Defective Uterine Spiral Artery Remodeling and Placental Senescence in a Pregnant Rat Model of Polycystic Ovary Syndrome

Abstract

Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still unclear, as are whether hyperandrogenism and insulin resistance, the two common manifestations of polycystic ovary syndrome, affect uterine SpA remodeling. This study verified previous work in which exposure to 5-dihydrotestosterone (DHT) and insulin (INS) in rats during pregnancy resulted in hyperandrogenism, insulin intolerance, and higher fetal mortality. It also found that exposure to DHT and INS dysregulated the expression of angiogenesis-related genes in the uterus and placenta. It also decreased expression of endothelial nitric oxide synthase and matrix metallopeptidases 2 and 9, increased fibrotic collagen deposits in the uterus, and reduced expression of marker genes for SpA-associated trophoblast giant cells. These changes were related to a greater proportion of unremodeled uterine SpAs and a smaller proportion of highly remodeled arteries in DHT + INS–exposed rats. Placentas from DHT + INS–exposed rats exhibited decreased basal and labyrinth zone regions, reduced maternal blood spaces, diminished labyrinth vascularity, and an imbalance in the abundance of vascular and smooth muscle proteins. Furthermore, placentas from DHT + INS–exposed rats showed expression of placental insufficiency markers and a significant increase in cell senescence–associated protein levels. Altogether, this work demonstrates increased pregnancy complications in polycystic ovary syndrome may be mediated by problems with uterine SpA remodeling, placental functionality, and placental senescence. Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still unclear, as are whether hyperandrogenism and insulin resistance, the two common manifestations of polycystic ovary syndrome, affect uterine SpA remodeling. This study verified previous work in which exposure to 5-dihydrotestosterone (DHT) and insulin (INS) in rats during pregnancy resulted in hyperandrogenism, insulin intolerance, and higher fetal mortality. It also found that exposure to DHT and INS dysregulated the expression of angiogenesis-related genes in the uterus and placenta. It also decreased expression of endothelial nitric oxide synthase and matrix metallopeptidases 2 and 9, increased fibrotic collagen deposits in the uterus, and reduced expression of marker genes for SpA-associated trophoblast giant cells. These changes were related to a greater proportion of unremodeled uterine SpAs and a smaller proportion of highly remodeled arteries in DHT + INS–exposed rats. Placentas from DHT + INS–exposed rats exhibited decreased basal and labyrinth zone regions, reduced maternal blood spaces, diminished labyrinth vascularity, and an imbalance in the abundance of vascular and smooth muscle proteins. Furthermore, placentas from DHT + INS–exposed rats showed expression of placental insufficiency markers and a significant increase in cell senescence–associated protein levels. Altogether, this work demonstrates increased pregnancy complications in polycystic ovary syndrome may be mediated by problems with uterine SpA remodeling, placental functionality, and placental senescence. Polycystic ovary syndrome (PCOS) is a syndrome of reproductive, metabolic, and psychological aberrations and affects up to 18% of adult women worldwide.1Joham A.E. Norman R.J. Stener-Victorin E. Legro R.S. Franks S. Moran L.J. Boyle J. Teede H.J. Polycystic ovary syndrome.Lancet Diabetes Endocrinol. 2022; 10: 668-680Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Although no single etiological factor can fully account for the spectrum of abnormalities in PCOS, hyperandrogenism/androgen excess and insulin (INS) resistance have emerged as key clinical hallmarks that are attributed to the development and progression of PCOS.2Hoeger K.M. Dokras A. Piltonen T. Update on PCOS: consequences, challenges, and guiding treatment.J Clin Endocrinol Metab. 2021; 106: e1071-e1083Crossref PubMed Scopus (139) Google Scholar Women with PCOS are at high risk for several pregnancy-related complications and adverse obstetric outcomes,3Palomba S. de Wilde M.A. Falbo A. Koster M.P. La Sala G.B. Fauser B.C. Pregnancy complications in women with polycystic ovary syndrome.Hum Reprod Update. 2015; 21: 575-592Crossref PubMed Scopus (352) Google Scholar,4Palomba S. Is fertility reduced in ovulatory women with polycystic ovary syndrome? an opinion paper.Hum Reprod. 2021; 36: 2421-2428Crossref PubMed Scopus (52) Google Scholar such as miscarriage5Bahri Khomami M. Joham A.E. Boyle J.A. Piltonen T. Silagy M. Arora C. Misso M.L. Teede H.J. Moran L.J. Increased maternal pregnancy complications in polycystic ovary syndrome appear to be independent of obesity-a systematic review, meta-analysis, and meta-regression.Obes Rev. 2019; 20: 659-674Crossref PubMed Scopus (89) Google Scholar,6Cai H. Mol B.W. Gordts S. Wang H. Wang T. Li N. Shi J. Early and late pregnancy loss in women with polycystic ovary syndrome undergoing IVF/ICSI treatment: a retrospective cohort analysis of 21 820 pregnancies.BJOG. 2020; 128: 1160-1169Crossref PubMed Scopus (13) Google Scholar and preeclampsia.7Zahid S. Khan M.Z. Gowda S. Faza N.N. Honigberg M.C. Vaught A.J. Guan C. Minhas A.S. Michos E.D. Trends, predictors, and outcomes of cardiovascular complications associated with polycystic ovary syndrome during delivery hospitalizations: a national inpatient sample analysis (2002-2019).J Am Heart Assoc. 2022; 11e025839Google Scholar, 8Farland L.V. Stern J.E. Liu C.L. Cabral H.J. Coddington C.C. Diop H. Dukhovny D. Hwang S. Missmer S.A. Polycystic ovary syndrome and risk of adverse pregnancy outcomes: a registry linkage study from Massachusetts.Hum Reprod. 2022; 37: 2690-2699Crossref PubMed Scopus (4) Google Scholar, 9Chatzakis C. Tsakmaki E. Psomiadou A. Charitakis N. Eleftheriades M. Dinas K. Goulis D. Sotiriadis A. Different pregnancy outcomes according to the polycystic ovary syndrome diagnostic criteria: a systematic review and meta-analysis of 79 studies.Fertil Steril. 2022; 117: 854-881Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar There is currently no effective prevention or cure for patients with PCOS with pregnancy complications.2Hoeger K.M. Dokras A. Piltonen T. Update on PCOS: consequences, challenges, and guiding treatment.J Clin Endocrinol Metab. 2021; 106: e1071-e1083Crossref PubMed Scopus (139) Google Scholar,3Palomba S. de Wilde M.A. Falbo A. Koster M.P. La Sala G.B. Fauser B.C. Pregnancy complications in women with polycystic ovary syndrome.Hum Reprod Update. 2015; 21: 575-592Crossref PubMed Scopus (352) Google Scholar Despite findings showing uterine and placental dysfunction,10Palomba S. Falbo A. Chiossi G. Tolino A. Tucci L. La Sala G.B. Zullo F. Early trophoblast invasion and placentation in women with different PCOS phenotypes.Reprod Biomed Online. 2014; 29: 370-381Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,11Palomba S. Piltonen T.T. Giudice L.C. Endometrial function in women with polycystic ovary syndrome: a comprehensive review.Hum Reprod Update. 2021; 27: 584-618Crossref PubMed Scopus (120) Google Scholar the precise mechanisms leading to PCOS-induced pregnancy-related complications are not fully understood. Maternal uterine spiral artery (SpA) remodeling is a prerequisite for successful pregnancy,12Cha J. Sun X. Dey S.K. Mechanisms of implantation: strategies for successful pregnancy.Nat Med. 2012; 18: 1754-1767Crossref PubMed Scopus (880) Google Scholar and impaired or excessive SpA remodeling often causes pregnancy-related complications in humans.13Staff A.C. Fjeldstad H.E. Fosheim I.K. Moe K. Turowski G. Johnsen G.M. Alnaes-Katjavivi P. Sugulle M. Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia.Am J Obstet Gynecol. 2022; 226: S895-S906Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar In healthy pregnancies, during early to middle gestation, remodeled SpAs demonstrate endothelial cell (EC) re-endothelialization and vascular smooth muscle cell (VSMC) dedifferentiation,14Ma X. L. Liu J. X. Li Wang the of spiral artery vascular smooth muscle during Reprod. 2021; PubMed Scopus Google A. spiral artery muscle Reprod. 2019; PubMed Scopus Google Scholar which can be such as muscle smooth muscle protein and the of and and matrix maternal and and to the SpA remodeling K.M. for trophoblast cell development and to uterine spiral artery 2021; PubMed Scopus Google Scholar of also that at the of and are in the of vascular M.P. A. A. H. and PubMed Scopus Google Scholar and is associated with pregnancy X. Liu F. J. Li Wang C.C. and in at the of J Reprod Scopus Google Scholar work that endothelial function is impaired in patients with PCOS with endothelial in women with polycystic ovary syndrome: of the 2019; PubMed Scopus Google Scholar, of excess and on endothelial function in women with polycystic ovary PubMed Scopus Google Scholar, S. T. M. Norman R.J. Polycystic ovary syndrome is associated with and endothelial in and Full Text Full Text PDF PubMed Scopus Google Scholar and in J. M. P. G. in a of PCOS: of increased PubMed Scopus Google A. J. N. M. P. G. and insulin resistance, not changes in the development of endothelial in a of polycystic ovary syndrome 2015; PubMed Scopus Google Scholar Furthermore, impaired endothelial function is associated with in women with polycystic ovary Biomed Online. Full Text Full Text PDF PubMed Scopus Google Scholar a maternal vascular abnormalities and PCOS-induced It been that exposure to DHT and INS in rats PCOS hyperandrogenism, INS intolerance, and increased fetal M. X. Liu G. J. Li J. P. X. H. M. H. and insulin resistance uterine in association with and J Endocrinol Metab. 2019; PubMed Scopus Google H. M. X. Liu G. Li J. P. S. Li M. H. and insulin fetal for placental abnormalities and in rats that the clinical of polycystic ovary 2019; PubMed Scopus Google Scholar by this and have also a association and the expression of and vascular genes in M. X. Liu G. J. Li J. P. X. H. M. H. and insulin resistance uterine in association with and J Endocrinol Metab. 2019; PubMed Scopus Google Scholar, H. M. X. Liu G. Li J. P. S. Li M. H. and insulin fetal for placental abnormalities and in rats that the clinical of polycystic ovary 2019; PubMed Scopus Google Scholar, H. J. D. Liu H. Li H. uterine and in the during 2019; Scopus Google Scholar from clinical that women with PCOS a reduced of trophoblast invasion and blood in uterine S. T. Falbo A. A. Tolino A. Tucci L. La Sala G.B. Zullo F. and findings of the in women with polycystic ovary syndrome.Hum Reprod. PubMed Scopus Google S. T. Falbo A. A. G. Tolino A. Zullo F. Tucci L. La Sala G.B. trophoblast invasion in women with polycystic ovary syndrome: an Clin Endocrinol Metab. 2012; PubMed Scopus Google Scholar These findings to that in PCOS hyperandrogenism and INS loss is in to impaired maternal SpA remodeling of re-endothelialization and is a that can be by and A. A.C. E. P. roles of in and J. PubMed Scopus Google Scholar and this uterine and placental of causes cell to impaired and with trophoblast Reprod. 2022; 37: PubMed Scopus Google to the and of Reprod. 2022; PubMed Scopus Google Scholar which is linked to and pregnancy P. J. J. J. L.J. S. S. pregnancy loss is associated with a during the 2020; PubMed Scopus Google H. T. K. K. K. K. K. of in during to Reprod. 2020; PubMed Scopus Google Scholar of to the invasion of the during P. G. K. S. T. P. T. K. M. X. J. J. G. M. C. A.E. J. M. J. and are hallmarks of PubMed Scopus Google Scholar have that the of in is in the of D. J. Sun L. J. PCOS by 2021; PubMed Scopus Google D. S.K. K. exposure and function and in adult a hallmarks of polycystic syndrome 2022; PubMed Scopus Google Scholar whether the hyperandrogenism and INS resistance in PCOS uterine and placental not been a M. X. Liu G. J. Li J. P. X. H. M. H. and insulin resistance uterine in association with and J Endocrinol Metab. 2019; PubMed Scopus Google H. M. X. Liu G. Li J. P. S. Li M. H. and insulin fetal for placental abnormalities and in rats that the clinical of polycystic ovary 2019; PubMed Scopus Google Scholar the study to whether the remodeling of maternal SpA and markers for in the uterus and is by hyperandrogenism and INS resistance during The and from this study the of hyperandrogenism and INS resistance on maternal uterine SpA remodeling and placental during rats of were of and from the of were on at at and to with and rats on the of were with of the at a The of a as pregnancy and this as with the for N. A. S. M. A. M. P. K. M. F. P. K. T. H. The for 2020; PubMed Scopus Google Scholar and were and in the and of the of and the rats were two the and of an of and 2 the and DHT in with INS in to hyperandrogenism and INS The of DHT and INS were on the of previous M. X. Liu G. J. Li J. P. X. H. M. H. and insulin resistance uterine in association with and J Endocrinol Metab. 2019; PubMed Scopus Google H. M. X. Liu G. Li J. P. S. Li M. H. and insulin fetal for placental abnormalities and in rats that the clinical of polycystic ovary 2019; PubMed Scopus Google Scholar the in and DHT + INS–exposed as M. X. Liu G. J. Li J. P. X. H. M. H. and insulin resistance uterine in association with and J Endocrinol Metab. 2019; PubMed Scopus Google H. M. X. Liu G. Li J. P. S. Li M. H. and insulin fetal for placental abnormalities and in rats that the clinical of polycystic ovary 2019; PubMed Scopus Google Scholar were at which is maternal SpA remodeling is and blood is increased to the and for the in G. Maternal uterine vascular remodeling during 2014; 21: PubMed Scopus Google Scholar blood from the and at for the of The maternal uterus and as as were and were for of and and or in and at for and The of and with a as M. J. T. P. M. H. mechanisms of and in polycystic ovary uterine J. PubMed Scopus Google M. L. D. M. H. of the uterine with and of the 2022; PubMed Scopus Google Scholar The are in were in and a The for genes were as the to the of and expression in The expression of and not different from the study expression with the and the of as by the of for protein factor matrix nitric oxide synthase endothelial nitric oxide factor placental protein of vascular endothelial factor A. in a protein factor matrix nitric oxide synthase endothelial nitric oxide factor placental protein of vascular endothelial factor A. of protein were and a of the analysis and been in previous M. J. T. P. M. H. mechanisms of and in polycystic ovary uterine J. PubMed Scopus Google M. L. D. M. H. of the uterine with and of the 2022; PubMed Scopus Google Scholar The and are in The the and a of the on a to for in protein and were and the protein were to the protein in in This of endothelial cell of smooth muscle protein muscle in a of endothelial cell of smooth muscle protein muscle of the uterine and placental by and and according to the and were to protein and according to M. J. T. P. M. H. mechanisms of and in polycystic ovary uterine J. PubMed Scopus Google Scholar, M. L. D. M. H. of the uterine with and of the 2022; PubMed Scopus Google Scholar, M. Li X. P. Li J. M. H. of and in women with PCOS are by in Reprod. 2020; PubMed Scopus Google Scholar The and are in were on a and were an with a The of and in the uterus by The of the different of uterine SpA remodeling on the of and with and according to previous F. C. T. de P. H. trophoblast spiral artery remodeling and in the in 2014; PubMed Scopus Google for cell in spiral remodeling in early J Full Text Full Text PDF PubMed Scopus Google Scholar The from different were and The of the of blood in by the of or of blood and a The sample and analysis were according to the of the previous with N. J. P. M. a to for 2014; Full Text Full Text PDF PubMed Scopus Google Scholar were by in for at and at at were with a of and in for by with a at The were in at and in in of to of at The were for by and for for and in for and for for and at and in and for at with and at the were in and for at The were with in with and for at by in with for at were with in with and for at and with with for at and the were with a of for by with a at the were with for and in and in at with a to the and to the analysis of the of the uterine and placental for analysis as M. X. Liu G. J. Li J. P. X. H. M. H. and insulin resistance uterine in association with and J Endocrinol Metab. 2019; PubMed Scopus Google H. M. X. Liu G. Li J. P. S. Li M. H. and insulin fetal for placental abnormalities and in rats that the clinical of polycystic ovary 2019; PubMed Scopus Google Scholar were a with an The of the DHT and as as INS and were The and of and were were the for The to the were and for the the two were by that not have a two were by the are as and and were were from the in the of and were higher in DHT + INS–exposed rats rats. no significant changes in or were in DHT + INS–exposed rats with rats. DHT + INS–exposed rats exhibited reduced and increased INS and for INS resistance Furthermore, to DHT and INS decreased and These are with the that exposure to DHT and INS hyperandrogenism and INS resistance and loss in M. X. Liu G. J. Li J. P. X. H. M. H. and insulin resistance uterine in association with and J Endocrinol Metab. 2019; PubMed Scopus Google H. M. X. Liu G. Li J. P. S. Li M. H. and insulin fetal for placental abnormalities and in rats that the clinical of polycystic ovary 2019; PubMed Scopus Google Scholar whether hyperandrogenism and INS resistance affect in the uterus and the expression of a of angiogenesis-related N. Arora changes in the and early PubMed Scopus Google Scholar by in the expression of vascular endothelial factor and the expression of and placental factor in the uterus of DHT + INS–exposed rats with In the expression of and also in the of DHT + INS–exposed rats There no significant in the expression of uterine or or placental and DHT + INS–exposed rats. Furthermore, increased of and were in the uterus, not the of DHT + INS–exposed rats with rats and The are with previous M. X. Liu G. J. Li J. P. X. H. M. H. and insulin resistance uterine in association with and J Endocrinol Metab. 2019; PubMed Scopus Google H. M. X. Liu G. Li J. P. S. Li M. H. and insulin fetal for placental abnormalities and in rats that the clinical of polycystic ovary 2019; PubMed Scopus Google Scholar nitric oxide synthase synthase is a key for the of the in the vascular T. nitric oxide synthase in vascular from to PubMed Scopus Google Scholar and the and are that to in H. G. and function of matrix and PubMed Scopus Google Scholar by the expression of and decreased in the uterus of DHT + INS–exposed rats with the rats There also a in the expression of in the uterus of DHT + INS this not different to that in rats. These that hyperandrogenism and INS resistance uterine remodeling, and endothelial function during of the changes underlying uterine as a of hyperandrogenism and INS resistance during analysis of genes that are highly by the trophoblast giant that the and to SpA remodeling in A.C. cell at the during pregnancy.Nat Scopus Google Scholar in the expression of of 2 protein and decreased in the uterus of DHT + INS–exposed rats with the In significant in the expression of factor a marker for fetal endothelial a common marker for and and 2 a marker for A.C. cell at the during pregnancy.Nat Scopus Google Scholar were in the uterus of DHT + INS–exposed rats with There no significant in the expression of the a marker of in to DHT + INS The expression of and not and also in the of DHT + INS–exposed rats These that hyperandrogenism and INS resistance reduced and in the uterus and placenta. the of hyperandrogenism and INS resistance on the of the uterus, and were In the uterus on not in the and in the and by and with in the in DHT + INS–exposed in the and and in the and by the of vascular by with The of vascular the of uterine SpA remodeling in DHT + INS–exposed rats with rats. and in the vascular were in not in DHT + INS–exposed rats Despite with in collagen found in DHT + INS–exposed rats not in rats. This by increased fibrotic collagen deposits in the of the and in DHT + INS–exposed rats with that in were fully in the vascular in the loss of in the vascular in the and in the and and of DHT + INS–exposed the vascular analysis showed that the of unremodeled uterine SpAs vascular the of fully remodeled uterine SpAs to no vascular decreased in DHT + INS–exposed rats with decreased in rats to DHT and INS with fetal loss the loss of is a for the of maternal uterine SpA J. The of vascular smooth muscle cell and during uterine spiral artery remodeling in J. 2012; PubMed Scopus Google Scholar with for and to an of the of uterine blood at the and analysis that of blood for and in the and in DHT + INS–exposed rats with Furthermore, a of the of in DHT + INS–exposed rats These are with the that hyperandrogenism and INS resistance maternal uterine vascular abnormalities and SpA remodeling. In the loss of the to the of uterine SpA remodeling during early X. L. Liu J. X. Li Wang the of spiral artery vascular smooth muscle during Reprod. 2021; PubMed Scopus Google A. spiral artery muscle Reprod. 2019; PubMed Scopus Google Scholar the of hyperandrogenism and INS resistance on the and and to the and of markers and for in the uterus of rats to DHT and in no in uterine or protein abundance and DHT + INS–exposed uterine protein abundance increased in DHT + INS–exposed rats with analysis showed that in and in and showed in the and the and in DHT + INS–exposed rats with rats. higher in the uterine blood of rats to DHT and INS with the uterine from rats. There are different of SpA remodeling in the maternal in and rats during early pregnancy X. L. Liu J. X. Li Wang the of spiral artery vascular smooth muscle during Reprod. 2021; PubMed Scopus Google F. C. T. de P. H. trophoblast spiral artery remodeling and in the in 2014; PubMed Scopus Google Scholar Although in of remodeling, and highly remodeled uterine highly remodeled and SpAs were in analysis showed that the of unremodeled uterine SpAs vascular the of highly remodeled uterine SpAs and vascular decreased in DHT + INS–exposed rats with These a the of and uterine SpA remodeling the of hyperandrogenism and INS placental and of the also be by hyperandrogenism and INS resistance analysis of placental at showed that the basal zone and labyrinth zone were in and DHT + INS–exposed rats Despite their the of the basal labyrinth and were decreased in DHT + INS–exposed rats with which is to women with S. T. Falbo A. A. Tolino A. Tucci L. La Sala G.B. Zullo F. and findings of the in women with polycystic ovary syndrome.Hum Reprod. PubMed Scopus Google X. Wang F. fetal and placental in women with polycystic ovary syndrome: analysis on fetal and placental 2020; 21: PubMed Scopus (6) Google M.P. de Wilde M.A. M.L. Fauser B.C. in women with polycystic ovary syndrome.Hum Reprod. 2015; Google Scholar Furthermore, as by and and of the placental labyrinth zone decreased and maternal blood in DHT + INS–exposed rats with rats Furthermore, of the placental fetal that rats exhibited endothelial cell DHT + INS–exposed rats exhibited endothelial cell and in association with increased blood analysis that the abundance of and the abundance of in placentas from DHT + INS–exposed rats with rats of factor K. Shi H. A.C. G. R.S. demonstrates the of the 2014; PubMed Scopus Google Scholar and P. R.J. N. J.E. K.M. N. A. N. L. S. is a of with placental function and fetal 2020; PubMed Scopus Google E. J. T. A. P. M. N. S. and placental is associated with placental J Mol 2021; PubMed Scopus Google Scholar protein 2 A. D. D. N. C. P. P. E. S. C. M. protein 2 placental of placental PubMed Scopus Google Scholar and T. H. M. K. M. H. H. T. H. A. T. A. of on and that 2021; PubMed Scopus Google Scholar and protein are associated with placental analysis showed that the expression of and the expression of and in placentas from DHT + INS–exposed rats with rats In with the expression of angiogenesis-related genes in the uterus and and the that hyperandrogenism and INS resistance placental and vascular abnormalities and in placental may a in uterine and placental H. T. K. K. K. K. K. of in during to Reprod. 2020; PubMed Scopus Google P. G. K. S. T. P. T. K. M. X. J. J. G. M. C. A.E. J. M. J. and are hallmarks of PubMed Scopus Google Scholar and cell to impaired and with trophoblast Reprod. 2022; 37: PubMed Scopus Google Scholar, to the and of Reprod. 2022; PubMed Scopus Google Scholar, P. J. J. J. L.J. S. S. pregnancy loss is associated with a during the 2020; PubMed Scopus Google Scholar were to whether hyperandrogenism and INS resistance the expression of and a protein marker of and N. M. M. in a marker of and 2021; PubMed Scopus Google in the uterus and placenta. analysis that DHT and INS exposure not or protein in the uterus the exposure increased and not protein in the Furthermore, exposure to DHT and INS decreased protein in the uterus a for protein in the with the These demonstrate that is by hyperandrogenism and INS resistance in a The of pregnancy loss S. de Wilde M.A. Falbo A. Koster M.P. La Sala G.B. Fauser B.C. Pregnancy complications in women with polycystic ovary syndrome.Hum Reprod Update. 2015; 21: 575-592Crossref PubMed Scopus (352) Google Scholar,4Palomba S. Is fertility reduced in ovulatory women with polycystic ovary syndrome? an opinion paper.Hum Reprod. 2021; 36: 2421-2428Crossref PubMed Scopus (52) Google Scholar,11Palomba S. Piltonen T.T. Giudice L.C. Endometrial function in women with polycystic ovary syndrome: a comprehensive review.Hum Reprod Update. 2021; 27: 584-618Crossref PubMed Scopus (120) Google Scholar in in have been to which and mechanisms are uterine and protein M. J. T. P. M. H. mechanisms of and in polycystic ovary uterine J. PubMed Scopus Google M. L. D. M. H. of the uterine with and of the 2022; PubMed Scopus Google M. F. S. D. Wang X. X. M. H. Increased uterine protein abundance in and in rats with hyperandrogenism and insulin Mol 2021;

Topics & Concepts