Effects of hormonal contraception on systemic metabolism

Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood. Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24–49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception. Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery. Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.

[1]  Dajiang J. Liu,et al.  Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease , 2016, Science.

[2]  T. Spector,et al.  Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes , 2015, European Journal of Human Genetics.

[3]  Carol Coupland,et al.  Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases , 2015, BMJ : British Medical Journal.

[4]  Markus Perola,et al.  Sex hormone-binding globulin associations with circulating lipids and metabolites and the risk for type 2 diabetes: observational and causal effect estimates. , 2015, International journal of epidemiology.

[5]  Tom R. Gaunt,et al.  Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts. , 2015, Circulation.

[6]  Michael J. Pencina,et al.  Hyperlipidemia in Early Adulthood Increases Long-Term Risk of Coronary Heart Disease , 2015, Circulation.

[7]  Pasi Soininen,et al.  Quantitative serum nuclear magnetic resonance metabolomics in cardiovascular epidemiology and genetics. , 2015, Circulation. Cardiovascular genetics.

[8]  T. Mostafa,et al.  Cardiovascular risk in Egyptian healthy consumers of different types of combined oral contraceptives pills: A comparative study , 2015, Endocrine.

[9]  Samuli Ripatti,et al.  Metabolic Signatures of Adiposity in Young Adults: Mendelian Randomization Analysis and Effects of Weight Change , 2014, PLoS medicine.

[10]  S. Bojesen,et al.  Genetically low vitamin D concentrations and increased mortality: mendelian randomisation analysis in three large cohorts , 2014, BMJ : British Medical Journal.

[11]  G. Mercuro,et al.  Serum metabolomic profiles suggest influence of sex and oral contraceptive use. , 2014, American journal of translational research.

[12]  A. Avenell,et al.  Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis. , 2014, The American journal of clinical nutrition.

[13]  T. Lehtimäki,et al.  A metabolic view on menopause and ageing , 2014, Nature Communications.

[14]  Anette Varbo,et al.  Triglycerides and cardiovascular disease , 2014, The Lancet.

[15]  Simon G Thompson,et al.  Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. , 2014, Annals of internal medicine.

[16]  Toomas Haller,et al.  Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons , 2014, PLoS medicine.

[17]  D. Lawlor,et al.  Pregnancy characteristics and women's future cardiovascular health: an underused opportunity to improve women's health? , 2014, Epidemiologic reviews.

[18]  Tanya M. Teslovich,et al.  Common variants associated with plasma triglycerides and risk for coronary artery disease , 2013, Nature Genetics.

[19]  T. Stijnen,et al.  Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis , 2013, BMJ : British Medical Journal.

[20]  M. Laakso,et al.  Glycerol and Fatty Acids in Serum Predict the Development of Hyperglycemia and Type 2 Diabetes in Finnish Men , 2013, Diabetes Care.

[21]  Chi Pang Wen,et al.  Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention , 2013, The Lancet.

[22]  W. Mosher,et al.  Contraceptive methods women have ever used: United States, 1982-2010. , 2013, National health statistics reports.

[23]  Terho Lehtimäki,et al.  Branched-Chain and Aromatic Amino Acids Are Predictors of Insulin Resistance in Young Adults , 2013, Diabetes Care.

[24]  J. Hugon-Rodin,et al.  Hormonal contraceptives and arterial disease: an epidemiological update. , 2013, Best practice & research. Clinical endocrinology & metabolism.

[25]  J. Hugon-Rodin,et al.  Hormonal contraceptives and venous thromboembolism: an epidemiological update. , 2013, Best practice & research. Clinical endocrinology & metabolism.

[26]  R. Sitruk-Ware,et al.  Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills. , 2013, Best practice & research. Clinical endocrinology & metabolism.

[27]  B. Nordestgaard,et al.  Remnant cholesterol as a causal risk factor for ischemic heart disease. , 2013, Journal of the American College of Cardiology.

[28]  P. O’Reilly,et al.  Long-term Leisure-time Physical Activity and Serum Metabolome , 2013, Circulation.

[29]  F. Rosendaal,et al.  Effect of ethinylestradiol dose and progestagen in combined oral contraceptives on plasma sex hormone‐binding globulin levels in premenopausal women , 2013, Journal of thrombosis and haemostasis : JTH.

[30]  Markus Abt,et al.  Effects of dalcetrapib in patients with a recent acute coronary syndrome. , 2012, The New England journal of medicine.

[31]  John Spertus,et al.  Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study , 2012, The Lancet.

[32]  Harold I Feldman,et al.  Estimating glomerular filtration rate from serum creatinine and cystatin C. , 2012, The New England journal of medicine.

[33]  Niels Keiding,et al.  Thrombotic stroke and myocardial infarction with hormonal contraception. , 2012, The New England journal of medicine.

[34]  S. Chanock,et al.  Genome-Wide Association Study of Circulating Estradiol, Testosterone, and Sex Hormone-Binding Globulin in Postmenopausal Women , 2012, PloS one.

[35]  Tuija Tammelin,et al.  Metabolic Signatures of Insulin Resistance in 7,098 Young Adults , 2012, Diabetes.

[36]  Christopher M. Estes,et al.  The effect of obesity and low-dose oral contraceptives on carbohydrate and lipid metabolism. , 2012, Contraception.

[37]  Markus Perola,et al.  Genome-wide association study identifies multiple loci influencing human serum metabolite levels , 2012, Nature Genetics.

[38]  E. Løkkegaard,et al.  Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9 , 2011, BMJ : British Medical Journal.

[39]  Markus Perola,et al.  Metabonomic, transcriptomic, and genomic variation of a population cohort , 2010, Molecular systems biology.

[40]  Olli Saarela,et al.  Contribution of 30 Biomarkers to 10-Year Cardiovascular Risk Estimation in 2 Population Cohorts: The MONICA, Risk, Genetics, Archiving, and Monograph (MORGAM) Biomarker Project , 2010, Circulation.

[41]  S. Skouby,et al.  Contraceptive use and behavior in the 21st century: a comprehensive study across five European countries , 2004, The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception.

[42]  Reino Laatikainen,et al.  High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism. , 2009, The Analyst.

[43]  Shahrul Mt-Isa,et al.  Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. , 2009, JAMA.

[44]  A. Lalonde,et al.  Contraceptive use among Canadian women of reproductive age: results of a national survey. , 2009, Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC.

[45]  J. Liao,et al.  Genetically elevated C-reactive protein and ischemic vascular disease , 2009, Current atherosclerosis reports.

[46]  T. Lehtimäki,et al.  Use of combined oral contraceptives alters metabolic determinants and genetic regulation of C‐reactive protein. The Cardiovascular Risk in Young Finns Study , 2009, Scandinavian journal of clinical and laboratory investigation.

[47]  Risto Telama,et al.  Cohort profile: the cardiovascular risk in Young Finns Study. , 2008, International journal of epidemiology.

[48]  M. McCarthy,et al.  Comparison of metabolic and inflammatory outcomes in women who used oral contraceptives and the levonorgestrel-releasing intrauterine device in a general population. , 2008, American journal of obstetrics and gynecology.

[49]  K. Kaski,et al.  1H NMR metabonomics approach to the disease continuum of diabetic complications and premature death , 2008, Molecular systems biology.

[50]  J. Ménard,et al.  Effects of oral and transvaginal ethinyl estradiol on hemostatic factors and hepatic proteins in a randomized, crossover study. , 2007, The Journal of clinical endocrinology and metabolism.

[51]  J. Kopple.  Phenylalanine and tyrosine metabolism in chronic kidney failure. , 2007, The Journal of nutrition.

[52]  L. Hansson,et al.  Treatment with combined oral contraceptives induces a rise in serum C‐reactive protein in the absence of a general inflammatory response , 2006, Journal of thrombosis and haemostasis : JTH.

[53]  J. Aldrighi,et al.  Evaluation of lipid profile in adolescents during long-term use of combined oral hormonal contraceptives. , 2005, Contraception.

[54]  Mark I. McCarthy,et al.  Early Life Factors and Blood Pressure at Age 31 Years in the 1966 Northern Finland Birth Cohort , 2004, Hypertension.

[55]  K. Nair,et al.  Impairment of phenylalanine conversion to tyrosine in end-stage renal disease causing tyrosine deficiency. , 2004, Kidney international.

[56]  A. Algra,et al.  Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial. , 2004, Blood.

[57]  W. März,et al.  Double-blind, randomized study comparing the effects of two monophasic oral contraceptives containing ethinylestradiol (20 microg or 30 microg) and levonorgestrel (100 microg or 150 microg) on lipoprotein metabolism. , 2004, Contraception.

[58]  R. B. Machado,et al.  Clinical and metabolic aspects of the continuous use of a contraceptive association of ethinyl estradiol (30 microg) and gestodene (75 microg). , 2004, Contraception.

[59]  C. Gerlinger,et al.  A randomized study over 13 cycles to assess the influence of oral contraceptives containing ethinylestradiol combined with drospirenone or desogestrel on carbohydrate metabolism. , 2003, Contraception.

[60]  F. Laporte,et al.  Effects of two low-dose oral contraceptives containing ethinylestradiol and either desogestrel or levonorgestrel on serum lipids and lipoproteins with particular regard to LDL size. , 2001, Contraception.

[61]  K. Nair,et al.  The kidney is an important site for in vivo phenylalanine-to-tyrosine conversion in adult humans: A metabolic role of the kidney. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[62]  I. Godsland,et al.  Occlusive vascular diseases in oral contraceptive users. Epidemiology, pathology and mechanisms. , 2000, Drugs.

[63]  S. Møller,et al.  Effects of oral contraceptives on plasma neutral amino acids and cholesterol during a menstrual cycle , 1996, European Journal of Clinical Pharmacology.

[64]  J. Foidart,et al.  Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. , 1995, The Journal of clinical endocrinology and metabolism.

[65]  S. Møller,et al.  Tyrosine metabolism in users of oral contraceptives. , 1995, Life sciences.

[66]  I. Godsland,et al.  The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism , 1991 .

[67]  C. Potera,et al.  Effect of oral alanine loads on plasma amino acids in oral contraceptive users and control women. , 1978, The American journal of clinical nutrition.

[68]  T. Peters,et al.  Quantitative changes in plasma amino acids induced by oral contraceptives. , 1971, Clinical science.