{"paper_id":"b7125fa3-2f42-4acf-826d-69586661d0df","body_text":"Vol:.(1234567890)\nReproductive Sciences (2023) 30:2016–2018\nhttps://doi.org/10.1007/s43032-022-01150-3\n1 3\nGENERAL GYNECOLOGY: COMMENTARY\nGlycolysis and Heavy Menstrual Bleeding\nKalle T. Rytkönen1,2 \nReceived: 14 October 2022 / Accepted: 11 December 2022 / Published online: 27 December 2022 \n© The Author(s) 2022\nAbstract\nMenstrual cycle is a major determinant in female reproductive health. In a recent report, Mao et al. (2022) associated defi-\ncient glycolysis with heavy menstrual bleeding. This commentary summarizes these recent findings and the importance of \nglycolysis and decidualization in endometrial function. It will also discuss if in the light of the recent findings menstrual \nbleeding is better conceived as a primary endometrial disorder inherent to endometrium or as a secondary endometrial dis-\norder caused by other endometrial conditions.\nKeywords Uterus · Endometrium · Glycolysis · Heavy menstrual bleeding · Decidualization · Hypoxia\nFemale reproductive health is dependent on the cyclic men-\nstruation-related renewal of the uterine endometrium. In each \nmenstrual cycle, the endometrial cells differentiate (decidualize) \nto prepare the uterus either for pregnancy or for menstrual dis-\ncharge. This hormonally fine-tuned cycle consists of proliferative, \nsecretory, and menstrual phases. Deviations in these phases may \ncause reproductive disorders and conditions including abnormal \nmenstrual bleeding or heavy menstrual bleeding (HMB) that \naffect up to one-third of reproductive-aged women [1].\nThe renewal and regrowth of the endometrium require \nconsiderable energetic input. Proliferative endometrium relies \nrelatively more on aerobic energy production, whereas during \nthe secretory phase, larger proportion of the energy is produced \nanaerobically via glycolysis [2]. Concordantly, glycolysis has \nbeen shown to be necessary for endometrial stromal decidu-\nalization [3] that enables implantation/pregnancy or menstrua-\ntion. However, the importance of glycolysis for menstruation \nhas remained understudied. Recently, a study by Chenyu Mao, \nXishi Liu, and Sun-Wei Guo reports that decreased glycolysis \nis associated with heavy menstrual bleeding [4]. To prove this \nhypothesis, the authors utilized a series of mouse experiments, \ncell culture experiments, and studies of relevant human samples.\nIn order to study the correlation between glycolysis and \nmenstruation, Mao et al. used mouse model to mimic human \nmenstruation and repair [4]. Mice do not menstruate, but with \nhormone stimulation, human-like menses can be induced also \nin mice. More specifically, mice were first treated with estro-\ngen to induce endometrial proliferation and progesterone to \ninduce decidualization. Subsequently, a drop in progesterone \nlevels in mice-induced endometrial breakdown and bleed-\ning similarly as in human cycle. The authors observed that \nthe protein levels of glycolytic genes, including enzymes and \ntransporters, are increased in the decidualized uterus compared \nto non-decidualized uterus. By using inhibitor of glycolytic \nenzyme hexokinase 2 (HK2) and immunohistochemistry, they \ndemonstrated that inhibition of glycolysis reduced inflamma-\ntory response and impaired the menstruation-associated repair \nprocess of the endometrium. This also resulted in increased \nblood loss measured using cotton balls inserted and collected \nafter progesterone withdrawal. Additionally, in a human \nendometrial epithelial cell line, the same inhibitor treatment \nresulted in reduced cell proliferation and migration.\nEarlier studies have shown that hypoxia occurs in the endo-\nmetrium during menstruation. With the same mouse model, \nit was shown that menstruation-associated hypoxia stabilizes \nthe levels of the hypoxia inducible factor 1alpha (HIF-1alpha) \nand that this transcription factor is essential for proper endome-\ntrial repair during menstruation [5]. Generally, HIF-1alpha is a \nwell-studied regulator of hypoxia adaptation and evolutionary \nconserved inducer of glycolytic genes. Now, in an additional \nsimulated mouse experiment, Mao et al. study the relation-\nship between HIF-1alpha, glycolysis, and endometrial repair. \n * Kalle T. Rytkönen \n katury@utu.fi\n1 Institute of Biomedicine, Research Centre for Integrative \nPhysiology and Pharmacology, University of Turku, \nKiinamyllynkatu 10, 20014 Turku, Finland\n2 Turku Bioscience Centre, University of Turku and Åbo \nAkademi University, Tykistökatu 6, 20520 Turku, Finland\n\n2017Reproductive Sciences (2023) 30:2016–2018 \n1 3\nBy using inhibitors of HIF-1alpha and HK2 (glycolysis), the \nauthors observed that inhibiting glycolysis effectively disrupted \nmenstrual repair even in the presence of hypoxia dependent \nHIF-1alpha stabilization. This further enforced the conclusion \nof importance of specifically glycolytic metabolism, not just \nhypoxia per se, in the menstrual repair.\nLastly, the authors collected samples from patients who \nhad experienced heavy menstrual bleeding and measured \nthe amount of blood loss was with menstrual pictogram in \nabsorbing menstrual towels. Patients that had more than \n100 mL of menstrual blood loss were defined as excessive \nbleeding group, and those who had less than 100 mL of \nmenstrual blood loss were defined as control group. The \nauthors discovered reduced immunostaining of HK2 indicat-\ning reduced glycolysis in women with excessive menstrual \nbleeding suggesting that defective glycolysis causes heavy \nmenstrual bleeding also in humans.\nOn a more fundamental level, it still remains unresolved \nwhether endometrial disorders that lead to heavy menstrual \nbleeding are primary endometrial disorders or secondary \nendometrial disorders. In a primary endometrial disorder, \ndefects in endometrial tissue or cells directly function -\nally cause the bleeding disorder, whereas in a secondary \nendometrial disorder physically measurable condition such \nas adenomyosis, uterine polyps and leiomyoma (uterine \nfibroids) cause heavy bleeding as a secondary effect [1].\nIn Mao et al. study, the patient samples were adjacent \nto adenomyosis lesions. Adenomyosis is a condition where \nendometrial cells penetrate to the myometrium, the muscle \nlayer outside the uterus, and generate lesions. The proxim-\nity of the samples to adenomyosis lesions suggests that the \ndescribed defect in glycolysis could be specific to adenomy-\nosis-induced heavy menstrual bleeding. On the other hand, \nconsidering the experiments conducted in mouse, in vitro \nand in human samples as a whole indicates that glycoly -\nsis per se is important for normal menstrual repair, which \nin turn suggests that glycolysis defect would be a primary \ndisorder.\nDownregulation of endometrial glycolytic genes such \nas HK2 has also been observed in preeclampsia [6 ]. Could \nthis observation advice whether defected glycolysis caus-\ning heavy bleeding should be viewed as primary or second-\nary disorder? In preeclampsia, that is a pregnancy disorder \ncharacterized by high maternal blood pressure, downregu-\nlation the endometrial HK2 was associated with defective \ndecidualization and considered as a potential contributor to \npreeclampsia [6]. Similarly, in the study by Mao et al., the \nobserved downregulation of inflammation and reduced cell \nmigration is also a general sign of decidualization defect. \nFurthermore, non-pregnant menstruation and parturition that \nends pregnancy have several molecular similarities [7]; both \nare preceded by progesterone-induced decidualization and \nsubsequent progesterone withdrawal. Thus, in both cases, \nthe downregulation of glycolytic enzymes can be conceived \nas evidence of decidualization defect, which would also \ninclude the view of endometrial glycolysis defect as pri-\nmary endometrial disorder originating from the endometrial \ncell functions, and not as a secondary effect from physically \nmeasured conditions such as adenomyosis. On the other \nhand, adenomyosis have also been associated with higher \noccurrence of preeclampsia [8]—making it, again, more dif-\nficult to evaluate the causality. In any case, collectively, the \nevidence points out that a well-balanced glycolytic drive is \nessential for healthy endometrial function.\nCurrently, hormonal interventions are the most common \ntreatments for heavy menstruation, including levonorgestrel-\nreleasing intra-uterine devices. The usefulness of these has \nbecome evident during last decades, but for some patients, \nother than hormonal medications may be beneficial. The \nresults from Mao et al. suggest that non-hormonal treat-\nments, potentially based on enforcing the HIF pathway or \nglycolysis to alleviate heavy menstruation, are plausible.\nFunding Open Access funding provided by University of Turku (UTU) \nincluding Turku University Central Hospital.\nData Availability Discussed data available in the original publications.\nDeclarations \nConflict of Interest The author declares no competing interests.\nOpen Access This article is licensed under a Creative Commons Attri-\nbution 4.0 International License, which permits use, sharing, adapta-\ntion, distribution and reproduction in any medium or format, as long \nas you give appropriate credit to the original author(s) and the source, \nprovide a link to the Creative Commons licence, and indicate if changes \nwere made. The images or other third party material in this article are \nincluded in the article's Creative Commons licence, unless indicated \notherwise in a credit line to the material. If material is not included in \nthe article's Creative Commons licence and your intended use is not \npermitted by statutory regulation or exceeds the permitted use, you will \nneed to obtain permission directly from the copyright holder. To view a \ncopy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.\nReferences\n 1. Jain V, Chodankar RR, Maybin JA, Critchley HOD. Uterine bleed-\ning: how understanding endometrial physiology underpins men-\nstrual health. Nat Rev Endocrinol. 2022;18(5):290–308.\n 2. Rosado A, Hernández O, Aznar R, Hicks JJ. Comparative glyco-\nlytic metabolism in the normal and in the copper treated human \nendometrium. Contraception. 1976;13(1):17–29.\n 3. Kommagani R, Szwarc MM, Kovanci E, Gibbons WE, Putluri \nN, Maity S, et al. Acceleration of the glycolytic flux by steroid \nreceptor coactivator-2 is essential for endometrial decidualization. \nTeixeira JM, editor. PLoS Genet. 2013;9(10):e1003900.\n\n2018 Reproductive Sciences (2023) 30:2016–2018\n1 3\n 4. Mao C, Liu X, Guo SW. Decreased glycolysis at menstruation is \nassociated with increased menstrual blood loss. Reprod Sci. 2022. \nhttps:// doi. org/ 10. 1007/ s43032- 022- 01066-y.\n 5. Maybin JA, Murray AA, Saunders PTK, Hirani N, Carmeliet P, \nCritchley HOD. Hypoxia and hypoxia inducible factor-1α are \nrequired for normal endometrial repair during menstruation. Nat \nCommun. 2018;9(1):295.\n 6. Lv H, Tong J, Yang J, Lv S, Li W-P, Zhang C, et al. Dysregulated \npseudogene HK2P1 may contribute to preeclampsia as a compet-\ning endogenous RNA for hexokinase 2 by impairing decidualiza-\ntion. Hypertens. 2018;71(4):648–58.\n 7. Pavlicev M, Norwitz ER. Human parturition: nothing more than \na delayed menstruation. Reprod Sci. 2018;25(2):166–73.\n 8. Harada T, Taniguchi F, Harada T. Increased risk of obstetric \ncomplications in patients with adenomyosis: a narrative literature \nreview. Reprod Med Biol. 2022;21(1):e12473.\nPublisher’s Note Springer Nature remains neutral with regard to \njurisdictional claims in published maps and institutional affiliations.","source_license":"CC0","license_restricted":false}