Cited by 247Reproductive Health and ContraceptionEstrogen and related hormone effectsMenopause: Health Impacts and Treatments

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Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills

Sitruk-Ware, Regine, Nath, Anita·2013·Best Practice & Research Clinical Endocrinology & Metabolism

DOI 10.1016/j.beem.2012.09.004

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Abstract

Estrogen and progestins have been used by millions of women as effective combined oral contraceptives. Oral contraceptives (OCs) modify surrogate markers such as lipoproteins, insulin response to glucose, and coagulation factors, that have been associated with cardiovascular and venous risk. Ethinyl-Estradiol (EE) exerts a stronger effect that natural estradiol (E2) on hepatic metabolism. New progestins with high specificity have been designed to avoid interaction with other receptors and prevent androgenic, estrogenic or glucocorticoid related side-effects. The risks and benefits of new progestins used in contraception depend upon their molecular structure, the type and dose of associated estrogen, and the delivery route. The lower impact of E2-based combinations on metabolic surrogate markers may result in an improved safety profile, but only clinical outcomes are relevant to assess the risk. Large surveillance studies are warranted to confirm this hypothesis.

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Kangasniemi, M. H., Haverinen, A., Luiro, K., Hiltunen, J. K., Komsi, E. K., Arffman, R. K., Heikinheimo, O., Tapanainen, J. S., & Piltonen, T. T. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa186 · Cited by 22
Hormone-based models for comparing menstrual cycle and hormonal contraceptive effects on human resting-state functional connectivity
Casto, K. V., Jordan, T. R., & Petersen, N. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.101036 · Cited by 24
“As a result, OC use significantly inhibits hypothalamic-pituitary-ovarian activity, effectively reducing overall serum levels of endogenous progesterone and estradiol (Porcu et al., 2019; Rapkin et al., 2006; Sitruk-Ware & Nath, 2013).”
Background
Association between Reproductive Factors and Age-Related Macular Degeneration in Postmenopausal Women: The Korea National Health and Nutrition Examination Survey 2010-2012
Cho, B., Heo, J. W., Shin, J. P., Ahn, J., Kim, T. W., & Chung, H. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102816 · Cited by 21
“OCP increase the levels of prothrombin fragments, fibrinogen, plasmin–antiplasmin complex, and protein C activity, and decrease antithrombin activity and the level of tissue-plasminogen activator [27,28].”
Background
Hormone phase influences sympathetic responses to high levels of lower body negative pressure in young healthy women
Usselman, C. W., Nielson, C. A., Luchyshyn, T. A., Gimon, T. I., Coverdale, N. S., Uum, S. H. M. V., & Shoemaker, J. K. (2016) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00190.2016 · Cited by 20
“The effects of synthetic estrogens, such as those in HCs, may be stronger than those exerted by endogenous estradiol (44), indicating a potential mechanism by which vascular reactivity may be more impaired in women using HCs relative to women in the ML phase of the menstrual cycle.”
L-glutamine ameliorates adipose-hepatic dysmetabolism in OC-treated female rats
Olaniyi, K. S., & Olatunji, L. A. (2020) · Journal of Endocrinology · doi:10.1530/joe-19-0582 · Cited by 20
Heterogeneous Circulating Angiogenic Cell Responses to Acute Maximal Exercise
Shill, D. D., Marshburn, M. P., Hempel, H. K., Lansford, K. A., & Jenkins, N. T. (2016) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000001029 · Cited by 18
“Synthetic sex hormone-based contraceptive therapies maintain low concentrations of endogenous estrogen and progesterone throughout the menstrual cycle, and have been shown to alter metabolism, hemostasis, and vascular function (6,32).”
Background
Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial
Kangasniemi, M. H., Arffman, R. K., Joenväärä, S., Haverinen, A., Luiro, K., Tohmola, T., Renkonen, R., Heikinheimo, O., Tapanainen, J. S., & Piltonen, T. T. (2023) · Human Reproduction · doi:10.1093/humrep/deac250 · Cited by 19
“As the progestin component of COCs modulates the estrogen effects, the net effect of a COC depends on both the type of estrogen and the properties of the progestin (Sitruk-Ware and Nath, 2013; Abou-Ismail et al., 2020).”
BackgroundInfluential
Hormonal contraceptives as disruptors of competitive behavior: Theoretical framing and review
Arthur, L. C., Casto, K. V., & Blake, K. R. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.101015 · Cited by 20
ADVERSE EFFECT OF COMBINED ORAL CONTRACEPTIVE PILLS
Shukla, A., Jamwal, R., & Bala, K. (2016) · Asian Journal of Pharmaceutical and Clinical Research · doi:10.22159/ajpcr.2017.v10i1.14565 · Cited by 18
“Besides, progestin-only contraceptive pills are a contraceptive method that may be the better option for women with several routes of administration are available these days [6].”
Background
Ethinyl estradiol vs estradiol valerate in combined oral contraceptives—effect on glucose tolerance: a randomized, controlled clinical trial
Haverinen, A., Kangasniemi, M., Luiro, K., Piltonen, T., Heikinheimo, O., & Tapanainen, J. S. (2021) · Contraception · doi:10.1016/j.contraception.2020.10.014 · Cited by 17
Effects of oral contraceptives on spatial cognition depend on pharmacological properties and phase of the contraceptive cycle
Hampson, E., Morley, E. E., Evans, K. L., & Fleury, C. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.888510 · Cited by 17
“The estrane- and early gonane-based OCs used in Study 1 have stronger androgenic effects in vivo (but often contain higher doses of EE2) than many OCs based on 3 or 4 generation progestins (10, 66), some of which have anti-androgen effects at concentrations used therapeutically (e.”
Background
Oestrogens in oral contraception: considerations for tailoring prescription to women’s needs
Fruzzetti, F., Fidecicchi, T., & Gambacciani, M. (2024) · The European Journal of Contraception & Reproductive Health Care · doi:10.1080/13625187.2024.2334350 · Cited by 18
Hormonal Contraception and the Brain: Examining Cognition and Psychiatric Disorders
Laird, S., Ney, L. J., Felmingham, K. L., & Gogos, A. (2019) · Current Psychiatry Research and Reviews · doi:10.2174/1573400515666190521113841 · Cited by 19
Are the Effects of Oral and Vaginal Contraceptives on Bone Formation in Young Women Mediated via the Growth Hormone-IGF-I Axis?
Allaway, H. C. M., Misra, M., Ricker, E. A., Stone, M. S., Weaver, C. M., Petkus, D. L., & Souza, M. J. D. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00334 · Cited by 16
“However, COC use may result in reduced hepatic IGF-I synthesis in young women (18, 19), likely due to the “first pass effect,” by which EEmetabolism in the liver decreases hepatic synthesis of IGF-I (20).”
Background
Anthropometric indices, blood pressure, and lipid profile status among women using progestin-only contraceptives: comparative cross-sectional study
Shiferaw, M., Kassahun, W. D., & Zawdie, B. (2021) · BMC Women s Health · doi:10.1186/s12905-021-01178-8 · Cited by 16
Prevalence of type 2 diabetes mellitus compared between lean and overweight/obese patients with polycystic ovarian syndrome: a 5-year follow-up study
Chantrapanichkul, P., Indhavivadhana, S., Wongwananuruk, T., Techatraisak, K., Dangrat, C., & Sa‐nga‐areekul, N. (2020) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-019-05423-2 · Cited by 16
DIAGNOSIS OF ENDOCRINE DISEASE: Drug-induced endocrinopathies and diabetes: a combo-endocrinology overview
Diamanti‐Kandarakis, E., Duntas, L. H., Kanakis, G., Kandaraki, E., Karavitaki, N., Kassi, E. N., Livadas, S., Mastorakos, G. P., Migdalis, I. N., Miras, A. D., et al. (2019) · European Journal of Endocrinology · doi:10.1530/eje-19-0154 · Cited by 15
Can We Measure the Individual Prothrombotic or Prohemorrhagic Tendency by Global Coagulation Tests?
Reda, S., Morimont, L., Douxfils, J., & Rühl, H. (2020) · Hämostaseologie · doi:10.1055/a-1153-5824 · Cited by 17
Brazilian Guideline on Menopausal Cardiovascular Health – 2024
de Oliveira, G. M. M., de Almeida, M. C. C., Artucio, C., Espíndola, L. N., Rivera, M. A. M., Filho, A. L. D. S., Marques-Santos, C., Fernandes, C. E., Albuquerque, C. J. D. M., Freire, C. M. V., et al. (2024) · Arquivos Brasileiros de Cardiologia · doi:10.36660/abc.20240478i · Cited by 17
Needs and preferences of women users of oral contraceptives in selected countries in Central and Eastern Europe
Fait, T., Buryak, D., Cirstoiu, M.-M., Luczai, E., & Janczura, R. (2018) · Drugs in Context · doi:10.7573/dic.212510 · Cited by 14
Alopecia due to high androgen index contraceptives
Graves, K. Y., Smith, B. J., & Nuccio, B. C. (2018) · JAAPA · doi:10.1097/01.jaa.0000541476.24116.c4 · Cited by 13
Intraoperative Blood Loss in Female Patients with Adolescent Idiopathic Scoliosis during Different Phases of the Menstrual Cycle
Li, C., Xie, Y., Li, Z., Yang, M., Sun, X., Fan, J., Zhu, H. Y. X., Wang, C., & Li, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0112499 · Cited by 13
“We speculate that the reason for this may be the consumption during menstruation and the relatively low level of sex hormone during menstruation, since oral estrogen increases fibrinogen concentration in blood [41, 42].”
Background
The Impact of Ethinyl Estradiol on Metformin Action on Prolactin Levels in Women with Hyperprolactinemia
Krysiak, R. G., Szkróbka, W., & Okopień, B. (2019) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-0921-6420 · Cited by 13
Serum Metabolome Changes in Relation to Prothrombotic State Induced by Combined Oral Contraceptives with Drospirenone and Ethinylestradiol
Swanepoel, A. C., Bester, J., Emmerson, O., Soma, P., Beukes, D., van Reenen, M., Loots, D. T., & du Preez, I. (2020) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2020.0009 · Cited by 13
“…synthesis to a greater extent than some of the natural estrogens and can induce powerful stimulation of liver proteins and coagulation factors especially when combined with an anti-androgenic progestin, such as DRSP, which cannot fully counteract the effects of EE (Sitruk-Ware and Nath, 2013).”
Pooled analysis of bleeding profile, efficacy and safety of oral oestradiol valerate/dienogest in women aged 25 and under
Jensen, J. T., Bitzer, J., Nappi, R. E., Ahlers, C., Bannemerschult, R., & Parke, S. (2020) · The European Journal of Contraception & Reproductive Health Care · doi:10.1080/13625187.2020.1731734 · Cited by 12
Herbal supplements interactions with oral oestrogen‐based contraceptive metabolism and transport
Hlengwa, N., Muller, C. J. F., Basson, A. K., Bowles, S., Louw, J., & Awortwe, C. (2020) · Phytotherapy Research · doi:10.1002/ptr.6623 · Cited by 13
“This led to structural modification in the synthesis of the steroid hormones that did not exert these secondary unwanted effects (Sitruk-Ware & Nath, 2013).”
Background
A safety evaluation of current medications for adult women with the polycystic ovarian syndrome not pursuing pregnancy
Luque‐Ramírez, M., Ortiz-Flores, A. E., Nattero‐Chávez, L., & Escobar-Morreale, H. F. (2020) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2020.1839409 · Cited by 11
Reproductive drugs and environmental contamination: quantum, impact assessment and control strategies
Kaur, H., Bala, M., & Bansal, G. (2018) · Environmental Science and Pollution Research · doi:10.1007/s11356-018-2754-z · Cited by 11
Reproductive factors, genetic susceptibility and risk of type 2 diabetes: A prospective cohort study
Fan, G., Liu, Q., Bi, J., Qin, X., Fang, Q., Luo, F., Huang, X., Li, H., Wang, Y., & Song, L. (2024) · Diabetes & Metabolism · doi:10.1016/j.diabet.2024.101560 · Cited by 10
l-glutamine supplementation exerts cardio-renal protection in estrogen-progestin oral contraceptive-treated female rats
Olaniyi, K. S., Sabinari, I. W., & Olatunji, L. A. (2019) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2019.103305 · Cited by 11
Use of contraception before and after a diabetes diagnosis: An observational matched cohort study
Horwitz, M. E. M., Pace, L. E., Schwarz, E. B., & Ross‐Degnan, D. (2021) · Primary care diabetes · doi:10.1016/j.pcd.2021.02.012 · Cited by 10
Testosterone, Athletic Context, Oral Contraceptive Use, and Competitive Persistence in Women
Casto, K., Arthur, L. C., Hamilton, D. K., & Edwards, D. A. (2021) · Adaptive Human Behavior and Physiology · doi:10.1007/s40750-021-00180-6 · Cited by 10
Heme-nitrosylated hemoglobin and oxidative stress in women consuming combined contraceptives. Clinical application of the EPR spectroscopy
Lobysheva, I. I., Eeckhoudt, S. V., Zotti, F. D., Rifahi, A., Pothen, L., Beauloye, C., & Balligand, J. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.03.039 · Cited by 10
“The estrogenic component of CPs was shown to increase hepatic metabolism with higher production of lipoproteins and of procoagulant proteins depending on the potency of the estrogen; similar adverse effects proportional to the androgenicity of the progestins have been observed [15,16].”
Background
Does dietary exposure to 17α-ethinylestradiol alter biomarkers related with endocrine disruption and oxidative stress in the adult triploid of Danio rerio?
Weiserova, Z., Blahová, J., Dobukova, V., Maršálek, P., Hodkovicová, N., Lenz, J., Tichý, F., Franěk, R., Pšenička, M., Franc, A., et al. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.161911 · Cited by 9
Nomegestrol acetate/17-beta estradiol: a review of efficacy, safety, and patient acceptability
Akintomide, H., & Panicker, S. (2015) · Open Access Journal of Contraception · doi:10.2147/oajc.s61942 · Cited by 9
“32 No remarkable changes in the blood pressure measurements from baseline were observed in the two 1-year comparison studies conducted across Europe, Asia and Australia, 20 and the Americas 19 involving a total of 2,130 women who used NOMAC/E2.”
Organokines and liver enzymes in adolescent girls with polycystic ovary syndrome during randomized treatments
García-Beltrán, C., Peyrou, M., Navarro‐Gascon, A., López‐Bermejo, A., de Zegher, F., Villarroya, F., & Ibáñez, L. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1325230 · Cited by 8
“However, this approach has a limited capacity to improve metabolic status (3, 25, 26) and may cause sustained unfavorable changes in hepatic markers (25, 27).”
Background
High prevalence of insulin resistance assessed by the glucose clamp technique in hormonal and non-hormonal contraceptive users
Melhado‐Kimura, V., Alegre, S. M., Pavin, E. J., dos Santos, P. D. N. S., Bahamondes, L. G., & Fernandes, A. M. D. S. (2014) · The European Journal of Contraception & Reproductive Health Care · doi:10.3109/13625187.2014.961599 · Cited by 8
Oxidative Stress in Polycystic Ovary Syndrome: Impact of Combined Oral Contraceptives
Santander, N. G., Figueroa, E. G., González‐Candia, A., Maliqueo, M. A., Echiburú, B., Crisosto, N., & Salas‐Pérez, F. (2024) · Antioxidants · doi:10.3390/antiox13101168 · Cited by 8
Late Effects of Parasellar Lesion Treatment: Hypogonadism and Infertility
Sbardella, E., Minnetti, M., Pofi, R., Cozzolino, A., Greco, E., Gianfrilli, D., & Isidori, A. M. (2020) · Neuroendocrinology · doi:10.1159/000508107 · Cited by 8
Epidemiological Survey on the Perception of Adverse Effects in Women Using Contraceptive Methods in Brazil
Pannain, G. D., Rodrigues, V. D. O., Abreu, M., & Lima, G. B. (2022) · Revista Brasileira Ginecologia e Obstetrícia · doi:10.1055/s-0041-1741410 · Cited by 8
“6 Even though both types of pills can inhibit follicle-stimulating hormone (FSH) and luteinizing hormone (LH) suf ﬁ - ciently to prevent ovulation, the combined pills have greater antigonadotrophic and ovulation-inhibition effects.”
Background
Polycystic Ovary Syndrome
Sood, M., Zweig, S. B., Tolentino, M. C., Strizhevsky, M., & Poretsky, L. (2015) · Springer eBooks · doi:10.1007/978-3-319-20797-1_33-1 · Cited by 8
In vitro effects of estrogen and progesterone containing drugs on human erythrocyte carbonic anhydrase I and II isozymes in women smokers and nonsmokers
Taşkın, M. İ., Bilen, Ç., Ergün, A., Gençer, N., & Inceboz, U. S. (2015) · Journal of the Chinese Medical Association · doi:10.1016/j.jcma.2015.03.014 · Cited by 8
“New progestins with high specificity have been designed to avoid interaction with other receptors and prevent androgenic, estrogenic, or glucocorticoid related side effects, and to prevent other undesirable side-effects especially on lipoproteins, clotting factors, and insulin sensitivity.(6) Cigarette smoking (CS) is…”
Background
A current perspective into young female sex hormone replacement: a review
Giordano Imbroll, M., & Gruppetta, M. (2020) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2020.1816820 · Cited by 7

Authors: Sitruk-Ware, R., & Nath, A.
Affiliations: Population Council (US)
Corresponding author: Sitruk-Ware, Regine
ORCID: Sitruk-Ware, Regine
Nath, Anita
Venue: Best Practice & Research Clinical Endocrinology & Metabolism
Publisher: Elsevier BV
Published: 2013-02
Volume: 27
Issue: 1
Pages: 13-24
ISSN: 1521-690X (ISSN-L)
DOI: 10.1016/j.beem.2012.09.004
OpenAlex: W2101802759
Cited by: 247
References: 79
Citations by year: 2026: 14 · 2025: 17 · 2024: 23 · 2023: 45 · 2022: 18 · 2021: 24 · 2020: 22 · 2019: 19 · 2018: 9 · 2017: 12 · 2016: 12 · 2015: 12 · 2014: 17 · 2013: 3
FWCI: 1.58
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Best Practice & Research Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
Keywords: oral contraceptives, ethinyl estradiol, progestins, hepatic metabolism, lipoproteins, insulin response, coagulation factors, cardiovascular risk, venous thromboembolism, contraceptive safety
MeSH terms: Contraceptives, Oral, Hormonal, Estrogens, Female, Humans, Progestins

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Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills

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