{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:36:00Z","timestamp":1771461360655,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DIPLOMICS network","award":["PSTD220322391"],"award-info":[{"award-number":["PSTD220322391"]}]},{"name":"Department of Science and Innovation","award":["PSTD220322391"],"award-info":[{"award-number":["PSTD220322391"]}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["PSTD220322391"],"award-info":[{"award-number":["PSTD220322391"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Oral hormonal contraceptive users carry the risk of venous thrombosis and increased mortality. This study aimed to comprehensively profile the serum metabolome of participants using a combination of drospirenone (DRSP) and ethinyl estradiol (EE) containing oral contraceptives (COCs). The MxP Quant 500 kit for liquid chromatography mass tandem spectrometry (LC-MS\/MS) was used to analyse the 22 controls and 44 COC users (22 on a low EE dose (DRSP\/20EE) and 22 on a higher EE dose (DRSP\/30EE)). The kit\u2019s results were compared to our internally developed untargeted and targeted metabolomics methods previously applied to this cohort. Of the 630 metabolites included in the method, 277 provided desirable results (consistently detected above their detection limits), and of these, 5 had p-values &lt; 0.05, including betaine, glutamine, cortisol, glycine, and choline. Notably, these variations were observed between the control and COC groups, rather than among the two COC groups. Partial least squares-discriminant analysis revealed 49 compounds with VIP values \u2265 1, including amino acids and their derivatives, ceramides, phosphatidylcholines, and triglycerides, among others. Ten differential compounds were consistent with our previous studies, reinforcing the notion of COCs inducing a prothrombotic state and increased oxidative stress. Although only a limited number of compounds were deemed usable, these were quantified with high reliability and facilitated the identification of meaningful biological differences among the sample groups. In addition to substantiating known drug-induced variations, new hypotheses were also generated.<\/jats:p>","DOI":"10.3390\/metabo13101092","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T02:54:43Z","timestamp":1697684083000},"page":"1092","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Metabolomic Profiling of Hormonal Contraceptive Use in Young Females Using a Commercially Available LC-MS\/MS Kit"],"prefix":"10.3390","volume":"13","author":[{"given":"Tania","family":"Grobler","sequence":"first","affiliation":[{"name":"Centre for Human Metabolomics, North-West University, Potchefstroom 2531, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5202-9097","authenticated-orcid":false,"given":"Monique","family":"Opperman","sequence":"additional","affiliation":[{"name":"Centre for Human Metabolomics, North-West University, Potchefstroom 2531, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janette","family":"Bester","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Health Sciences, School of Medicine, University of Pretoria, Pretoria 0002, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albe Carina","family":"Swanepoel","sequence":"additional","affiliation":[{"name":"Centre for Human Metabolomics, North-West University, Potchefstroom 2531, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5456-3931","authenticated-orcid":false,"given":"Ilse","family":"du Preez","sequence":"additional","affiliation":[{"name":"Centre for Human Metabolomics, North-West University, Potchefstroom 2531, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,18]]},"reference":[{"key":"ref_1","unstructured":"United Nations (2019). Contraceptive Use by Method 2019: Data Booklet."},{"key":"ref_2","unstructured":"WHO (2023). Web Annex A. World Health Organization Model List of Essential Medicines\u201423rd List, 2023, The Selection and Use of Essential Medicines 2023: Executive Summary of the Report of the 24th Who Expert Committee on the Selection and Use of Essential Medicineses."},{"key":"ref_3","first-page":"Cd010813","article-title":"Combined Oral Contraceptives: Venous Thrombosis","volume":"3","author":"Stegeman","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.gim.2022.03.017","article-title":"Structured Approaches to Implementation of Clinical Genomics: A Scoping Review","volume":"24","author":"Brown","year":"2022","journal-title":"Genet Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.jaci.2022.08.016","article-title":"Possibilities and Promise: Leveraging Advances in Transcriptomics for Clinical Decision Making in Allergic Diseases","volume":"150","author":"Moore","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cca.2020.04.015","article-title":"Recent Advances in Robotic Protein Sample Preparation for Clinical Analysis and Other Biomedical Applications","volume":"507","author":"Urban","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"117333","DOI":"10.1016\/j.trac.2023.117333","article-title":"Machine Learning Facilitates the Application of Mass Spectrometry-Based Metabolomics to Clinical Analysis: A Review of Early Diagnosis of High Mortality Rate Cancers","volume":"168","author":"Ngan","year":"2023","journal-title":"TrAC Trends Anal. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/cpt.134","article-title":"Metabolomic Signatures for Drug Response Phenotypes: Pharmacometabolomics Enables Precision Medicine","volume":"98","author":"Weinshilboum","year":"2015","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1089\/omi.2020.0009","article-title":"Serum Metabolome Changes in Relation to Prothrombotic State Induced by Combined Oral Contraceptives with Drospirenone and Ethinylestradiol","volume":"24","author":"Swanepoel","year":"2020","journal-title":"OMICS J. Integr. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s11306-021-01825-z","article-title":"The Effect of Combined Oral Contraceptives Containing Drospirenone and Ethinylestradiol on Serum Levels of Amino Acids and Acylcarnitines","volume":"17","author":"Swanepoel","year":"2021","journal-title":"Metabolomics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/jemt.22378","article-title":"Estrogen Causes Ultrastructural Changes of Fibrin Networks During the Menstrual Cycle: A Qualitative Investigation","volume":"77","author":"Swanepoel","year":"2014","journal-title":"Microsc. Res. Tech."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1136\/jfprhc-2012-100397","article-title":"Characterisation of the Pharmacokinetics of Ethinylestradiol and Drospirenone in Extended-Cycle Regimens: Population Pharmacokinetic Analysis from a Randomised Phase Iii Study","volume":"39","author":"Reif","year":"2013","journal-title":"J. Fam. Plann. Reprod. Health Care"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/emph\/eox009","article-title":"Oral Contraceptives Cause Evolutionarily Novel Increases in Hormone Exposure: A Risk Factor for Breast Cancer","volume":"2017","author":"Lovett","year":"2017","journal-title":"Evol. Med. Public Health"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"W388","DOI":"10.1093\/nar\/gkab382","article-title":"Metaboanalyst 5.0: Narrowing the Gap between Raw Spectra and Functional Insights","volume":"49","author":"Pang","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/0009-8981(87)90183-5","article-title":"The Effect of Oral Contraceptives on Plasma-Free and Salivary Cortisol and Cortisone","volume":"165","author":"Meulenberg","year":"1987","journal-title":"Clin. Chim. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/nrendo.2012.134","article-title":"Regulation of Cortisol Bioavailability\u2014Effects on Hormone Measurement and Action","volume":"8","author":"Perogamvros","year":"2012","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1160\/TH04-10-0652","article-title":"High Dose Dexamethasone Increases Circulating P-Selectin and Von Willebrand Factor Levels in Healthy Men","volume":"94","author":"Jilma","year":"2005","journal-title":"Thromb. Haemost."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1097\/00001721-199904000-00006","article-title":"Abnormalities of Von Willebrand Factor Are Also Part of the Prothrombotic State of Cushing\u2019s Syndrome","volume":"10","author":"Casonato","year":"1999","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1097\/00001721-199212000-00013","article-title":"The Fibrinolytic Potential in Patients with Cushing\u2019s Disease: A Clue to Their Hypercoagulable State","volume":"3","author":"Patrassi","year":"1992","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_20","first-page":"3662","article-title":"Anticoagulant Prophylaxis Markedly Reduces Thromboembolic Complications in Cushing\u2019s Syndrome","volume":"87","author":"Boscaro","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/BF03343697","article-title":"Markers of Activation of Coagulation and Fibrinolysis in Patients with Cushing\u2019s Syndrome","volume":"23","author":"Fatti","year":"2000","journal-title":"J. Endocrinol. Invest"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"R101","DOI":"10.1530\/EJE-15-0308","article-title":"Mechanisms in Endocrinology: The Spectrum of Haemostatic Abnormalities in Glucocorticoid Excess and Defect","volume":"173","author":"Isidori","year":"2015","journal-title":"Eur. J. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1111\/jth.13265","article-title":"The Influence of Corticosteroids on Hemostasis in Healthy Subjects","volume":"14","author":"Majoor","year":"2016","journal-title":"J. Thromb. Haemost."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"H1922","DOI":"10.1152\/ajpheart.00364.2002","article-title":"Inhibitory Effect of Glucocorticoid on Coronary Artery Endothelial Function","volume":"283","author":"Rogers","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13357","DOI":"10.1073\/pnas.96.23.13357","article-title":"Down-Regulation of the Expression of Endothelial No Synthase Is Likely to Contribute to Glucocorticoid-Mediated Hypertension","volume":"96","author":"Wallerath","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1161\/01.RES.0000050588.35034.3C","article-title":"Glucocorticoid Excess Induces Superoxide Production in Vascular Endothelial Cells and Elicits Vascular Endothelial Dysfunction","volume":"92","author":"Iuchi","year":"2003","journal-title":"Circ. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/s41598-017-01274-6","article-title":"The Biomarker and Causal Roles of Homoarginine in the Development of Cardiometabolic Diseases: An Observational and Mendelian Randomization Analysis","volume":"7","author":"Oksala","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12217","DOI":"10.1038\/s41598-018-30708-y","article-title":"Plasma Homoarginine Concentrations According to Use of Hormonal Contraception","volume":"8","author":"Helm","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.theriogenology.2014.05.003","article-title":"Estrogen Stimulates Expression of Chicken Hepatic Vitellogenin Ii and Very Low-Density Apolipoprotein Ii through Er-A","volume":"82","author":"Li","year":"2014","journal-title":"Theriogenology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1253\/circj.CJ-08-0240","article-title":"Serum L-Homoarginine Concentration Is Elevated During Normal Pregnancy and Is Related to Flow-Mediated Vasodilatation","volume":"72","author":"Valtonen","year":"2008","journal-title":"Circ. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1152\/physrev.2000.80.3.1107","article-title":"Creatine and Creatinine Metabolism","volume":"80","author":"Wyss","year":"2000","journal-title":"Physiol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1093\/ije\/dyw147","article-title":"Effects of Hormonal Contraception on Systemic Metabolism: Cross-Sectional and Longitudinal Evidence","volume":"45","author":"Wang","year":"2016","journal-title":"Int. J. Epidemiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1515\/cclm-2012-0518","article-title":"Metabolic Crosstalk between Choline\/1-Carbon Metabolism and Energy Homeostasis","volume":"51","author":"Zeisel","year":"2013","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_34","unstructured":"Shils, M.E., and Shike, M. (2006). Modern Nutrition in Health and Disease, Lippincott Williams & Wilkins. [10th ed.]."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1093\/ajcn\/81.6.1383","article-title":"Plasma Choline and Betaine and Their Relation to Plasma Homocysteine in Normal Pregnancy1","volume":"81","author":"Holm","year":"2005","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.3945\/ajcn.112.054189","article-title":"Low Folate Status Enhances Pregnancy Changes in Plasma Betaine and Dimethylglycine Concentrations and the Association between Betaine and Homocysteine","volume":"97","author":"Ballesteros","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3945\/jn.114.201095","article-title":"Metabolite Profile Analysis Reveals Association of Vitamin B-6 with Metabolites Related to One-Carbon Metabolism and Tryptophan Catabolism but Not with Biomarkers of Inflammation in Oral Contraceptive Users and Reveals the Effects of Oral Contraceptives on These Processes","volume":"145","author":"Coats","year":"2015","journal-title":"J. Nutr."},{"key":"ref_38","unstructured":"Jacobs, T. (2022). An Analytical Method to Investigate the Metabolites and Co-Factors of the Methionine-Homocysteine Cycle in Women Using Combined Oral Contraceptives and Non-Users, North-West University, Potchefstroom Campus."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Velasquez, M.T., Ramezani, A., Manal, A., and Raj, D.S. (2016). Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins, 8.","DOI":"10.3390\/toxins8110326"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1023\/B:NERE.0000010436.44223.f8","article-title":"Taurine Biosynthetic Enzymes and Taurine Transporter: Molecular Identification and Regulations","volume":"29","author":"Tappaz","year":"2004","journal-title":"Neurochem. Res."},{"key":"ref_41","first-page":"293","article-title":"Role of Taurine in Vasculature: An Overview of Experimental and Human Studies","volume":"1","author":"Abebe","year":"2011","journal-title":"Am. J. Cardiovasc. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"G277","DOI":"10.1152\/ajpgi.00107.2014","article-title":"Estradiol Decreases Taurine Level by Reducing Cysteine Sulfinic Acid Decarboxylase via the Estrogen Receptor-A in Female Mice Liver","volume":"308","author":"Ma","year":"2014","journal-title":"Am. J. Physiol. Gastrointest."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1093\/ajcn\/29.9.956","article-title":"Effect of Oral Contraceptives and Vitamin B6 Supplements on Alanine and Glycine Metabolism","volume":"29","author":"Rose","year":"1976","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Campesi, I., Sanna, M., Zinellu, A., Carru, C., Rubattu, L., Bulzomi, P., Seghieri, G., Tonolo, G., Palermo, M., and Rosano, G. (2012). Oral Contraceptives Modify DNA Methylation and Monocyte-Derived Macrophage Function. Biol. Sex Differ., 3.","DOI":"10.1186\/2042-6410-3-4"},{"key":"ref_45","first-page":"614","article-title":"Serum Metabolomic Profiles Suggest Influence of Sex and Oral Contraceptive Use","volume":"6","author":"Ruoppolo","year":"2014","journal-title":"Am. J. Transl. Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Anderson, G.M. (2023). Determination of Indolepropionic Acid and Related Indoles in Plasma, Plasma Ultrafiltrate, and Saliva. Metabolites, 13.","DOI":"10.3390\/metabo13050602"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1136\/jcp.25.3.252","article-title":"Oral Contraceptives and Tryptophan Metabolism: Effects of Oestrogen in Low Dose Combined with a Progestagen and of a Low-Dose Progestagen (Megestrol Acetate) Given Alone","volume":"25","author":"Rose","year":"1972","journal-title":"J. Clin. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1111\/j.1753-4887.2011.00419.x","article-title":"Oral Contraceptive Use: Impact on Folate, Vitamin B6, and Vitamin B12 Status","volume":"69","author":"Wilson","year":"2011","journal-title":"Nutr. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1016\/j.clnu.2018.11.029","article-title":"Clinical Association between the Metabolite of Healthy Gut Microbiota, 3-Indolepropionic Acid and Chronic Kidney Disease","volume":"38","author":"Sun","year":"2019","journal-title":"Clin. Nutr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.1111\/brv.12765","article-title":"Diverse Roles of Microbial Indole Compounds in Eukaryotic Systems","volume":"96","author":"Kumar","year":"2021","journal-title":"Biol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1016\/j.jvs.2017.09.029","article-title":"Plasma Microbiome-Modulated Indole- and Phenyl-Derived Metabolites Associate with Advanced Atherosclerosis and Postoperative Outcomes","volume":"68","author":"Cason","year":"2018","journal-title":"J. Vasc. Surg."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Hua, X., Cao, Y., Morgan, D.M., Miller, K., Chin, S.M., Bellavance, D., and Khalili, H. (2022). Longitudinal Analysis of the Impact of Oral Contraceptive Use on the Gut Microbiome. J. Med. Microbiol., 71.","DOI":"10.1099\/jmm.0.001512"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1177\/1076029616683802","article-title":"Oral Contraceptives and Hrt Risk of Thrombosis","volume":"24","author":"Gialeraki","year":"2017","journal-title":"Clin. Appl. Thromb."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"993","DOI":"10.3389\/fneur.2019.00993","article-title":"Oral Contraceptive Use and Increased Risk of Stroke: A Dose\u2013Response Meta-Analysis of Observational Studies","volume":"10","author":"Li","year":"2019","journal-title":"Front. Neurol."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/10\/1092\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:09:21Z","timestamp":1760130561000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/10\/1092"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,18]]},"references-count":54,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["metabo13101092"],"URL":"https:\/\/doi.org\/10.3390\/metabo13101092","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,18]]}}}