Impact of Physiological Fluctuations of Sex Hormones During the Menstrual Cycle on Glucose Metabolism and the Gut Microbiota

Abstract

Diabetes mellitus is one of the most prevalent chronic diseases. Previous studies have shown differences in glucose metabolism between males and females. Moreover, difficulties in medication adherence have been reported in females with type 2 diabetes. These observations are believed to be caused by fluctuations in sex hormone concentrations during the menstrual cycle. Furthermore, gut microbiota is linked to female host metabolism and sex hormone production. Understanding the interactions between fluctuating hormone concentrations during the menstrual cycle, gut microbiota, and glucose metabolism in humans is significant because of the increasing prevalence of diabetes and the consequent need to expand preventive efforts. A literature search was performed to determine and summarize the existing evidence, deduce future research needs to maintain female health, and investigate the relationship between the physiological menstrual cycle and glucose metabolism. Studies from 1967 to 2020 have already examined the relationship between variations during the menstrual cycle and glucose metabolism in healthy female subjects using an oral-glucose tolerance test or intravenous glucose tolerance test. However, the overall number of studies is rather small and the results are contradictory, as some studies detected differences in glucose concentrations depending on the different cycle phases, whereas others did not. Some studies reported lower glucose levels in the follicular phase than in the luteal phase, whereas another study detected the opposite. Data on gut microbiota in relation to the menstrual cycle are limited. Conflicting results exist when examining the effect of hormonal contraceptives on the gut microbiota and changes in the course of the menstrual cycle. The results indicate that the menstrual cycle, especially fluctuating sex hormones, might impact the gut microbiota composition.

The menstrual cycle may affect the gut microbiota composition and glucose metabolism. These results indicate that glucose tolerance may be the greatest in the follicular phase; however, further well-conducted studies are needed to support this assumption.

Keywords

menstrual cycle - diabetes - autoimmunity - insulin resistance - intestinal microbiome - female health - glucose homeostasis

^‡ Equal contribution: Alina Schieren, Sandra Koch

Publication History

Received: 15 August 2023
Received: 10 January 2024

Accepted: 18 January 2024

Accepted Manuscript online:
21 February 2024

Article published online:
10 April 2024

• References

• 1 World Health Organization. Non communicable diseases. 2022 https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases
• 2 Sun H, Saeedi P, Karuranga S. et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract 2022; 183: 109119
• 3 Boyns DR, Crossley JN, Abrams ME. et al. Oral glucose tolerance and related factors in a normal population sample. I. Blood sugar, plasma insulin, glyceride, and cholesterol measurements and the effects of age and sex. Br Med J 1969; 1: 595-598
• 4 Macdonald I, Crossley JN. Glucose tolerance during the menstrual cycle. Diabetes 1970; 19: 450-452
• 5 Bundesärztekammer BÄK. Kassenärztliche Bundesvereinigung (KBV), Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Nationale VersorgungsLeitlinie Typ-2-Diabetes – Langfassung, Version. 3. 2023
• 6 Blaak EE. Sex differences in the control of glucose homeostasis. Curr Opin Clin Nutr Metab Care 2008; 11: 500-504
• 7 Flanagan DE, Holt RIG, Owens PC. et al. Gender differences in the insulin-like growth factor axis response to a glucose load. Acta Physiologica 2006; 187: 371-378
• 8 Basu R, Dalla Man C, Campioni M. et al. Effects of age and sex on postprandial glucose metabolism: Differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction. Diabetes 2006; 55: 2001-2014
• 9 Borissova A-M, Tankova T, Kirilov G. et al. Gender-dependent effect of ageing on peripheral insulin action. Int J Clin Pract 2005; 59: 422-426
• 10 Frias JP, Macaraeg GB, Ofrecio J. et al. Decreased susceptibility to fatty acid-induced peripheral tissue insulin resistance in women. Diabetes 2001; 50: 1344-1350
• 11 Perseghin G, Scifo P, Pagliato E. et al. Gender factors affect fatty acids-induced insulin resistance in nonobese humans: effects of oral steroidal contraception. J Clin Endocrinol Metab 2001; 86: 3188-3196
• 12 Gaete X, Vivanco M, Eyzaguirre FC. et al. Menstrual cycle irregularities and their relationship with HbA1c and insulin dose in adolescents with type 1 diabetes mellitus. Fertil Steril 2010; 94: 1822-1826
• 13 Brown SA, Jiang B, McElwee-Malloy M. et al. Fluctuations of hyperglycemia and insulin sensitivity are linked to menstrual cycle phases in women with T1D. J Diabetes Sci Technol 2015; 9: 1192-1199
• 14 Cramer HI. The influence of menstruation on carbohydrate tolerance in diabetes mellitus. Can Med Assoc J 1942; 47: 51-55
• 15 Walsh CH, Malins JM. Menstruation and control of diabetes. Br Med J 1977; 2: 177-179
• 16 Milionis C, Ilias I, Venaki E. et al. The effect of menstrual hormonal fluctuations on the glycaemic control in women with type 1 diabetes mellitus. Practical Diabetes 2023; 40: 35-39
• 17 Ezenwaka EC, Akanji AO, Adejuwon CA. et al. Insulin responses following glucose administration in menstruating women. IntJ Gynaecol Obstet 1993; 42: 155-159
• 18 van Genugten RE, Utzschneider KM, Tong J. et al. Effects of sex and hormone replacement therapy use on the prevalence of isolated impaired fasting glucose and isolated impaired glucose tolerance in subjects with a family history of type 2 diabetes. Diabetes 2006; 55: 3529-3535
• 19 Kim YS, Unno T, Kim BY. et al. Sex differences in gut microbiota. World J Mens Health 2020; 38: 48-60
• 20 Adlercreutz H, Martin F. Oestrogen in human pregnancy faeces. Acta Endocrinologica 1976; 83: 410-419
• 21 Santos-Marcos JA, Mora-Ortiz M, Tena-Sempere M. et al. Interaction between gut microbiota and sex hormones and their relation to sexual dimorphism in metabolic diseases. Biol Sex Differ 2023; 14: 4
• 22 Wu H, Ballantyne CM. Metabolic inflammation and insulin resistance in obesity. Circ Res 2020; 126: 1549-1564
• 23 Kinoshita M, Suzuki Y, Saito Y. Butyrate reduces colonic paracellular permeability by enhancing PPARgamma activation. Biochem Biophys Res Commun 2002; 293: 827-831
• 24 Isayama K, Rini DM, Yamamoto Y. et al. Propionate regulates tight junction barrier by increasing endothelial-cell selective adhesion molecule in human intestinal Caco-2 cells. Exp Cell Res 2023; 425: 113528
• 25 Zhou Z, Sun B, Yu D. et al. Gut microbiota: An important player in type 2 diabetes mellitus. Front Cell Infect Microbiol 2022; 12: 834485
• 26 Arora T, Bäckhed F. The gut microbiota and metabolic disease: Current understanding and future perspectives. J Intern Med 2016; 280: 339-349
• 27 van Deuren T, Blaak EE, Canfora EE. Butyrate to combat obesity and obesity-associated metabolic disorders: Current status and future implications for therapeutic use. Obes Rev 2022; 23: e13498
• 28 Fillenberg S. Der menstruelle Zyklus. In: Lasch L, Fillenberg S, eds. Basiswissen Gynäkologie und Geburtshilfe. 1st ed. Berlin: Springer; 2017: 134-136
• 29 Bull JR, Rowland SP, Scherwitzl EB. et al. Real-world menstrual cycle characteristics of more than 600,000 menstrual cycles. NPJ Digit Med 2019; 2: 83
• 30 Tramunt B, Smati S, Grandgeorge N. et al. Sex differences in metabolic regulation and diabetes susceptibility. Diabetologia 2020; 63: 453-461
• 31 Anagnostis P, Christou K, Artzouchaltzi A-M. et al. Early menopause and premature ovarian insufficiency are associated with increased risk of type 2 diabetes: A systematic review and meta-analysis. Eur J Endocrinol 2019; 180: 41-50
• 32 Kanaya AM, Herrington D, Vittinghoff E. et al. Glycemic effects of postmenopausal hormone therapy: The Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003; 138: 1-9
• 33 Margolis KL, Bonds DE, Rodabough RJ. et al Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: Results from the Women’s Health Initiative Hormone Trial. 0012-186X 2004; 47: 1175-1187
• 34 Jarrett RJ, Graver HJ. Changes in oral glucose tolerance during the menstrual cycle. Br Med J 1968; 2: 528-529
• 35 Cudworth AG, Veevers A. Carbohydrate metabolism in the menstrual cycle. Br J Obstet Gynaecol 1975; 82: 162-169
• 36 Walsh CH, O’Sullivan DJ. Studies of glucose tolerance, insulin and growth hormone secretion during the menstrual cycle in healthy women. Ir J Med Sci 1975; 144: 18-24
• 37 Peppler U, Thefeld W, Wincenty U. Oraler Glukosetoleranztest bei Frauen in Abhängigkeit vom Menstruationszyklus. Klin Wochenschr 1978; 56: 659-669
• 38 Bonora E, Zavaroni I, Alpi O. et al. Influence of the menstrual cycle on glucose tolerance and insulin secretion. AJOG 1987; 157: 140-141
• 39 Toth EL, Suthijumroon A, Crockford PM. et al. Insulin action does not change during the menstrual cycle in normal women. J Clin Endocrinol Metab 1987; 64: 74-80
• 40 Busby MJ, Bellantoni MF, Tobin JD. et al. Glucose tolerance in women: The effects of age, body composition, and sex hormones. J Am Geriatr Soc 1992; 40: 497-502
• 41 Brennan IM, Feltrin KL, Nair NS. et al. Effects of the phases of the menstrual cycle on gastric emptying, glycemia, plasma GLP-1 and insulin, and energy intake in healthy lean women. Am J Physiol Gastrointest Liver Physiol 2009; 297: 602-610
• 42 Williams JS, Stimpson TV, Tremblay JC. et al. The influence of acute hyperglycaemia on brachial artery flow-mediated dilatation in the early and late follicular phases of the menstrual cycle. Exp Physiol 2019; 104: 957-966
• 43 Varlamov O, Bethea CL, Roberts CT. Sex-specific differences in lipid and glucose metabolism. Front Endocrinol (Lausanne) 2014; 5: 241
• 44 Godsland IF. Oestrogens and insulin secretion. Diabetologia 2005; 48: 2213-2220
• 45 Kasarinaite A, Sinton M, Saunders PTK. et al. The influence of sex hormones in liver function and disease. Cells 2023; 12
• 46 Spellacy WN, Carlson KL, Schade SL. Menstrual cycle carbohydrate metabolism: Studies on plasma insulin and blood glucose levels during an intravenous glucose tolerance test. AJOG 1967; 99: 382-386
• 47 Kumagai S, Holmäng A, Björntorp P. The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol Scand 1993; 149: 91-97
• 48 Yki-Järvinen H. Insulin sensitivity during the menstrual cycle. J Clin Endocrinol Metab 1984; 59: 350-353
• 49 Valdes CT, Elkind-Hirsch KE. Intravenous glucose tolerance test-derived insulin sensitivity changes during the menstrual cycle. J Clin Endocrinol Metab 1991; 72: 642-646
• 50 MacGregor KA, Gallagher IJ, Moran CN. Relationship between insulin sensitivity and menstrual cycle Is modified by BMI, fitness, and physical activity in NHANES. J Clin Endocrinol Metab 2021; 106: 2979-2990
• 51 Pulido JME, Salazar MA. Changes in insulin sensitivity, secretion and glucose effectiveness during menstrual cycle. Arch Med Res 1999; 30: 19-22
• 52 Yeung EH, Zhang C, Mumford SL. et al. Longitudinal study of insulin resistance and sex hormones over the menstrual cycle: The BioCycle Study. J Clin Endocrinol Metab 2010; 95: 5435-5442
• 53 Zarei S, Mosalanejad L, Ghobadifar MA. Blood glucose levels, insulin concentrations, and insulin resistance in healthy women and women with premenstrual syndrome: A comparative study. Clin Exp Reprod Med 2013; 40: 76-82
• 54 Hummel J, Benkendorff C, Fritsche L. et al. Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase. Nat Metab 2023; 5: 1475-1482
• 55 Bingley CA, Gitau R, Lovegrove JA. Impact of menstrual cycle phase on insulin sensitivity measures and fasting lipids. Horm Metab Res 2008; 40: 901-906
• 56 Mayer EJ, Newman B, Austin MA. et al. Genetic and environmental influences on insulin levels and the insulin resistance syndrome: an analysis of women twins. Am J Epidemiol 1996; 143: 323-332
• 57 Clarke SL, Reaven GM, Leonard D. et al. Cardiorespiratory fitness, body mass index, and markers of insulin resistance in apparently healthy women and men. Am J Med 2020; 133: 825-830
• 58 Batista MC, Cartledge TP, Zellmer AW. et al. Effects of aging on menstrual cycle hormones and endometrial maturation. Fertil Steril 1995; 64: 492-499
• 59 Lasquety MG, Rodriguez D, Fehring RJ. The influence of BMI levels on phases of the menstrual cycle and presumed ovulation. Linacre Q 2012; 79: 451-459
• 60 Knuth UA, Hull MGR, Jacobs HS. Amenorrhoea and loss of weight. Br J Obstet Gynaecol 1977; 84: 801-807
• 61 Webb P. 24-hour energy expenditure and the menstrual cycle. AJCN 1986; 44: 614-619
• 62 Solomon SJ, Kurzer MS, Calloway DH. Menstrual cycle and basal metabolic rate in women. AJCN 1982; 36: 611-616
• 63 Anyanwagu U, Idris I, Donnelly R. Drug-induced diabetes mellitus: Evidence for statins and other drugs affecting glucose metabolism. Clin Pharmacol Ther 2016; 99: 390-400
• 64 Cagnacci A, Biasioli A. The Effect of Hormonal Contraceptives on Metabolism. In: Meriggiola MC, Gemzell-Danielsson K, eds. Female and male contraception. Trends in andrology and sexual medicine. 1st ed. Cham: Springer International Publishing; Imprint Springer; 2021: 299-317
• 65 Godsland IF, Crook D, Simpson R. et al. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990; 323: 1375-1381
• 66 van der Vange N, Kloosterboer HJ, Haspels AA. Effect of seven low-dose combined oral contraceptive preparations on carbohyrate metabolism. AJOG 1987; 156: 918-922
• 67 Catalano PM, Tyzbir ED, Roman NM. et al. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. AJOG 1991; 165: 1667-1672
• 68 Adam S, McIntyre HD, Tsoi KY. et al. Pregnancy as an opportunity to prevent type 2 diabetes mellitus: FIGO Best Practice Advice. Int J Gynaecol Obstet 2023; 160: 56-67
• 69 World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications: Report of a WHO consultation. Part 1: diagnosis and classification of diabetes mellitus. 1999 https://apps.who.int/iris/handle/10665/66040
• 70 Horowitz M, Edelbroek MAL, Wishart JM. et al. Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia 1993; 36: 857-862
• 71 Titchenal CA, Hatfield K, Dunn M. et al. Does prior exercise affect oral glucose tolerance test results?. JISSN 2008; 5 Suppl 1
• 72 Prystupa K, Renklint R, Chninou Y. et al. Comprehensive validation of fasting-based and oral glucose tolerance test-based indices of insulin secretion against gold standard measures. BMJ Open Diabetes Res Care 2022; 10: e002909
• 73 Bergman RN, Finegood DT, Ader M. Assessment of insulin sensitivity in vivo. Endocr Rev 1985; 6: 45-86
• 74 Ignell C, Berntorp K. Evaluation of the relationship between capillary and venous plasma glucose concentrations obtained by the HemoCue Glucose 201+system during an oral glucose tolerance test. Scand J Clin Lab Invest 2011; 71: 670-675
• 75 Lin G, Siddiqui R, Lin Z. et al. Blood glucose variance measured by continuous glucose monitors across the menstrual cycle. NPJ Digit Med 2023; 6: 140
• 76 Porta M, Greenland S, Hernán MS. et al. A dictionary of Epidemiology. 6th ed. Oxford University Press; Oxford: 2014
• 77 Su H-W, Yi Y-C, Wei T-Y. et al. Detection of ovulation, a review of currently available methods. Bioeng Transl Med 2017; 2: 238-246
• 78 Palmnäs-Bédard MSA, Costabile G, Vetrani C. et al. The human gut microbiota and glucose metabolism: A scoping review of key bacteria and the potential role of SCFAs. AJCN 2022; 116: 862-874
• 79 Wachsmuth HR, Weninger SN, Duca FA. Role of the gut-brain axis in energy and glucose metabolism. Exp Mol Med 2022; 54: 377-392
• 80 Simon M-C, Sina C, Ferrario PG. et al. Gut microbiome analysis for personalized nutrition: The state of science. Mol Nutr Food Res 2023; 67: e2200476
• 81 Zhou Y-D, Liang F-X, Tian H-R. et al Mechanisms of gut microbiota-immune-host interaction on glucose regulation in type 2 diabetes. 1664-302X 2023; 14: 1121695
• 82 Müller M, Canfora EE, Blaak EE. Gastrointestinal transit time, glucose homeostasis and metabolic health: Modulation by dietary fibers. Nutrients 2018; 10: 275
• 83 Asnicar F, Leeming ER, Dimidi E. et al. Blue poo: Impact of gut transit time on the gut microbiome using a novel marker. Gut 2021; 70: 1665-1674
• 84 Jung H-K, Kim D-Y, Moon I-H. Effects of gender and menstrual cycle on colonic transit time in healthy subjects. Korean J Intern Med 2003; 18: 181-186
• 85 Córdova-Fraga T, Huerta-Franco R, Gutiérrez-Juárez G. et al. The colon transit time in different phases of the menstrual cycle: Assessed with biomagnetic technique. Neurol Clin Neurophysiol 2004; 2004: 31
• 86 Kamm MA, Farthing MJ, Lennard-Jones JE. Bowel function and transit rate during the menstrual cycle. 0017-5749 1989; 30: 605-608
• 87 Liu C-Y, Chen L-B, Liu P-Y. et al. Effects of progesterone on gastric emptying and intestinal transit in male rats. World J Gastroenterol 2002; 8: 338
• 88 Matos JF, Americo MF, Sinzato YK. et al. Role of sex hormones in gastrointestinal motility in pregnant and non-pregnant rats. World J Gastroenterol 2016; 22: 5761
• 89 Lawson M, Kern F, Everson GT. Gastrointestinal transit time in human pregnancy: Prolongation in the second and third trimesters followed by postpartum normalization. Gastroenterology 1985; 89: 996-999
• 90 Chiloiro M, Darconza G, Piccioli E. et al. Gastric emptying and orocecal transit time in pregnancy. J Gastroenterol 2001; 36: 538-543
• 91 Wada T, Hori S, Sugiyama M. et al. Progesterone inhibits glucose uptake by affecting diverse steps of insulin signaling in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab 2010; 298: E881-E888
• 92 Lee SR, Choi W-Y, Heo JH. et al. Progesterone increases blood glucose via hepatic progesterone receptor membrane component 1 under limited or impaired action of insulin. Sci Rep 2020; 10: 16316
• 93 Jensen MM, Pedersen HE, Clemmensen KKB. et al. Associations between physical activity and gastrointestinal transit times in people with normal weight, overweight, and obesity. J Nutr 2024; 154: 41-48
• 94 Sandberg AA, Slaunwhite WR. Studies on phenolic steroids in human subjects. VII. Metabolic fate of estriol and its glucuronide. J Clin Invest 1965; 44: 694-702
• 95 Benedek G, Zhang J, Nguyen H. et al. Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells. J Neuroimmunol 2017; 310: 51-59
• 96 Sasaki H, Kawamura K, Kawamura T. et al. Distinctive subpopulations of the intestinal microbiota are present in women with unexplained chronic anovulation. Reprod Biomed Online 2019; 38: 570-578
• 97 Liang Z, Di N, Li L. et al. Gut microbiota alterations reveal potential gut-brain axis changes in polycystic ovary syndrome. J Endocrinol Invest 2021; 44: 1727-1737
• 98 Acharya KD, Gao X, Bless EP. et al. Estradiol and high fat diet associate with changes in gut microbiota in female ob/ob mice. Sci Rep 2019; 9: 20192
• 99 Mihajlovic J, Leutner M, Hausmann B. et al. Combined hormonal contraceptives are associated with minor changes in composition and diversity in gut microbiota of healthy women. Environ Microbiol 2021; 23: 3037-3047
• 100 Krog MC, Hugerth LW, Fransson E. et al. The healthy female microbiome across body sites: Effect of hormonal contraceptives and the menstrual cycle. Hum Reprod 2022; 37: 1525-1543
• 101 Chen KLA, Liu X, Zhao YC. et al. Long-term administration of conjugated estrogen and bazedoxifene decreased murine fecal β-glucuronidase activity without impacting overall microbiome community. Sci Rep 2018; 8: 8166
• 102 Vandeputte D, Commer L, Tito RY. et al. Temporal variability in quantitative human gut microbiome profiles and implications for clinical research. Nat Commun 2021; 12: 6740
• 103 Welt CK. Normal menstrual cycle. 17 April 2023 https://www.uptodate.com/contents/normal-menstrual-cycle?search=physiology-of-the-normal-menstrual&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H176499083 [cited 2023 Oct 23]