CC BY 4.0 · Rev Bras Ginecol Obstet 2023; 45(11): e676-e682
DOI: 10.1055/s-0043-1776030
Original Article
Infertility

Endometrial Progesterone and Estrogen Receptors in Relation to Hormonal Levels in Women with Unexplained Recurrent Miscarriage

Receptores endometriais de progesterona e estrogênio em relação aos níveis hormonais em mulheres com aborto recorrente inexplicável
1   Ain Shams University Maternity Hospital, Abbaseya Square, Cairo, Egypt.
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1   Ain Shams University Maternity Hospital, Abbaseya Square, Cairo, Egypt.
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1   Ain Shams University Maternity Hospital, Abbaseya Square, Cairo, Egypt.
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1   Ain Shams University Maternity Hospital, Abbaseya Square, Cairo, Egypt.
› Institutsangaben

Abstract

Objective Recurrent miscarriage has been linked to hormonal disturbance due to dysregulation of its receptors rather than to the availability of the hormone. We aimed to investigate endometrial expression of progesterone and estrogen receptors in relation to serum and endometrial hormonal levels in unexplained recurrent miscarriage.

Methods The present case control study included 20 cases with unexplained recurrent miscarriage and 20 parous women as controls. Ovulation was confirmed using an ovulation kit and 10 to 12 days after detecting the urinary luteinizing hormone surge, all women were subjected to a blood sample and to an endometrial biopsy. Progesterone and estrogen levels were measured in serum and in endometrial tissue and receptor concentrations were in the endometrial sample.

Results Women with recurrent miscarriage showed significantly lower concentration of receptors in both the cytoplasm and the nucleus of endometrial tissue compared with controls. The nuclear/cytoplasm ratio of progesterone receptor was significantly higher in cases compared with controls, implicating that recurrent miscarriage is probably linked to nongenomic activity of the hormone; this was also significant for estrogen receptor. Serum progesterone and estrogen hormonal levels were comparable between groups while both hormones were significantly reduced in the endometrium of recurrent miscarriage cases. Receptors significantly correlated with endometrial hormonal level but not to serum level.

Conclusion Recurrent miscarriage might be linked to reduced endometrial progesterone and estrogen receptors and appears to be more related to nongenomic activity of progesterone. Endometrial receptors expression correlates to tissue hormonal level rather than to serum hormonal level.

Contributions

Gomaa I: study conception, project development, protocol development, data analysis. Sabry A: protocol development, data collection, manuscript drafting. Allam IS: study conception, data analysis. Ashoush S: project development, data collection. Reda A: data interpretation, manuscript writing. All authors critically revised the manuscript and approved the final version.




Publikationsverlauf

Eingereicht: 21. Februar 2023

Angenommen: 07. August 2023

Artikel online veröffentlicht:
29. November 2023

© 2023. Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Royal College of Obstetricians and gynecologists. The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. Green top guideline no. 17 ( 2011
  • 2 American College of Obstetricians and gynecologists. ACOG practice bulletin. management of recurrent pregnancy loss. Int J Gynaecol Obstet 2002; 78 (02) 179-190 DOI: 10.1016/s0020-7292(02)00197-2.
  • 3 Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middledorp S. et al; ESHRE Guideline Group on RPL. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018; 2018 (02) hoy004 DOI: 10.1093/hropen/hoy004.
  • 4 Di Renzo GC, Giardina I, Clerici G, Brillo E, Gerli S. Progesterone in normal and pathological pregnancy. Horm Mol Biol Clin Investig 2016; 27 (01) 35-48 DOI: 10.1515/hmbci-2016-0038.
  • 5 Wetendorf M, DeMayo FJ. The progesterone receptor regulates implantation, decidualization, and glandular development via a complex paracrine signaling network. Mol Cell Endocrinol 2012; 357 (1-2): 108-118 DOI: 10.1016/j.mce.2011.10.028.
  • 6 Check JH, Cohen R. The role of progesterone and the progesterone receptor in human reproduction and cancer. Expert Rev Endocrinol Metab 2013; 8 (05) 469-484 DOI: 10.1586/17446651.2013.827380.
  • 7 Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology. Cochrane Database Syst Rev 2019; 2019 (11) CD003511 DOI: 10.1002/14651858.CD003511.pub5.
  • 8 Coomarasamy A, Williams H, Truchanowicz E, Seed PT, Small R, Quenby S. et al. PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. Health Technol Assess 2016; 20 (41) 1-92 DOI: 10.3310/hta20410.
  • 9 Carranza-Lira S, Blanquet J, Tserotas K, Calzada L. Endometrial progesterone and estradiol receptors in patients with recurrent early pregnancy loss of unknown etiology–preliminary report. Med Sci Monit 2000; 6 (04) 759-762
  • 10 Häkkinen MR, Heinosalo T, Saarinen N, Linnanen T, Voutilainen R, Lakka T. et al. Analysis by LC-MS/MS of endogenous steroids from human serum, plasma, endometrium and endometriotic tissue. J Pharm Biomed Anal 2018; 152: 165-172 DOI: 10.1016/j.jpba.2018.01.034.
  • 11 Patel B, Elguero S, Thakore S, Dahoud W, Bedaiwy M, Mesiano S. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update 2015; 21 (02) 155-173 DOI: 10.1093/humupd/dmu056.
  • 12 Agrawal V, Jaiswal MK, Jaiswal YK. Lipopolysaccharide-induced modulation in the expression of progesterone receptor and estradiol receptor leads to early pregnancy loss in mouse. Zygote 2012; DOI: 10.1017/S0967199412000330. PubMed
  • 13 Bahia W, Finan RR, Al-Mutawa M, Haddad A, Soua A, Janhani F. et al. Genetic variation in the progesterone receptor gene and susceptibility to recurrent pregnancy loss: a case-control study. BJOG 2018; 125 (06) 729-735 DOI: 10.1111/1471-0528.14949.
  • 14 Razdaibiedina A, Khobzey M, Tkachenko V, Vorobiova I. Effects of Single-Nucleotide Polymorphisms in Cytokine, Toll-Like Receptor, and Progesterone Receptor Genes on Risk of Miscarriage. Hindawi Obstet Gynecol International 2018; 2018 DOI: 10.1155/2018/9272749. PubMed
  • 15 Fazleabas AT. Progesterone resistance in a baboon model of endometriosis. Semin Reprod Med 2010; 28 (01) 75-80 DOI: 10.1055/s-0029-1242997.
  • 16 Gibson DA, Esnal-Zufiaurre A, Bajo-Santos C, Collins F, Critchley HOD, Saunders PTK. Profiling the expression and function of oestrogen receptor isoform ER46 in human endometrial tissues and uterine natural killer cells. Hum Reprod 2020; 35 (03) 641-651 DOI: 10.1093/humrep/dez306.
  • 17 Takaya Y, Matsubayashi H, Kitaya K, Nishiyama R, Yamaguchi K, Takeuchi T. et al. Minimum values for midluteal plasma progesterone and estradiol concentrations in patients who achieved pregnancy with timed intercourse or intrauterine insemination without a human menopausal gonadotropin. BMC Res Notes 2018; 11 (01) 61 DOI: 10.1186/s13104-018-3188-x.
  • 18 Mote PA, Johnston JF, Manninen T, Tuohimaa P, Clarke CL. Detection of progesterone receptor forms A and B by immunohistochemical analysis. J Clin Pathol 2001; 54 (08) 624-630
  • 19 Rahnama R, Rafiee M, Fouladi S, Akbari-Fakhrabadi M, Mehrabian F, Rezaei A. Gene expression analysis of membrane progesterone receptors in women with recurrent spontaneous abortion: a case control study. BMC Res Notes 2019; 12 (01) 790 DOI: 10.1186/s13104-019-4787-x.
  • 20 Salazar EL, Calzada L. The role of progesterone in endometrial estradiol- and progesterone-receptor synthesis in women with menstrual disorders and habitual abortion. Gynecol Endocrinol 2007; 23 (04) 222-225 DOI: 10.1080/09513590701254030.
  • 21 Liang Q, Tong L, Xiang L, Shen S, Pan C, Liu C. et al. Correlations of the expression of γδ T cells and their co-stimulatory molecules TIGIT, PD-1, ICOS and BTLA with PR and PIBF in the peripheral blood and decidual tissues of women with unexplained recurrent spontaneous abortion. Clin Exp Immunol 2021; 203 (01) 55-65 DOI: 10.1111/cei.13534.
  • 22 Marquardt RM, Kim TH, Shin JH, Jeong JW. Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?. Int J Mol Sci 2019; 20 (15) 3822 DOI: 10.3390/ijms2015382.
  • 23 Mulac-Jericevic B, Conneely OM. Reproductive tissue selective actions of progesterone receptors. Reproduction 2004; 128 (02) 139-146
  • 24 Verma P, Verma R, Nair RR, Budhwar S, Khanna A, Agrawal NR. et al. Altered crosstalk of estradiol and progesterone with Myeloid-derived suppressor cells and Th1/Th2 cytokines in early miscarriage is associated with early breakdown of maternal-fetal tolerance. Am J Reprod Immunol 2019; 81 (02) e13081 DOI: 10.1111/aji.13081.
  • 25 Sallam HN, Sallam A, Ezzeldin F, Agamia AF, Abou-Ali A. Reference values for the midluteal plasma progesterone concentration: evidence from human menopausal gonadotropin-stimulated pregnancy cycles. Fertil Steril 1999; 71 (04) 711-714
  • 26 Conneely OM, Mulac-Jericevic B, Lydon JP, De Mayo FJ. Reproductive functions of the progesterone receptor isoforms: lessons from knock-out mice. Mol Cell Endocrinol 2001; 179 (1-2): 97-103 DOI: 10.1016/s0303-7207(01)00465-8.
  • 27 Sabbir MG. Progesterone induced Warburg effect in HEK293 cells is associated with post-translational modifications and proteasomal degradation of progesterone receptor membrane component 1. J Steroid Biochem Mol Biol 2019; 191: 105376 DOI: 10.1016/j.jsbmb.2019.105376.
  • 28 Diep CH, Ahrendt H, Lange CA. Progesterone induces progesterone receptor gene (PGR) expression via rapid activation of protein kinase pathways required for cooperative estrogen receptor alpha (ER) and progesterone receptor (PR) genomic action at ER/PR target genes. Steroids 2016; 114: 48-58 DOI: 10.1016/j.steroids.2016.09.004.
  • 29 Li TC, Spuijbroek MD, Tuckerman E, Anstie B, Loxley M, Laird S. Endocrinological and endometrial factors in recurrent miscarriage. BJOG 2000; 107 (12) 1471-1479