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

Sitruk-Ware, Regine; Nath, Anita

doi:10.1016/j.beem.2012.09.004

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

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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Estrogens have a positive effect on lipid metabolism, increasing HDL-C and decreasing LDL-C, while progestins, depending on their type and androgenicity, may counteract these positive estrogenic effects.
“Estrogens have a positive effect on lipid metabolism, increasing HDL-C and decreasing LDL-C, while progestins, depending on their type and androgenicity, may counteract these positive estrogenic effects [23-25] .”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [25]

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The polycystic ovary syndrome: a position statement from the European Society of Endocrinology
Conway, G., Dewailly, D., Diamanti-Kandarakis, E., Escobar-Morreale, H. F., Franks, S., Gambineri, A., Kelestimur, F., Macut, D., Micic, D., Pasquali, R., et al. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0253 · Cited by 676 · see citing works
Sex differences in lipids: a life course approach
Holven, K. B., & Roeters van Lennep, J. (2023) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2023.117270 · Cited by 180 · see citing works
Treatment strategies for women with polycystic ovary syndrome
Jin, P., & Xie, Y. (2017) · Gynecological Endocrinology · doi:10.1080/09513590.2017.1395841 · Cited by 175 · see citing works
“Some studies have found that ethinylestradiol has stronger effects on liver metabolism than natural estradiol, including the synthesis of SHBG, angiotensin, and some blood coagulation factors dependent on estrogen [22].”
Background
Cross-Sex Hormonal Treatment and Body Uneasiness in Individuals with Gender Dysphoria
Fisher, A. D., Castellini, G., Bandini, E., Casale, H., Fanni, E., Benni, L., Ferruccio, N., Meriggiola, M. C., Manieri, C., Gualerzi, A., et al. (2013) · The Journal of Sexual Medicine · doi:10.1111/jsm.12413 · Cited by 147 · see citing works
Combined hormonal contraceptives: prescribing patterns, compliance, and benefits versus risks
Brynhildsen, J. (2014) · Therapeutic Advances in Drug Safety · doi:10.1177/2042098614548857 · Cited by 143 · see citing works
“…the ethinyl group also changes the properties of the molecule making EE far more potent than E2 as EE does not bind to sex hormone-binding globulin (SHBG), is resistant to enzymatic degradation by 17-beta-hydroxylas and has a higher affinity for the estrogen receptor [Sitruk-Ware and Nath, 2013].”
Background
Cardiovascular disease in transsexual persons treated with cross-sex hormones: reversal of the traditional sex difference in cardiovascular disease pattern
Gooren, L. J., Wierckx, K., & Giltay, E. J. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0011 · Cited by 136 · see citing works
Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review
Asscheman, H., T'Sjoen, G. G., Lemaire, A., Mas, M., Meriggiola, M. C., Mueller, A., Kühn, A., Dhejne, C., Morel-Journel, N., & Gooren, L. J. (2013) · Andrologia · doi:10.1111/and.12150 · Cited by 133 · see citing works
“The prothrombotic effect of ethinyl oestradiol was ascribed to its molecular structure rather than to the first-pass liver effect which ethinyl oestradiol shares with all other types of oral oestrogens (Toorians et al., 2003; Sitruk-Ware & Nath, 2013).”
Background
Effects of hormonal contraception on systemic metabolism: cross-sectional and longitudinal evidence
Wang, Q., Würtz, P., Auro, K., Morin-Papunen, L., Kangas, A. J., Soininen, P., Tiainen, M., Tynkkynen, T., Joensuu, A., Havulinna, A. S., et al. (2016) · International Journal of Epidemiology · doi:10.1093/ije/dyw147 · Cited by 117 · see citing works
A Review on Sex Steroid Hormone Estrogen Receptors in Mammals and Fish
Amenyogbe, E., Chen, G., Wang, Z., Lü, X., Mingde, L., & Lin, A. Y. (2020) · International Journal of Endocrinology · doi:10.1155/2020/5386193 · Cited by 113 · see citing works
Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone
Klipping, C., Duijkers, I., Mawet, M., Maillard, C., Bastidas, A., Jost, M., & Foidart, J.-M. (2021) · Contraception · doi:10.1016/j.contraception.2021.01.001 · Cited by 108 · see citing works
A systematic review of the impact of oral contraceptives on cognition.
Warren, A. M., Gurvich, C., Worsley, R., & Kulkarni, J. (2014) · Contraception · doi:10.1016/j.contraception.2014.03.015 · Cited by 104 · see citing works
“The most commonly used estrogen analogue is ethinylestradiol [3], though recent innovation has seen the introduction of physiological forms of estrogen such as estradiol and estradiol valerate [4,5].”
Background
Role of Oxidative Stress in Obese and Nonobese PCOS Patients
Uçkan, K., Demir, H., Turan, K., Sarıkaya, E., & Demir, C. (2022) · International Journal of Clinical Practice · doi:10.1155/2022/4579831 · Cited by 97 · see citing works
“New generation endogenous estrogens, such as dienogest [47], 17-estradiol, estradiol valerate, and estetrol [48] reduce the risk of treatment.”
Approach to the Patient: Contraception in Women With Polycystic Ovary Syndrome
Yıldız, B. O. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3196 · Cited by 90 · see citing works
“Most of these side effects lessen significantly after the first few months of use (8).”
BackgroundInfluential
The scientific body of knowledge – Whose body does it serve? A spotlight on oral contraceptives and women’s health factors in neuroimaging
Taylor, C. M., Pritschet, L., & Jacobs, E. G. (2020) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2020.100874 · Cited by 88 · see citing works
“Almost all consist of a combination of two synthetic sex hormones, ethinyl estradiol and progestin, that act predominantly on endogenous sex steroid hormone receptors (Louw-du Toit et al., 2017; Sitruk-Ware and Nath, 2013).”
Background
MECHANISMS IN ENDOCRINOLOGY: Epidemiology of hormonal contraceptives-related venous thromboembolism
Hugon‐Rodin, J., Gompel, A., & Plu‐Bureau, G. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0527 · Cited by 80 · see citing works
Sources, concentrations, and exposure effects of environmental gestagens on fish and other aquatic wildlife, with an emphasis on reproduction
Orlando, E. F., & Ellestad, L. E. (2014) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2014.03.038 · Cited by 77 · see citing works
An Update on Contraception in Polycystic Ovary Syndrome
Oguz, S. H., & Yildiz, B. O. (2021) · Endocrinology and Metabolism · doi:10.3803/enm.2021.958 · Cited by 76 · see citing works
“EE use leads to increased synthesis of liver proteins including lipoproteins, angiotensinogen, and estrogen-dependent clotting factors [9], which are associated with the main adverse events attributed to COCs.”
BackgroundInfluential
A case–control analysis of oral contraceptive use and breast cancer subtypes in the African American Breast Cancer Epidemiology and Risk Consortium
Bethea, T. N., Rosenberg, L. A., Hong, C., Troester, M. A., Lunetta, K. L., Bandera, E. V., Schedin, P. S., Kolonel, L. N., Olshan, A. F., Ambrosone, C. B., et al. (2015) · Breast Cancer Research · doi:10.1186/s13058-015-0535-x · Cited by 74 · see citing works
“The estrogen and progestin composition of OCs has varied, with declining doses of hormones and new types of progestin introduced over time [40,60,61].”
Background
Environmental Gestagens Activate Fathead Minnow (Pimephales promelas) Nuclear Progesterone and Androgen Receptorsin Vitro
Ellestad, L. E., Cardon, M. C., Chambers, I. G., Farmer, J., Hartig, P. C., Stevens, K. E., Villeneuve, D. L., Wilson, V. S., & Orlando, E. F. (2014) · Environmental Science & Technology · doi:10.1021/es501428u · Cited by 65 · see citing works
Combined oral contraceptives and/or antiandrogens versus insulin sensitizers for polycystic ovary syndrome: a systematic review and meta-analysis
Luque-Ramírez, M., Nattero-Chávez, L., Ortiz Flores, A. E., & Escobar-Morreale, H. F. (2018) · Human Reproduction Update · doi:10.1093/humupd/dmx039 · Cited by 62 · see citing works
Oxidative Stress Is Increased in Combined Oral Contraceptives Users and Is Positively Associated with High-Sensitivity C-Reactive Protein
Cauci, S., Xodo, S., Buligan, C., Colannino, C., Barbina, M., Barbina, G., & Francescato, M. P. (2021) · Molecules · doi:10.3390/molecules26041070 · Cited by 61 · see citing works
“Abbreviations BMI Body mass index CI Confidence interval CVD Cardiovascular disease FORT Free oxygen radical test hsCRP High-sensitivity C-reactive protein IQR Interquartile range: from 25th to 75th percentile NF-kB Nuclear factor kappa-light-chain-enhancer of activated B cells Nrf2 Nuclear erytroid 2-like factor-2 OC…”
BackgroundInfluential
Interactions between Food and Drugs, and Nutritional Status in Renal Patients: A Narrative Review
D’Alessandro, C., Benedetti, A., Di Paolo, A., Giannese, D., & Cupisti, A. (2022) · Nutrients · doi:10.3390/nu14010212 · Cited by 66 · see citing works
“Steroidal anti-inflammatory drugs, estrogen-progestin preparations and antidiabetic drugs (both oral and injectable ones) affect glucose and/or fat metabolism [28].”
Background
Body Composition and Markers of Cardiometabolic Health in Transgender Youth Compared With Cisgender Youth
Nokoff, N., Scarbro, S. L., Moreau, K. L., Zeitler, P. S., Nadeau, K. J., Juarez‐Colunga, E., & Kelsey, M. M. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgz029 · Cited by 58 · see citing works
Effect of sex, menstrual cycle phase, and monophasic oral contraceptive pill use on local and central arterial stiffness in young adults
Priest, S. E., Shenouda, N., & MacDonald, M. J. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00039.2018 · Cited by 56 · see citing works
Oral contraceptives in the central nervous system: Basic pharmacology, methodological considerations, and current state of the field.
Hampson, E. (2022) · Frontiers in neuroendocrinology (Print) · doi:10.1016/j.yfrne.2022.101040 · Cited by 46 · see citing works
Dyslipidemia management in women of reproductive potential: An Expert Clinical Consensus from the National Lipid Association
Agarwala, A., Dixon, D. L., Gianos, E., Kirkpatrick, C. F., Michos, E. D., Satish, P., Birtcher, K. K., Braun, L. T., Pillai, P., Watson, K., et al. (2024) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2024.05.005 · Cited by 57 · see citing works
Effects of oral contraceptives on metabolic parameters in adult premenopausal women: a meta-analysis
Silva-Bermudez, L. S., Toloza, F. J. K., Perez-Matos, M. C., de Souza, R. J., Banfield, L., Vargas-Villanueva, A., & Mendivil, C. O. (2020) · Endocrine Connections · doi:10.1530/ec-20-0423 · Cited by 52 · see citing works
“Even though in observational studies gestodene induced significant increases in HDLc (2), our study showed a numerically marginal increase.”
Combined Oral Contraceptives Increase High-Sensitivity C-Reactive Protein but Not Haptoglobin in Female Athletes
Cauci, S., Francescato, M. P., & Curcio, F. (2016) · Sports Medicine · doi:10.1007/s40279-016-0534-9 · Cited by 49 · see citing works
“Additionally, we observed slightly reduced concentrations of alkaline phosphatase in OC users, this is likely due to the reduction of bone resorption produced by estrogens [39, 53].”
BackgroundResultInfluential
Aqueous exposure to the progestin, levonorgestrel, alters anal fin development and reproductive behavior in the eastern mosquitofish (Gambusia holbrooki)
Frankel, T., Meyer, M. T., & Orlando, E. F. (2016) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2016.01.007 · Cited by 47 · see citing works
Risk for Venous Thromboembolism in Transgender Patients Undergoing Cross-Sex Hormone Treatment: A Systematic Review
Kotamarti, V. S., Greige, N., Heiman, A. J., Patel, A., & Ricci, J. A. (2021) · The Journal of Sexual Medicine · doi:10.1016/j.jsxm.2021.04.006 · Cited by 46 · see citing works
Polycystic Ovary Syndrome
Sood, M., Zweig, S. B., Tolentino, M. C., Strizhevsky, M., & Poretsky, L. (2017) · Springer eBooks · doi:10.1007/978-3-319-18741-9_33 · Cited by 43 · see citing works
Risk of Venous Thromboembolism in Transgender People Undergoing Hormone Feminizing Therapy: A Prevalence Meta-Analysis and Meta-Regression Study
Totaro, M., Palazzi, S., Castellini, C., Parisi, A., D’Amato, F., Tienforti, D., Baroni, M. G., Francavilla, S., & Barbonetti, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.741866 · Cited by 43 · see citing works
Multicenter Analysis of Cardiometabolic-related Diagnoses in Transgender and Gender-Diverse Youth: A PEDSnet Study
Valentine, A., Davis, S., Furniss, A., Dowshen, N., Kazak, A. E., Lewis, C. S., Loeb, D. F., Nahata, L., Pyle, L. L., Schilling, L. M., et al. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac469 · Cited by 42 · see citing works
Hormonal contraceptive influences on cognition and psychopathology: Past methods, present inferences, and future directions
Beltz, A. M. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.101037 · Cited by 39 · see citing works
Discontinuation of modern hormonal contraceptives: an Italian survey
Fruzzetti, F., Perini, D., Fornaciari, L., Russo, M., Bucci, F., & Gadducci, A. (2016) · The European Journal of Contraception & Reproductive Health Care · doi:10.1080/13625187.2016.1234598 · Cited by 38 · see citing works
Comparative analysis of the effects of nomegestrol acetate/17 β-estradiol and drospirenone/ethinylestradiol on premenstrual and menstrual symptoms and dysmenorrhea
Witjes, H., Creinin, M. D., Poromaa, I. S., Nguyen, A. M., & Korver, T. (2015) · The European Journal of Contraception & Reproductive Health Care · doi:10.3109/13625187.2015.1016154 · Cited by 37 · see citing works
Oxidative Stress in Female Athletes Using Combined Oral Contraceptives
Cauci, S., Buligan, C., Marangone, M., & Francescato, M. P. (2016) · Sports Medicine - Open · doi:10.1186/s40798-016-0064-x · Cited by 36 · see citing works
“Future studies are warranted to assess if the observed blood rise of oxidative stress associated with OC use is estrogens and/or progestin related [22, 24, 41].”
BackgroundInfluential
Hormonal and natural contraceptives: a review on efficacy and risks of different methods for an informed choice
Genazzani, A. R., Fidecicchi, T., Arduini, D., Giannini, A., & Simoncini, T. (2023) · Gynecological Endocrinology · doi:10.1080/09513590.2023.2247093 · Cited by 35 · see citing works
“This capacity is lost from no-or anti-androgenic pro-gestins: this means that both the positive effect of estrogens on carbohydrate and lipid metabolism, and their stimulatory effects on coagulation factors are at their maximal expression with these pro-gestins [33].”
Background
Symptoms of mental disorders and oral contraception use: A systematic review and meta-analysis
Kraft, M. Z., Rojczyk, P., Weiß, T., Derntl, B., Kikinis, Z., Croy, I., & Heller, C. (2023) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2023.101111 · Cited by 38 · see citing works
The Effects of Hormonal Contraceptives on Glycemic Regulation
Cortés, M. E., & Alfaro, A. A. (2014) · The Linacre Quarterly · doi:10.1179/2050854914y.0000000023 · Cited by 34 · see citing works
Bisphenol A induces hepatic triglyceride level in adult male rare minnow Gobiocypris rarus
Mi, K., Chen, X., Lu, K., Zhu, Y., Zhang, M., Yang, H., Wei, W., & Zhang, Y. (2021) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2021.112050 · Cited by 34 · see citing works
Beyond a means of exposure: a new view of the mother in toxicology research
Catanese, M. C., Suvorov, A., & Vandenberg, L. N. (2014) · Toxicology Research · doi:10.1039/c4tx00119b · Cited by 34 · see citing works
Obesity and hormonal contraception: an overview and a clinician’s practical guide
Cipriani, S., Todisco, T., Scavello, I., Stasi, V. D., Maseroli, E., & Vignozzi, L. (2019) · Eating and Weight Disorders - Studies on Anorexia Bulimia and Obesity · doi:10.1007/s40519-019-00774-w · Cited by 37 · see citing works
Current use of combined hormonal contraception is associated with glucose metabolism disorders in perimenopausal women
Mosorin, M., Haverinen, A., Ollila, M., Nordström, T., Jokelainen, J. J., Keinanen-Kiukaanniemi, S. M., Puukka, K. S., Ruokonen, A., AUVINEN, J. P., Piltonen, T., et al. (2020) · European Journal of Endocrinology · doi:10.1530/eje-20-0406 · Cited by 33 · see citing works
Comparison of ESI– and APCI–LC–MS/MS methods: A case study of levonorgestrel in human plasma
Wang, R., Zhang, L., Zhang, Z., & Tian, Y. (2016) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2016.03.006 · Cited by 33 · see citing works
“As the use of oral contraceptives has increased globally, requirements of monitoring the pharmacokinetic behavior are gaining great importance [4].”
Background
Oral contraceptives and cognition: a systematic review.
Gurvich, C., Nicholls, I., Lavale, A., & Kulkarni, J. (2022) · Frontiers in neuroendocrinology (Print) · doi:10.1016/j.yfrne.2022.101052 · Cited by 29 · see citing works
Effects of hormonal contraceptive phase and progestin generation on stress-induced cortisol and progesterone release
Herrera, A. Y., Faude, S., Nielsen, S. E., Locke, M., & Mather, M. (2019) · Neurobiology of Stress · doi:10.1016/j.ynstr.2019.100151 · Cited by 30 · see citing works
“Some reports indicate that levonorgestrel increases LDL levels (Kiley and Hammond, 2007; Knopp et al., 2001; Sitruk-Ware and Nath, 2011, 2013) and decreases HDL (Bergink et al., 1982; Gaspard et al., 1985; Godsland et al., 1990; Kaupplnen-Makelln et al., 1992; Kiley and Hammond, 2007; McGuire et al., 1990; Ruokonen an…”
Influential
Influence of an oral contraceptive containing drospirenone on insulin sensitivity of healthy women
Cagnacci, A., Piacenti, I., Zanin, R., Xholli, A., & Tirelli, A. (2014) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2014.03.021 · Cited by 28 · see citing works
“Indeed, it has been reported that OCs containing ethynil-estradiol (EE) associatedwith androgenic 2nd and 3rd generation progestins, lead to a reduction of SI [3,4].”
Background
The effect of hormonal contraceptive therapy on clinical laboratory parameters: a literature review
Özcan, Ö., den Elzen, W. P. J., Hillebrand, J. J., den Heijer, M., van Loendersloot, L. L., Fischer, J., Hamer, H. M., de Jonge, R., & Heijboer, A. C. (2023) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm-2023-0384 · Cited by 27 · see citing works
“Although earlier progestins (norethindrone, MPA and CPA) could also affect metabolism [45], the latest progestin generations (NOMAC, DRSP and NES) essentially have no androgenic, estrogenic, or glucocorticoid-related adverse effects and no effects on fasting glucose or insulin levels [16, 43, 46].”
Oral Contraceptive Use does not Negatively Affect Body Composition and Strength Adaptations in Trained Women
Romance, R., Vargas-Molina, S., Espinar, S., Petro, J. L., Bonilla, D. A., Schoenfeld, B. J., Kreider, R. B., & Benítez‐Porres, J. (2019) · International Journal of Sports Medicine · doi:10.1055/a-0985-4373 · Cited by 29 · see citing works
“This is an important limiting factor, since differences have been observed in the type of contraceptive (monophasic vs triphasic) and in the dose/progestin used [6, 28].”
Background
Challenging Aspects of Research on the Influence of the Menstrual Cycle and Oral Contraceptives on Physical Performance
Hirschberg, A. L. (2022) · Sports Medicine · doi:10.1007/s40279-021-01616-5 · Cited by 28 · see citing works
Clinical effect of hormonal replacement therapy with estradiol associated with noretisterone or drospirenone. A prospective randomized placebo controlled study
Paoletti, A. M., Cagnacci, A., Carlo, C. D., Orrù, M., Neri, M., D’Alterio, M. N., & Melis, G. B. (2015) · Gynecological Endocrinology · doi:10.3109/09513590.2014.1003294 · Cited by 26 · see citing works
Pharmacodynamics of combined estrogen-progestin oral contraceptives 3. Inhibition of ovulation
Bastianelli, C., Farris, M., Rosato, E., Brosens, I. A., & Benagiano, G. (2018) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2018.1536544 · Cited by 26 · see citing works
“The well-known adverse effects of EE in COCs led to exploring the use of the natural hormone, estradiol-17β, because the use of natural estrogens has been hailed as capable of improving safety of COC with documented metabolic advantages [69].”
Background
Metabolic and laboratory effects of a progestin-only pill containing drospirenone 4 mg in comparison to desogestrel 75 µg: a double-blind, double-dummy, prospective, randomised study
Palacios, S., Colli, E., & Regidor, P. (2021) · The European Journal of Contraception & Reproductive Health Care · doi:10.1080/13625187.2021.1957094 · Cited by 25 · see citing works
“Depending on their pharmacological properties, they may counteract these positive oestrogenic effects [6,22,36]: COCs with a more androgenic progestin, such as LNG, show a decrease in HDL-cholesterol and an increase in LDL-Cholesterol, while COCs with rather anti-androgenic activity, such as DRSP, were shown to have a…”
Background
Tailored hormonal approach in women with premature ovarian insufficiency
Fruzzetti, F., Palla, G., Gambacciani, M., & Simoncini, T. (2019) · Climacteric · doi:10.1080/13697137.2019.1632284 · Cited by 24 · see citing works
The benefits of estetrol addition to drospirenone for contraception
Foidart, J. M., Gemzell‐Danielsson, K., Kubba, A., Douxfils, J., Creinin, M. D., & GASPARD, U. J. (2023) · AJOG Global Reports · doi:10.1016/j.xagr.2023.100266 · Cited by 23 · see citing works
Estradiol valerate in COC has more favorable inflammatory profile than synthetic ethinyl estradiol: a randomized trial
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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
“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 18 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
Hormonal Contraception and the Brain: Examining Cognition and Psychiatric Disorders
Laird, S., Ney, L., Felmingham, K., & Gogos, A. (2019) · Current Psychiatry Research and Reviews · doi:10.2174/1573400515666190521113841 · Cited by 18 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 15 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
“…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 · see citing works
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 11 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 10 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works

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 › Genetics › 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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