant placement. For statistical analysis, we categorized women into those with or without favorable vaginal bleeding at 3 and 12 months. Women with lower CXCL1 expression had a 6.8-fold increased risk of unfavorable vaginal bleeding at 3 months (OR 6.8, 95% CI 2.21-20.79, p < 0.001), while those with higher BCL6 and BMP6 expression had 6- and 5.1-fold increased risks, respectively. By the 12-month follow-up, women with lower CXCL1 expression had a 5.37-fold increased risk of unfavorable vaginal bleeding (OR 5.37, 95% CI 1.63-17.73, p = 0.006). Women with CXCL1 expression < 0.0675, BCL6 > 0.65, and BMP6 > 3.4 had a higher likelihood of experiencing unfavorable vaginal bleeding at 3 months, and CXCL1 < 0.158 at 12 months. Users of ENG contraceptive implants with elevated BCL6 and BMP6 expression exhibited a higher risk of breakthrough bleeding at the 3-month follow-up. Conversely, reduced CXCL1 expression was associated with an elevated risk of bleeding at both the 3 and 12-month follow-ups.
Identifiants
pubmed: 38745005
doi: 10.1038/s41598-024-61751-7
pii: 10.1038/s41598-024-61751-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
11062Subventions
Organisme : Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP)
ID : 2020/14899-9
Organisme : Conselho Nacional de Desenvolvimento Científico e Tecnológico
ID : 305179/2019-5
Informations de copyright
© 2024. The Author(s).
Références
Curtis, K. M., Ph, D. & Peipert, J. F. Long-acting reversible contraception. N. Engl. J. Med. 376, 461–468 (2017).
doi: 10.1056/NEJMcp1608736
pubmed: 28146650
Bahamondes, L. et al. A 3-year multicentre randomized controlled trial of etonogestrel- and levonorgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls. Hum. Reprod. 30, 2527–38 (2015).
doi: 10.1093/humrep/dev221
pubmed: 26409014
Henkel, A. & Goldthwaite, L. M. Management of bothersome bleeding associated with progestin-based long-acting reversible contraception: A review. Curr. Opin. Obstet. Gynecol. 32(6), 408–415 (2020).
doi: 10.1097/GCO.0000000000000664
pubmed: 32889971
Hickey, M. & Fraser, I. S. The structure of endometrial microvessels. Hum. Reprod. 15(Suppl 3), 57–66 (2000).
doi: 10.1093/humrep/15.suppl_3.57
pubmed: 11041222
Hickey, M. et al. Long-term progestin-only contraceptives result in reduced endometrial blood flow and oxidative stress. J. Clin. Endocrinol. Metab. 91(9), 3633–8. https://doi.org/10.1210/jc.2006-0724 (2006).
doi: 10.1210/jc.2006-0724
pubmed: 16757524
Shaaban, M. M. et al. Sonographic assessment of ovarian and endometrial changes during long-term Norplant use and their correlation with hormonal levels. Fertil. Steril. 59, 998–1002 (1993).
doi: 10.1016/S0015-0282(16)55917-2
pubmed: 8486202
Hadisaputra, W., Affandi, B., Witjaksono, J. & Rogers, P. A. W. Endometrial biopsy collection from women receiving Norplant®. Hum. Reprod. 11(Suppl_2), 31–4 (1996).
doi: 10.1093/humrep/11.suppl_2.31
pubmed: 8982743
Rogers, P. A. W. Endometrial vasculature in Norplant® users. Hum. Reprod. 11(Suppl. 2), 45–50 (1996).
doi: 10.1093/humrep/11.suppl_2.45
pubmed: 8982745
Hickey, M. et al. A longitudinal study of changes in endometrial microvascular density in Norplant® implant users. Contraception 59, 123–129 (1999).
doi: 10.1016/S0010-7824(99)00012-8
pubmed: 10361627
Lockwood, C. J., Krikun, G., Hausknecht, V., Wang, E. Y. & Schatz, F. Decidual cell regulation of hemostasis during implantation and menstruation. Ann. N. Y. Acad. Sci. 828(188–93), 23 (1997).
Lockwood, C. J., Krikun, G., Hausknecht, V. A., Papp, C. & Schatz, F. Matrix metalloproteinase and matrix metalloproteinase inhibitor expression in endometrial stromal cells during progestin-initiated decidualization and menstruation-related progestin withdrawal. Endocrinology 139(4607–13), 24 (1998).
Galant, C. et al. Temporal and spatial association of matrix metalloproteinases with focal endometrial breakdown and bleeding upon progestin-only contraception. J. Clin. Endocrinol. Metab. 85, 4827–34 (2000).
pubmed: 11134150
Krikun, G. et al. Abnormal uterine bleeding during progestin-only contraception may result from free radical-induced alterations in angiopoietin expression. Am. J. Pathol. 161, 979–986 (2002).
doi: 10.1016/S0002-9440(10)64258-7
pubmed: 12213726
pmcid: 1867248
Krikun, G. et al. Endometrial angiopoietin expression and modulation by thrombin and steroid accepted manuscript hormones: A mechanism for abnormal angiogenesis following long-term progestin-only contraception. Am. J. Pathol. 164, 2101–2107 (2004).
doi: 10.1016/S0002-9440(10)63768-6
pubmed: 15161644
pmcid: 1615777
Levy, D. et al. The endometrial approach in contraception. Ann. N. Y. Acad. Sci. 828, 59–83 (1997).
doi: 10.1111/j.1749-6632.1997.tb48524.x
pubmed: 9329824
Kayisli, O. G. et al. Progestins upregulate FKBP51 expression in human endometrial stromal cells to induce functional progesterone and glucocorticoid withdrawal: Implications for contraceptive-Associated abnormal uterine bleeding. PLoS One 13, e1410 (2015).
World Health Organization. Medical Eligibility Criteria for Contraceptive Use 5th edn. (World Health Organization, 2015).
Munro, M. G., Critchley, H. O. D., Fraser, I. S., FIGO Menstrual Disorders Committee. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int. J. Gynaecol. Obstet. 143(3), 393–408 (2018).
doi: 10.1002/ijgo.12666
pubmed: 30198563
Belsey, E. M., Machin, D. & d’Arcangues, C. The analysis of vaginal bleeding patterns induced by fertility regulating methods. World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction. Contraception 34(3), 253–260 (1986).
doi: 10.1016/0010-7824(86)90006-5
pubmed: 3539509
Grzechocińska, B., Dąbrowski, F., Cyganek, A., Panek, G. & Wielgoś, M. The role of metalloproteinases in endometrial remodelling during menstrual cycle. Ginekol. Pol. 88(6), 337–342 (2017).
doi: 10.5603/GP.a2017.0063
pubmed: 28727135
Bray, J. D. et al. Quantitative analysis of gene regulation by seven clinically relevant progestins suggests a highly similar mechanism of action through progesterone receptors in T47D breast cancer cells. J. Steroid Biochem. Mol. Biol. 97(4), 328–341 (2005).
doi: 10.1016/j.jsbmb.2005.06.032
pubmed: 16157482
Guzeloglu-Kayisli, O. et al. Long-acting progestin-only contraceptives enhance human endometrial stromal cell expressed neuronal pentraxin-1 and reactive oxygen species to promote endothelial cell apoptosis. J. Clin. Endocrinol. Metab. 99(10), E1957-1966 (2014).
doi: 10.1210/jc.2014-1770
pubmed: 25029423
pmcid: 4184079
Goldfien, G. A. et al. Progestin-containing contraceptives alter expression of host defense-related genes of the endometrium and cervix. Reprod. Sci. 22(7), 814–828 (2015).
doi: 10.1177/1933719114565035
pubmed: 25634912
pmcid: 4565478
Guzeloglu Kayisli, O. et al. Progestins upregulate FKBP51 expression in human endometrial stromal cells to induce functional progesterone and glucocorticoid withdrawal: Implications for contraceptive- associated abnormal uterine bleeding. PLoS One 10(10), e0137855 (2015).
doi: 10.1371/journal.pone.0137855
pubmed: 26436918
pmcid: 4593551
Kayisli, U. A. et al. Long-acting progestin-only contraceptives impair endometrial vasculature by inhibiting uterine vascular smooth muscle cell survival. Proc. Natl. Acad. Sci. U. S. A. 112(16), 5153–5158 (2015).
doi: 10.1073/pnas.1424814112
pubmed: 25847994
pmcid: 4413279
Ahn, S. H. et al. Immune-inflammation gene signatures in endometriosis patients. Fertil. Steril. 106(6), 1420-1431.e1427 (2016).
doi: 10.1016/j.fertnstert.2016.07.005
pubmed: 27475412
pmcid: 5683404
Shapiro, J. P. et al. Thrombin impairs human endometrial endothelial angiogenesis; implications for progestin-only contraceptive-induced abnormal uterine bleeding. Contraception 95(6), 592–601 (2017).
doi: 10.1016/j.contraception.2017.04.001
pubmed: 28433626
Smith-McCune, K. et al. Differential effects of the hormonal and copper intrauterine device on the endometrial transcriptome. Sci. Rep. 10(1), 6888 (2020).
doi: 10.1038/s41598-020-63798-8
pubmed: 32327684
pmcid: 7181869
Stocker, L., Cagampang, F. & Cheong, Y. Identifying stably expressed housekeeping genes in the endometrium of fertile women, women with recurrent implantation failure and recurrent miscarriages. Sci. Rep. 7(1), 14857 (2017).
doi: 10.1038/s41598-017-07901-6
pubmed: 29093507
pmcid: 5665911
Basso, K. & Dalla-Favera, R. Roles of BCL6 in normal and transformed germinal center B cells. Immunol. Rev. 247(1), 172–183 (2012).
doi: 10.1111/j.1600-065X.2012.01112.x
pubmed: 22500840
Ritter, A. et al. The function of oncogene B-Cell lymphoma 6 in the regulation of the migration and invasion of trophoblastic cells. Int. J. Mol. Sci. 21(21), 8393 (2020).
doi: 10.3390/ijms21218393
pubmed: 33182312
pmcid: 7664908
Louwen, F. et al. BCL6, a key oncogene, in the placenta, pre-eclampsia and endometriosis. Hum. Reprod. Update 28(6), 890–909 (2022).
doi: 10.1093/humupd/dmac027
pubmed: 35640966
pmcid: 9629482
De Conto, E., Matte, U. & Cunha-Filho, J. S. BMP-6 and SMAD4 gene expression is altered in cumulus cells from women with endometriosis-associated infertility. Acta Obstet. Gynecol. Scand. 100, 868–875 (2021).
doi: 10.1111/aogs.13931
pubmed: 32524577
Zhang, X. Y., Chang, H., Taylor, E. L., Liu, R. & Leung, P. C. K. BMP6 downregulates GDNF expression through SMAD1/5 and ERK1/2 signaling pathways in human granulosa-lutein cells. Endocrinology 159(8), 2926–2938 (2018).
doi: 10.1210/en.2018-00189
pubmed: 29750278
Ma, H. et al. Altered cytokine gene expression in peripheral blood monocytes across the menstrual cycle in primary dysmenorrhea: A case-control study. PLoS One 8(2), e55200. https://doi.org/10.1371/journal.pone.0055200 (2013).
doi: 10.1371/journal.pone.0055200
pubmed: 23390521
pmcid: 3563666
Amiri, K. I. & Richmond, A. Fine tuning the transcriptional regulation of the CXCL1 chemokine. Prog. Nucleic Acid Res. Mol. Biol. 74, 1–36 (2003).
doi: 10.1016/S0079-6603(03)01009-2
pubmed: 14510072
pmcid: 3140403
Baston-Büst, D. M. et al. CXCL1 expression in human decidua in vitro is mediated via the MAPK signalling cascade. Cytokine 64, 79–85 (2013).
doi: 10.1016/j.cyto.2013.07.023
pubmed: 23953856
Lau, T. M., Affandi, B. & Rogers, P. A. W. The effects of levonorgestrel implants on vascular endothelial growth factor expression in the endometrium. Mol. Hum. Reprod. 5, 57–63 (1999).
doi: 10.1093/molehr/5.1.57
pubmed: 10050663
Hiraoka, T. et al. Constant activation of STAT3 contributes to the development of adenomyosis in females. Endocrinology 163, 1–9 (2022).
doi: 10.1210/endocr/bqac044