Hyperandrogenism and insulin resistance modulate gravid uterine and placental ferroptosis in PCOS-like rats

in Journal of Endocrinology
Authors:
Yuehui Zhang Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China

Search for other papers by Yuehui Zhang in
Current site
Google Scholar
PubMed Close
,
Min Hu Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

Search for other papers by Min Hu in
Current site
Google Scholar
PubMed Close
,
Wenyan Jia Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China

Search for other papers by Wenyan Jia in
Current site
Google Scholar
PubMed Close
,
Guoqi Liu Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China

Search for other papers by Guoqi Liu in
Current site
Google Scholar
PubMed Close
,
Jiao Zhang Department of Acupuncture and Moxibustion, Second Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China

Search for other papers by Jiao Zhang in
Current site
Google Scholar
PubMed Close
,
Bing Wang Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China

Search for other papers by Bing Wang in
Current site
Google Scholar
PubMed Close
,
Juan Li Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

Search for other papers by Juan Li in
Current site
Google Scholar
PubMed Close
,
Peng Cui Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Gynecology, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China

Search for other papers by Peng Cui in
Current site
Google Scholar
PubMed Close
,
Xin Li Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China

Search for other papers by Xin Li in
Current site
Google Scholar
PubMed Close
,
Susanne Lager Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden

Search for other papers by Susanne Lager in
Current site
Google Scholar
PubMed Close
,
Amanda Nancy Sferruzzi-Perri Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

Search for other papers by Amanda Nancy Sferruzzi-Perri in
Current site
Google Scholar
PubMed Close
,
Yanhua Han Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China

Search for other papers by Yanhua Han in
Current site
Google Scholar
PubMed Close
,
Songjiang Liu Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China

Search for other papers by Songjiang Liu in
Current site
Google Scholar
PubMed Close
,
Xiaoke Wu Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China

Search for other papers by Xiaoke Wu in
Current site
Google Scholar
PubMed Close
,
Mats Brännström Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Search for other papers by Mats Brännström in
Current site
Google Scholar
PubMed Close
,
Linus R Shao Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Search for other papers by Linus R Shao in
Current site
Google Scholar
PubMed Close
, and
Håkan Billig Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Search for other papers by Håkan Billig in
Current site
Google Scholar
PubMed Close

Correspondence should be addressed to L R Shao: ruijin.shao@fysiologi.gu.se

*(Y Zhang and M Hu contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-20-0155
Volume/Issue:
Volume 246: Issue 3
Article Type:
Research Article
Page Range:
247–263
Online Publication Date:
Sep 2020
Copyright:
© 2020 Society for Endocrinology 2020
Restricted access
Rent on DeepDyve

Sign up for journal news

Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance and a high risk of miscarriage during pregnancy. Similarly, in rats, maternal exposure to 5α-dihydrotestosterone (DHT) and insulin from gestational day 7.5 to 13.5 leads to hyperandrogenism and insulin resistance and subsequently increased fetal loss. A variety of hormonal and metabolic stimuli are able to trigger different types of regulated cell death under physiological and pathological conditions. These include ferroptosis, apoptosis and necroptosis. We hypothesized that, in rats, maternal hyperandrogenism and insulin-resistance-induced fetal loss is mediated, at least in part, by changes in the ferroptosis, apoptosis and necroptosis pathways in the gravid uterus and placenta. Compared with controls, we found that co-exposure to DHT and insulin led to decreased levels of glutathione peroxidase 4 (GPX4) and glutathione, increased glutathione + glutathione disulfide and malondialdehyde, aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition and activated ERK/p38/JNK phosphorylation in the gravid uterus. In addition, we observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction in the uteri of rats co-exposed to DHT and insulin. However, in the placenta, DHT and insulin exposure only partially altered the expression of ferroptosis-related markers (e.g. region-dependent GPX4, glutathione + glutathione disulfide, malondialdehyde, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). Moreover, we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA in placentas of rats co-exposed to DHT and insulin. Further, DHT + insulin-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal hyperandrogenism and insulin resistance causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Our data also suggest that apoptosis and necroptosis may play a role in coordinating or compensating for hyperandrogenism and insulin-resistance-induced ferroptosis when the gravid uterus and placenta are dysfunctional.

Supplementary Materials

    • Supplementary Materials and Methods
    • Supplemental Figure 1. Analyses of body weight variations in pregnant rats exposed to DHT and/or insulin. Values are expressed as means ± SEM. Group differences across GDs in overall maternal body weight were evaluated using repeated measures ANOVA, with different treatments (Control, DHT+INS, DHT, INS) as the between-subjects factor and gestation days (GD 0.5-14.5) as the within-subjects factor. GD, gestational day. DHT, 5α-dihydrotestosterone; INS, insulin.
    • Supplemental Figure 2. Tissue expression of Gpx4 protein in the adult rats. Protein samples (left) were isolated from selective tissues (testis, epididymis, and ovary; n = 6/tissue). The level of Gpx4 protein expression was determined by Western blot analysis (right). Each lane corresponds to the different rat samples. Relative mobilities of molecular mass standards (MW) is shown (in kilodaltons) on the left.
    • Supplemental Figure 3. Tissue expression of Gpx4 protein in the adult rat uterus. The level and localization of uterine Gpx4 protein expression in the diestrus stage in rats were determined by Western blot (A) and immunohistochemical analyses (B). In the Western blot analysis, each lane corresponds to the different rat samples. Relative mobilities of molecular mass standards (MW) are shown (in kilodaltons) on the left. Immunohistochemical images are representative of 3−5 tissue replicates per group. Detailed views of the boxed areas are shown in the inset (B). L, lumen; Le, luminal epithelial cells; Ge, glandular epithelial cells; Str, stromal cells; Myo, myometrium. Scale bars (100 μm) are indicated in the photomicrographs.
    • Supplemental Figure 4. Iron deposition in the uterine sections from pregnant rats at GD 6 (A, A1-2) and pregnant rats exposed to vehicle and DHT+INS at GD 14.5 (B, B1-4). The sections were stained by DAB-enhanced Perls’ staining for iron accumulation. Images are representative of 5−8 tissue replicates per group. Yellow arrowheads indicate punctate cytoplasmic, and granular iron-positive staining. MD, mesometrial decidua; AD, antimesometrial decidua; Myo, myometrium. Scale bars (100 μm) are indicated in the photomicrographs. DHT, 5α-dihydrotestosterone; INS, insulin.
    • Supplemental Figure 5. Mitochondrial ultrastructural defects in mesometrial decidua, and basal and labyrinth zones in pregnant rats exposed to DHT and/or insulin at GD 14.5. Scale bars (2 μm) are indicated in the photomicrographs. DHT, 5α-dihydrotestosterone; INS, insulin.

Journal of Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 6951 285 16
PDF Downloads 5317 319 18

 

  • Collapse
  • Expand
Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
17
Article Type:
Research Article
Received Date:
28 May 2020
Accepted Date:
25 Jun 2020
Print Publication Date:
01 Sep 2020
Online Publication Date:
Sep 2020
Keywords:
ferroptosis; mitochondria; gravid uterus; placenta; PCOS

  • Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A & Gupta S 2012 The effects of oxidative stress on female reproduction: a review. Reproductive Biology and Endocrinology 10 49. (https://doi.org/10.1186/1477-7827-10-49)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, Lizneva D, Natterson-Horowtiz B, Teede HJ & Yildiz BO 2016 Polycystic ovary syndrome. Nature Reviews: Disease Primers 2 16057. (https://doi.org/10.1038/nrdp.2016.57)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bahri Khomami M, Joham AE, Boyle JA, Piltonen T, Silagy M, Arora C, Misso ML, Teede HJ & Moran LJ 2019 Increased maternal pregnancy complications in polycystic ovary syndrome appear to be independent of obesity – a systematic review, meta-analysis, and meta-regression. Obesity Reviews 20 659–674. (https://doi.org/10.1111/obr.12829)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Baithalu RK, Singh SK, Kumaresan A, Mohanty AK, Mohanty TK, Kumar S, Kerketta S, Maharana BR, Patbandha TK & Attupuram N et al.2017 Transcriptional abundance of antioxidant enzymes in endometrium and their circulating levels in Zebu cows with and without uterine infection. Animal Reproduction Science 177 79–87. (https://doi.org/10.1016/j.anireprosci.2016.12.008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Banuls C, Rovira-Llopis S, Martinez de Maranon A, Veses S, Jover A, Gomez M, Rocha M, Hernandez-Mijares A & Victor VM 2017 Metabolic syndrome enhances endoplasmic reticulum, oxidative stress and leukocyte-endothelium interactions in PCOS. Metabolism: Clinical and Experimental 71 153–162. (https://doi.org/10.1016/j.metabol.2017.02.012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cao C & Fleming MD 2016 The placenta: the forgotten essential organ of iron transport. Nutrition Reviews 74 421–431. (https://doi.org/10.1093/nutrit/nuw009)

  • Chen L, Hambright WS, Na R & Ran Q 2015 Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. Journal of Biological Chemistry 290 28097–28106. (https://doi.org/10.1074/jbc.M115.680090)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Choi ME, Price DR, Ryter SW & Choi AMK 2019 Necroptosis: a crucial pathogenic mediator of human disease. JCI Insight 4 e128834. (https://doi.org/10.1172/jci.insight.128834)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Conrad M, Schneider M, Seiler A & Bornkamm GW 2007 Physiological role of phospholipid hydroperoxide glutathione peroxidase in mammals. Biological Chemistry 388 1019–1025. (https://doi.org/10.1515/BC.2007.130)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dai C, Chen X, Li J, Comish P, Kang R & Tang D 2020 Transcription factors in ferroptotic cell death. Cancer Gene Therapy [epub]. (https://doi.org/10.1038/s41417-020-0170-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dalto DB, Roy M, Audet I, Palin MF, Guay F, Lapointe J & Matte JJ 2015 Interaction between vitamin B6 and source of selenium on the response of the selenium-dependent glutathione peroxidase system to oxidative stress induced by oestrus in pubertal pig. Journal of Trace Elements in Medicine and Biology 32 21–29. (https://doi.org/10.1016/j.jtemb.2015.05.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ding Y, Jiang Z, Xia B, Zhang L, Zhang C & Leng J 2019 Mitochondria-targeted antioxidant therapy for an animal model of PCOS-IR. International Journal of Molecular Medicine 43 316–324. (https://doi.org/10.3892/ijmm.2018.3977)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM & Yang WS, et al.2012 Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149 1060–1072. (https://doi.org/10.1016/j.cell.2012.03.042)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Escobar-Morreale HF 2012 Iron metabolism and the polycystic ovary syndrome. Trends in Endocrinology & Metabolism 23 509–515. (https://doi.org/10.1016/j.tem.2012.04.003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fassnacht M, Schlenz N, Schneider SB, Wudy SA, Allolio B & Arlt W 2003 Beyond adrenal and ovarian androgen generation: increased peripheral 5 alpha-reductase activity in women with polycystic ovary syndrome. Journal of Clinical Endocrinology & Metabolism 88 2760–2766. (https://doi.org/10.1210/jc.2002-021875)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Feng H, Schorpp K, Jin J, Yozwiak CE, Hoffstrom BG, Decker AM, Rajbhandari P, Stokes ME, Bender HG & Csuka JM, et al.2020 Transferrin receptor is a specific ferroptosis marker. Cell Reports 30 3411–3423.e7. (https://doi.org/10.1016/j.celrep.2020.02.049)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Forcina GC & Dixon SJ 2019 GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics 19 e1800311. (https://doi.org/10.1002/pmic.201800311)

  • Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A & Eggenhofer E, et al.2014 Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology 16 1180–1191. (https://doi.org/10.1038/ncb3064)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Galaris D, Barbouti A & Pantopoulos K 2019 Iron homeostasis and oxidative stress: an intimate relationship. Biochimica et Biophysica Acta. Molecular Cell Research 1866 118535. (https://doi.org/10.1016/j.bbamcr.2019.118535)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB & Jiang X 2019 Role of mitochondria in ferroptosis. Molecular Cell 73 354–363.e3. (https://doi.org/10.1016/j.molcel.2018.10.042)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gawel S, Wardas M, Niedworok E & Wardas P 2004 Malondialdehyde (MDA) as a lipid peroxidation marker. Wiadomosci Lekarskie 57 453–455.

  • Glintborg D, Jensen RC, Bentsen K, Schmedes AV, Brandslund I, Kyhl HB, Bilenberg N & Andersen MS 2018 Testosterone levels in third trimester in polycystic ovary syndrome: odense child cohort. Journal of Clinical Endocrinology & Metabolism 103 3819–3827. (https://doi.org/10.1210/jc.2018-00889)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gudipaty SA, Conner CM, Rosenblatt J & Montell DJ 2018 Unconventional ways to live and die: cell death and survival in development, homeostasis, and disease. Annual Review of Cell & Developmental Biology 34 311–332. (https://doi.org/10.1146/annurev-cellbio-100616-060748)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Guo Y, Zhang N, Zhang D, Ren Q, Ganz T, Liu S & Nemeth E 2019 Iron homeostasis in pregnancy and spontaneous abortion. American Journal of Hematology 94 184–188. (https://doi.org/10.1002/ajh.25341)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hu M, Zhang Y, Guo X, Jia W, Liu G, Zhang J, Cui P, Li J, Li W, Wu X, et al.2019a Perturbed ovarian and uterine glucocorticoid receptor signaling accompanies the balanced regulation of mitochondrial function and NFkappaB-mediated inflammation under conditions of hyperandrogenism and insulin resistance. Life Sciences 232 116681. (https://doi.org/10.1016/j.lfs.2019.116681)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hu M, Zhang Y, Guo X, Jia W, Liu G, Zhang J, Li J, Cui P, Sferruzzi-Perri AN, Han Y, et al.2019b Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant ROS production. American Journal of Physiology – Endocrinology & Metabolism 316 E794–E809. (https://doi.org/10.1152/ajpendo.00359.2018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Imai H, Hirao F, Sakamoto T, Sekine K, Mizukura Y, Saito M, Kitamoto T, Hayasaka M, Hanaoka K & Nakagawa Y 2003 Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene. Biochemical & Biophysical Research Communications 305 278–286. (https://doi.org/10.1016/s0006-291x(03)00734-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim JW, Kang KM, Yoon TK, Shim SH & Lee WS 2014 Study of circulating hepcidin in association with iron excess, metabolic syndrome, and BMP-6 expression in granulosa cells in women with polycystic ovary syndrome. Fertility & Sterility 102 548–554.e2. (https://doi.org/10.1016/j.fertnstert.2014.04.031)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim SJ, Xiao J, Wan J, Cohen P & Yen K 2017 Mitochondrially derived peptides as novel regulators of metabolism. Journal of Physiology 595 6613–6621. (https://doi.org/10.1113/JP274472)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kovtunovych G, Eckhaus MA, Ghosh MC, Ollivierre-Wilson H & Rouault TA 2010 Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution. Blood 116 6054–6062. (https://doi.org/10.1182/blood-2010-03-272138)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lai Q, Xiang W, Li Q, Zhang H, Li Y, Zhu G, Xiong C & Jin L 2018 Oxidative stress in granulosa cells contributes to poor oocyte quality and IVF-ET outcomes in women with polycystic ovary syndrome. Frontiers of Medicine 12 518–524. (https://doi.org/10.1007/s11684-017-0575-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lei P, Bai T & Sun Y 2019 Mechanisms of ferroptosis and relations with regulated cell death: a review. Frontiers in Physiology 10 139. (https://doi.org/10.3389/fphys.2019.00139)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, Sun B & Wang G 2020 Ferroptosis: past, present and future. Cell Death & Disease 11 88. (https://doi.org/10.1038/s41419-020-2298-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L & Azziz R 2016 Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertility & Sterility 106 6–15. (https://doi.org/10.1016/j.fertnstert.2016.05.003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lu SC 2009 Regulation of glutathione synthesis. Molecular Aspects of Medicine 30 42–59. (https://doi.org/10.1016/j.mam.2008.05.005)

  • Maliqueo M, Lara HE, Sanchez F, Echiburu B, Crisosto N & Sir-Petermann T 2013 Placental steroidogenesis in pregnant women with polycystic ovary syndrome. European Journal of Obstetrics, Gynecology, and Reproductive Biology 166 151–155. (https://doi.org/10.1016/j.ejogrb.2012.10.015)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mistry HD, Kurlak LO, Williams PJ, Ramsay MM, Symonds ME & Broughton Pipkin F 2010 Differential expression and distribution of placental glutathione peroxidases 1, 3 and 4 in normal and preeclamptic pregnancy. Placenta 31 401–408. (https://doi.org/10.1016/j.placenta.2010.02.011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mistry HD, Wilson V, Ramsay MM, Symonds ME & Broughton Pipkin F 2008 Reduced selenium concentrations and glutathione peroxidase activity in preeclamptic pregnancies. Hypertension 52 881–888. (https://doi.org/10.1161/HYPERTENSIONAHA.108.116103)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ng SW, Norwitz SG & Norwitz ER 2019 The impact of iron overload and ferroptosis on reproductive disorders in humans: implications for preeclampsia. International Journal of Molecular Sciences 20 3283. (https://doi.org/10.3390/ijms20133283)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Poss KD & Tonegawa S 1997 Heme oxygenase 1 is required for mammalian iron reutilization. PNAS 94 10919–10924. (https://doi.org/10.1073/pnas.94.20.10919)

  • Ramos RS, Oliveira ML, Izaguirry AP, Vargas LM, Soares MB, Mesquita FS, Santos FW & Binelli M 2015 The periovulatory endocrine milieu affects the uterine redox environment in beef cows. Reproductive Biology and Endocrinology 13 39. (https://doi.org/10.1186/s12958-015-0036-x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Riegman M, Bradbury MS & Overholtzer M 2019 Population dynamics in cell death: mechanisms of propagation. Trends in Cancer 5 558–568. (https://doi.org/10.1016/j.trecan.2019.07.008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rosenfield RL & Ehrmann DA 2016 The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocrine Reviews 37 467–520. (https://doi.org/10.1210/er.2015-1104)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schatz F, Guzeloglu-Kayisli O, Arlier S, Kayisli UA & Lockwood CJ 2016 The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. Human Reproduction Update 22 497–515. (https://doi.org/10.1093/humupd/dmw004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schneider M, Forster H, Boersma A, Seiler A, Wehnes H, Sinowatz F, Neumuller C, Deutsch MJ, Walch A & Hrabe de Angelis M et al.2009 Mitochondrial glutathione peroxidase 4 disruption causes male infertility. FASEB Journal 23 3233–3242. (https://doi.org/10.1096/fj.09-132795)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schoots MH, Gordijn SJ, Scherjon SA, van Goor H & Hillebrands JL 2018 Oxidative stress in placental pathology. Placenta 69 153–161. (https://doi.org/10.1016/j.placenta.2018.03.003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sharma S, Godbole G & Modi D 2016 Decidual control of trophoblast invasion. American Journal of Reproductive Immunology 75 341–350. (https://doi.org/10.1111/aji.12466)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sharp AN, Heazell AE, Crocker IP & Mor G 2010 Placental apoptosis in health and disease. American Journal of Reproductive Immunology 64 159–169. (https://doi.org/10.1111/j.1600-0897.2010.00837.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Silfen ME, Denburg MR, Manibo AM, Lobo RA, Jaffe R, Ferin M, Levine LS & Oberfield SE 2003 Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents. Journal of Clinical Endocrinology & Metabolism 88 4682–4688. (https://doi.org/10.1210/jc.2003-030617)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sir-Petermann T, Maliqueo M, Angel B, Lara HE, Perez-Bravo F & Recabarren SE 2002 Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Human Reproduction 17 2573–2579. (https://doi.org/10.1093/humrep/17.10.2573)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Spencer SJ, Cataldo NA & Jaffe RB 1996 Apoptosis in the human female reproductive tract. Obstetrical & Gynecological Survey 51 314–323. (https://doi.org/10.1097/00006254-199605000-00023)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK & Kagan VE et al.2017 Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171 273–285. (https://doi.org/10.1016/j.cell.2017.09.021)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sun X, Niu X, Chen R, He W, Chen D, Kang R & Tang D 2016 Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology 64 488–500. (https://doi.org/10.1002/hep.28574)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tang D, Kang R, Berghe TV, Vandenabeele P & Kroemer G 2019 The molecular machinery of regulated cell death. Cell Research 29 347–364. (https://doi.org/10.1038/s41422-019-0164-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Welsh AO 1993 Uterine cell death during implantation and early placentation. Microscopy Research & Technique 25 223–245. (https://doi.org/10.1002/jemt.1070250305)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R & Tang D 2016 Ferroptosis: process and function. Cell Death & Differentiation 23 369–379. (https://doi.org/10.1038/cdd.2015.158)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang H, He Y, Wang JX, Chen MH, Xu JJ, Jiang MH, Feng YL & Gu YF 2020 miR-30-5p-mediated ferroptosis of trophoblasts is implicated in the pathogenesis of preeclampsia. Redox Biology 29 101402. (https://doi.org/10.1016/j.redox.2019.101402)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang J, Bao Y, Zhou X & Zheng L 2019a Polycystic ovary syndrome and mitochondrial dysfunction. Reproductive Biology and Endocrinology: RB&E 17 67. (https://doi.org/10.1186/s12958-019-0509-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang Y, Meng F, Sun X, Sun X, Hu M, Cui P, Vestin E, Li X, Li W & Wu XK et al.2018 Hyperandrogenism and insulin resistance contribute to hepatic steatosis and inflammation in female rat liver. Oncotarget 9 18180–18197. (https://doi.org/10.18632/oncotarget.24477)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang Y, Sun X, Sun X, Meng F, Hu M, Li X, Li W, Wu XK, Brännström M & Shao R, et al.2016 Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus. Scientific Reports 6 30679. (https://doi.org/10.1038/srep30679)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang Y, Zhao W, Xu H, Hu M, Guo X, Jia W, Liu G, Li J, Cui P & Lager S et al.2019 Hyperandrogenism and insulin resistance-induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome. Journal of Physiology 597 3927–3950. (https://doi.org/10.1113/JP277879)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu LJ, Bagchi MK & Bagchi IC 1995 Ferritin heavy chain is a progesterone-inducible marker in the uterus during pregnancy. Endocrinology 136 4106–4115. (https://doi.org/10.1210/endo.136.9.7649119)

    • PubMed
    • Search Google Scholar
    • Export Citation