Oral, transdermal and vaginal combined contraceptives induce an increase in markers of chronic inflammation and impair insulin sensitivity in young healthy normal-weight women: a randomized study

Piltonen, T.; Puurunen, J.; Hedberg, P.; Ruokonen, A.; Mutt, S. J.; Herzig, K. H.; Nissinen, A.; Morin-Papunen, L.; Tapanainen, J. S.

doi:10.1093/humrep/des225

Cited by 94Reproductive Health and ContraceptionOvarian function and disordersAdipokines, Inflammation, and Metabolic Diseases

Oral, transdermal and vaginal combined contraceptives induce an increase in markers of chronic inflammation and impair insulin sensitivity in young healthy normal-weight women: a randomized study

Piltonen, T., Puurunen, J., Hedberg, P., Ruokonen, A., Mutt, S. J., Herzig, K. H., Nissinen, A., Morin-Papunen, L. +1 more·2012·Human Reproduction

DOI 10.1093/humrep/des225

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Abstract

STUDY QUESTION: What is the effect of alternative administration routes of combined contraceptives (CCs) on androgen secretion, chronic inflammation, glucose tolerance and lipid profile? SUMMARY ANSWER: The use of oral, transdermal and vaginal CCs impairs glucose tolerance and induces chronic inflammation. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Oral CCs worsen insulin sensitivity and are associated with increased levels of circulating inflammatory markers, whereas the metabolic effects of transdermal and vaginal CCs have been reported to be minimal. This is the first study comparing three different administration routes of CCs on metabolic variables. STUDY DESIGN, SIZE AND DURATION: This randomized (computer-generated) open-label 9-week follow-up study was conducted at the Oulu University Hospital, Finland. Fasting blood samples were collected at baseline and thereafter at 5 and 9 weeks of treatment, and serum levels of 17-hydroxyprogesterone, androstenedione, testosterone, C-reactive protein (CRP), sex hormone-binding globulin (SHBG), glucose, insulin, C-peptide, total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were measured. Oral glucose tolerance tests were performed and plasma levels of pentraxin 3 (PTX-3) were measured at 0 and 9 weeks. The randomization list, with an allocation ratio of 1:1:1 and block size of six, was computer generated and constructed by a pharmacist at the Oulu University Hospital. The research nurse controlled the randomization list and assigned participants to their groups at the first visit. PARTICIPANTS AND SETTING: Forty-two of 54 healthy women who entered the study used oral contraceptive pills (n = 13), transdermal contraceptive patches (n = 15) or contraceptive vaginal rings (n = 14) continuously for 9 weeks. Inclusion criteria were regular menstrual cycles, at least a 2-month washout as regards hormonal contraceptives and no medication. MAIN RESULTS AND THE ROLE OF CHANCE: Serum levels of SHBG increased and consequently the free androgen index (FAI) decreased in all study groups from baseline to 9 weeks of treatment [FAI, oral: 1.3 (95% confidence interval, CI: 0.94; 1.62) to 0.40 (0.25; 0.54); transdermal: 1.2 (0.96; 1.4) to 0.36 (0.30; 0.43); vaginal: 1.6 (1.1; 2.1) to 0.43 (0.29; 0.58), P < 0.001 in all groups]. Insulin sensitivity was reduced at 9 weeks in all three groups according to the Matsuda index [oral: 7.3 (5.5; 9.0) to 5.6 (3.9; 7.3); transdermal: 9.1 (6.7; 11.4) to 6.6 (4.5; 8.8); vaginal: 7.7 (5.9; 9.5) to 5.4 (3.9; 7.0), P= 0.004-0.024]. Levels of HDL cholesterol, triglycerides and CRP rose in all three groups [CRP, oral: 0.70 (0.38; 1.0) to 5.4 (1.0; 9.9) mg/l; transdermal: 0.77 (0.45; 1.1) to 2.9 (1.4;4.4) mg/l; vaginal: 0.98 (0.52; 1.4) to 3.7 (-0.25; 7.7, a negative value due to skewed distribution to right) mg/l, P≤ 0.002 in all groups] and PTX-3 levels increased in the oral and transdermal study groups (P = 0.007 and P = 0.002). WIDER IMPLICATIONS OF THE FINDINGS: Although the long-term consequences of the present results remain undetermined, these findings emphasize the importance of monitoring glucose metabolism during the use of CCs, especially in women with known risks of type 2 diabetes or cardiovascular diseases. BIAS, LIMITATIONS, GENERALIZABILITY: The number of subjects was relatively low. Moreover, the 9-week exposure to CCs is too short to draw conclusions about the long-term health consequences. However, as the subjects were healthy, normal-weight young women, the possible alterations in the glucose and inflammatory profiles among women with known metabolic risks might be even greater. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from the Academy of Finland, the Sigrid Jusélius Foundation, the Finnish Medical Foundation, the Research Foundation of Obstetrics and Gynecology, Oulu University Scholarship Foundation, the North Ostrobothnia Regional Fund of the Finnish Cultural Foundation, the Tyyni Tani Foundation of the University of Oulu and the Finnish-Norwegian Medical Foundation. No competing interests. TRIAL REGISTRATION NUMBER: NCT01087879.

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COCP does not have any major effects on carbohydrate metabolism in healthy women.
“COCP does not have any major effects on carbohydrate metabolism in healthy women, whereas the effect on lipid metabolism depends on the level of estrogen and type of progestin, with potential negative effects (78, 79, 80, 81).”
From Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis (2024) · cites this paper as [79]
The Discussion (page not supplied) reports that insulin sensitivity decreased in the oral contraceptive group, with increased insulin levels and worsened measures of glucose tolerance. Although fasting glucose remained unchanged, the paper concludes that the contraceptives studied had unfavourable effects on glucose metabolism—contrary to the attributed claim. (LLM, conf=0.91)
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COCP appears to increase CRP.
“COCP appears to increase CRP (79, 84, 85), yet the significance of these effects remains unknown.”
From Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis (2024) · cites this paper as [79]
The effect of COCP on lipid metabolism depends on the level of estrogen and type of progestin, with potential negative effects.
“COCP does not have any major effects on carbohydrate metabolism in healthy women, whereas the effect on lipid metabolism depends on the level of estrogen and type of progestin, with potential negative effects (78, 79, 80, 81).”
From Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis (2024) · cites this paper as [79]
Long-term and recent hormone use can affect biomarker profiles.
“In addition, long-term and recent hormone use can affect biomarker profiles (41–43)”
From World Endometriosis Research Foundation Endometriosis Phenome and biobanking harmonization project: II. Clinical and covariate phenotype data collection in endometriosis research (2014) · cites this paper as [41]
EE-containing contraceptives alter lipid metabolism, increasing especially high-density lipoprotein and triglycerides, but also affect glucose metabolism.
“EE-containing contraceptives alter lipid metabolism, increasing especially high-density lipoprotein and triglycerides, but also affect glucose metabolism (Morin-Papunen et al., 2008; Piltonen et al., 2012; Wang et al., 2016).”
From Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial (2023) · cites this paper as Piltonen et al., 2012

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Combined Oral Contraceptives Increase High-Sensitivity C-Reactive Protein but Not Haptoglobin in Female Athletes
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Ethnicity, sex, FADS genetic variation, and hormonal contraceptive use influence delta-5- and delta-6-desaturase indices and plasma docosahexaenoic acid concentration in young Canadian adults: a cross-sectional study
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Inflammation and Oral Contraceptive Use in Female Athletes Before the Rio Olympic Games
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Combined oral contraceptives plus spironolactone compared with metformin in women with polycystic ovary syndrome: a one-year randomized clinical trial
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Oral Contraceptive Use and Risks of Cancer in the NIH-AARP Diet and Health Study
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The Effects of Hormonal Contraceptives on Glycemic Regulation
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Combined oral contraceptive pill compared with no medical treatment in the management of polycystic ovary syndrome: a systematic review
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Plasma levels of pentraxin-3, an inflammatory protein involved in fertility, are reduced in women with polycystic ovary syndrome
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Extensive modulation of the circulating blood proteome by hormonal contraceptive use across two population studies
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Estradiol Valerate vs Ethinylestradiol in Combined Oral Contraceptives: Effects on the Pituitary-Ovarian Axis
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Bone markers in polycystic ovary syndrome: A multicentre study
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Fasting blood glucose, blood pressure and body mass index among combined oral contraceptive users in Chencha town Southern Ethiopia, 2019
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Combined oral contraceptive and nitric oxide synthesis inhibition synergistically causes cardiac hypertrophy and exacerbates insulin resistance in female rats
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The effects of different therapeutic modalities on cardiovascular risk factors in women with polycystıc ovary syndrome: A randomızed controlled study
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Plasma 25-Hydroxyvitamin D, Hormonal Contraceptive Use, and the Plasma Proteome in Caucasian, East Asian, and South Asian Young Adults
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Atherosclerosis-related biomarkers in women with endometriosis: The effects of dienogest and oral contraceptive therapy
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Broad Metabolome Alterations Associated with the Intake of Oral Contraceptives Are Mediated by Cortisol in Premenopausal Women
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Serum retinol-binding protein 4 levels in polycystic ovary syndrome
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Imaging the human brain on oral contraceptives: A review of structural imaging methods and implications for future research goals
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Oral and Vaginal Hormonal Contraceptives Induce Similar Unfavorable Metabolic Effects in Women with PCOS: A Randomized Controlled Trial
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l-glutamine supplementation exerts cardio-renal protection in estrogen-progestin oral contraceptive-treated female rats
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The Hypothalamic–Pituitary–Ovarian Axis, Menstrual and Oral Contraceptive Cycles: Regulation and Function in the Context of Exercise and Sport
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Associations between common contraceptive use and circulating inflammatory biomarkers
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The Combined Contraceptive Vaginal Ring: an Update
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Contraceptive challenges in adolescents living with or at risk of HIV
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Carbohydrate, lipid, bone and inflammatory markers in HIV-positive adolescents on antiretroviral therapy and hormonal contraception
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Plasma pentraxin 3 is higher in early ovarian hyperstimulation syndrome than in uncomplicated in vitro fertilization cycle of high-risk women
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The impact of lifestyle on the reproductive, metabolic, and psychological well-being of women with polycystic ovary syndrome (PCOS)
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Oral Contraceptives: Mind-Body Poison
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High-dose oral contraceptives induce hyperinsulinemia without altering immune activation in diet-induced obesity which persists even following a dietary low-fat diet intervention
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Harmonization of Clinical and Laboratory Data to Improve Biomarker Discovery in Endometriosis: WERF EPHect
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RISCOS E AGRAVOS A SAÚDE DO AGENTE COMUNITÁRIO DE SAÚDE
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DESIGN PARTICIPATIVO – DESENHAR COM CRIANÇAS PARA A PRÁTICA DE UMA ALIMENTAÇÃO SAUDÁVEL
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DOENÇA DE ALZHEIMER NA POPULAÇÃO SENI: ASPECTOS E CONSEQUÊNCIAS NEURODEGENERATIVOS
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ASSOCIAÇÃO ENTRE FATORES DE RISCO CARDIOVASCULAR, PROTEÍNA C REATIVA ULTRASSENSÍVEL E DILATAÇÃO FLUXO-MEDIADA DA ARTÉRIA BRAQUIAL EM PACIENTES USUÁRIAS DE ANTICONCEPCIONAL HORMONAL COMBINADO: UM ESTUDO TRANSVERSAL
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PROMOÇÃO DE AÇÕES EDUCATIVAS DE SAÚDE NA POPULAÇÃO EM SITUAÇÃO DE RUA
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GRUPO DE APOIO A PAIS DE PESSOAS NO TRANSTORNO DO ESPECTRO AUTISTA
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DETERMINAÇÃO DE CÁDMIO, CHUMBO E NÍQUEL EM TINTAS DE TATUAGEM POR ESPECTROMETRIA DE ABSORÇÃO ATÔMICA
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DESENVOLVIMENTO DE UMA FERRAMENTA PSICOLÓGICA PARA PACIENTES IMPOSSIBILITADOS DE SE COMUNICAR VERBALMENTE
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CÂNCER DE MAMA: DA PREVENÇÃO AO TRATAMENTO
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POLÍTICA NACIONAL DA SAÚDE INTEGRAL DA POPULAÇÃO NEGRA: ANÁLISE DO ACESSO À SAÚDE DA POPULAÇÃO QUILOMBOLA DE ALTOALEGRE EM HORIZONTE-CEARÁ
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A TELEMEDICINA COMO FERRAMENTA DE CONTINUIDADE DE CUIDADOS EM SAÚDE ÀS PESSOAS PRIVADAS DE LIBERDADE VIVENDO COM HIV/AIDS EM PERÍODO DE PANDEMIA: RELATO DE EXPERIÊNCIA
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AVALIANDO O PERFIL DO TRABALHADOR RURAL PARA O DESENVOLVIMENTO DE AÇÕES DE PREVENÇÃO
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PRÁTICA DE MULHERES FRENTE À REALIZAÇÃO DO EXAME DE PREVENÇÃO DE CÂNCER DE COLO DO ÚTERO
de Azevedo, T. G., Camboim, F. E. D. F., Matos, T. B., Silva, J. L., & Brandão, K. D. L. (2023) · Editora Reflexão Acadêmica eBooks · doi:10.51497/reflex.0000566
HANSENÍASE: UMA REALIDADE NEGLIGENCIADA
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Combined oral, transdermal and vaginal contraceptives worsen insulin resistance and chronic inflammation in young healthy normal weight women – A randomized study
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Glucose Metabolism and Insulin Resistance in Women with Polycystic Ovary Syndrome during Therapy with Oral Contraceptives Containing Cyproterone Acetate or Desogestrel
Cagnacci, A., Paoletti, A. M., Renzi, A., Orrù, M., Pilloni, M., Melis, G. B., & Volpe, A. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030328 · Cited by 69 · see citing works

Authors: Piltonen, T., Puurunen, J., Hedberg, P., Ruokonen, A., Mutt, S. J., Herzig, K. H., Nissinen, A., Morin-Papunen, L., & Tapanainen, J. S.
Affiliations: Oulu University Hospital (FI)
University of Oulu (FI)
Kuopio University Hospital (FI)
University of Helsinki (FI)
Corresponding author: Tapanainen, J. S.
ORCID: Piltonen, T.
Mutt, S. J.
Herzig, K. H.
Nissinen, A.
Morin-Papunen, L.
Tapanainen, J. S.
Venue: Human Reproduction
Publisher: Oxford University Press (OUP)
Published: 2012-07-18
Volume: 27
Issue: 10
Pages: 3046-3056
ISSN: 0268-1161 (ISSN-L)
1460-2350
DOI: 10.1093/humrep/des225
OpenAlex: W2043573826
Cited by: 94
References: 49
Citations by year: 2026: 9 · 2025: 1 · 2024: 4 · 2023: 23 · 2022: 7 · 2021: 4 · 2020: 6 · 2019: 7 · 2018: 1 · 2017: 10 · 2016: 6 · 2015: 4 · 2014: 4 · 2013: 5 · 2012: 3
FWCI: 4.94
Type: journal article
Language: en
Open access: closed
Locations: Human Reproduction (publishedVersion)
PubMed (publishedVersion)
Funders: Suomen Kulttuurirahasto
Pohjois-Pohjanmaan Rahasto
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords: combined oral contraceptives, contraceptive patch, contraceptive vaginal ring, route of administration, chronic inflammation, insulin sensitivity, glucose tolerance, androgen secretion, sex hormone-binding globulin, free androgen index, C-reactive protein, pentraxin 3, lipid profile, healthy young women, normal-weight women, insulin resistance, dyslipidemia
MeSH terms: Administration, Cutaneous, Administration, Intravaginal, Adult, Androgens, Androstenedione, Blood Glucose, C-Peptide, C-Reactive Protein, Contraceptive Agents, Female, Contraceptives, Oral, Combined, Female, Glucose, Glucose Tolerance Test, Humans, Insulin, Insulin Resistance, Lipoproteins, Sex Hormone-Binding Globulin, Testosterone, Biomarkers, 17-alpha-Hydroxyprogesterone

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Oral, transdermal and vaginal combined contraceptives induce an increase in markers of chronic inflammation and impair insulin sensitivity in young healthy normal-weight women: a randomized study

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