Cited by 239Reproductive Health and ContraceptionEstrogen and related hormone effectsOvarian function and disorders

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Effect of four different oral contraceptives on various sex hormones and serum-binding globulins

Wiegratz, I., Kutschera, E., Lee, J.H., Moore, C., Mellinger, U., Winkler, U.H., Kuhl, H.·2003·Contraception

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Abstract

In a double-blind, controlled, randomized, four-arm, bicentric clinical study, the effect of four oral contraceptives (OCs) on various hormone parameters and serum-binding globulins was investigated. Four groups with 25 volunteers each (18-35 years of age) were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 microg EE + 2 mg DNG (20EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 microg EE + 100 microg levonorgestrel (LNG) (EE/LNG). The study was completed by 91 subjects. Blood samples were taken after at least 12 h of fasting on Day 21-26 of the preceding control cycle and on Day 18-21 of the first, third and sixth treatment cycle. The serum concentrations of free testosterone were significantly decreased by about 40-60% in all four groups, while those of dehydroepiandrosterone sulfate (DHEAS) showed a time-dependent decrease during treatment. Except for EE/EV/DNG, which increased prolactin significantly during the third and sixth cycles, no change was observed with the EE-containing preparations. There was a significant increase in the levels of serum-binding globulins during treatment, which differed according to the composition of the OCs used. The rise in sex hormone-binding globulin (SHBG) was highest during intake of 30EE/DNG (+320%) and lowest with EE/LNG (+80%), while the effect of 20EE/DNG and EE/EV/DNG was similar (+270%). The thyroxine-binding globulin (TBG) levels increased significantly, by 50-60%, during treatment with the DNG-containing formulations, while the effect of EE/LNG was less significant (+30%). The rise in corticosteroid-binding globulin (CBG), which occurred in all groups, was most pronounced in women treated with 30EE/DNG (+90%) and least with EE/EV/DNG (+55%), indicating a strong influence of EE and no effect of the progestogen component. In all treatment groups, the frequency of intracyclic bleeding rose in the first treatment cycle and decreased thereafter. Cycle control was significantly better with 30EE/DNG or EE/LNG than with 20EE/DNG or EE/EV/DNG. There was no significant change in blood pressure, body mass index or pulse rate throughout the study. In conclusion, the DNG-containing OCs caused a higher rise in SHBG and TBG levels than the LNG-containing preparation. The effects on CBG suggest a lesser hepatic effect of 2 mg EV as compared to 20 or 30 microg EE. In contrast to EE, the use of estradiol in OCs appeared to increase prolactin release, while the cycle control was better with the OC containing 30 microg EE.

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Excess mortality in women with pituitary disease: a meta‐analysis
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Sex differences in cortisol levels in depression: A systematic review and meta-analysis
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Sex Hormones and Gender Role Relate to Gray Matter Volumes in Sexually Dimorphic Brain Areas
Pletzer, B. A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00592 · Cited by 55
Risks, benefits size and clinical implications of combined oral contraceptive use in women with polycystic ovary syndrome
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Effect of oral versus transdermal steroidal contraceptives on androgenic markers
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Human corticotropin releasing hormone test performance in the differential diagnosis between Cushing's disease and pseudo-Cushing state is enhanced by combined ACTH and cortisol analysis
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“Use of all COCs for 3–12 months, including EEþCPA, EEþDRSP and EEþCMA and EEþDSG increased SHBG levels (Tables 2–4 and Supplementary File 2).”
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Laboratory medicine: health evaluation in elite athletes
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“However, some factors affect androgen concentration such as oral contraceptive, which cause higher sex hormone binding globulin (SHBG) concentration [46], congenital adrenal hyperplasia associated with high testosterone levels and oligo- and amenorrhoea, usually linked with low androgen levels [30].”
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Analysis of baseline hypothalamic-pituitary-adrenal activity in late adolescence reveals gender specific sensitivity of the stress axis
Reynolds, R. M., Hii, H. L., Pennell, C. E., McKeague, I. W., Kloet, E. R. D., Lye, S., Stanley, F. J., Mattes, E., & Foster, J. K. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.11.010 · Cited by 42
“Finally, one in three Raine girls used oral contraceptives (OCs), which have been reported to enhance blood CBG and reduce free cortisol in adults (Kirschbaum et al., 1999; Wiegratz et al., 2003).”
Background
Relation of androgen receptor sensitivity and mood to sexual desire in hormonal contraception users
Elaut, E., Buysse, A., Sutter, P. D., Cuypere, G. D., Gerris, J., Deschepper, E., & T'Sjoen, G. G. (2011) · Contraception · doi:10.1016/j.contraception.2011.10.007 · Cited by 42
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Inflammation and Oral Contraceptive Use in Female Athletes Before the Rio Olympic Games
Larsen, B., Cox, A., Colbey, C., Drew, M., McGuire, H., Fazekas de St Groth, B., Hughes, D., Vlahovich, N., Waddington, G., Burke, L., et al. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00497 · Cited by 38
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Pharmacokinetic profile of nomegestrol acetate and 17β-estradiol after multiple and single dosing in healthy women
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Biosensor-based detection of reduced sex hormone-binding globulin binding capacities in response to growth-promoter administrations
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Biological sex differences in pharmacokinetics and adverse drug reactions
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“Additionally, AAG, which binds weakly basic drugs, displays lower levels in females due to lower synthesis mediated by estrogen (Englund et al. 2006; Wiegratz et al. 2003; Walle et al. 1983; Piafsky and Borga 1977; Kishino et al. 1995).”
Spironolactone for Hirsutism in Polycystic Ovary Syndrome
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The effect of oral contraceptives on the nitric oxide system and renal function
Cherney, D. Z. I., Scholey, J. W., Cattran, D. C., Kang, A. K., Zimpelmann, J., Kennedy, C., Lai, V., Burns, K. D., & Miller, J. A. (2007) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00351.2007 · Cited by 33
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Crewther, B. T., Hamilton, D. K., Casto, K. V., Kilduff, L. P., & Cook, C. J. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.04.017 · Cited by 34
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“Furthermore , oral contraceptives have been shown to produce enthinylestradiol-induced increases in corticosteroid binding globulin, which results in an increase total serum cortisol levels (Dhillo et al., 2002; Wiegratz et al., 2003a,b).”
No Associations Between Single Nucleotide Polymorphisms in Corticoid Receptor Genes and Heart Rate and Cortisol Responses to a Standardized Social Stress Test in Adolescents: The TRAILS Study
Bouma, E., Riese, H., Nolte, I. M., Oosterom, E., Verhulst, F. C., Ormel, J., & Oldehinkel, A. J. (2010) · Behavior Genetics · doi:10.1007/s10519-010-9385-6 · Cited by 33
“The underlying mechanism most likely involves the higher production of cortisol binding globuline (GBC) when estrogen levels are high (Wiegratz et al. 2003).”
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Evidence for a Non-Genomic Action of Testosterone in Skeletal Muscle Which may Improve Athletic Performance: Implications for the Female Athlete.
Dent, J. R., Fletcher, D. K., & McGuigan, M. R. (2012) · Europe PMC (PubMed Central) · Cited by 32
Biochemical and Physiological Aspects of Endogenous Androgens
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Estradiol Valerate/Dienogest: A Novel Combined Oral Contraceptive
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Hormonal Contraceptive Use Does Not Affect Strength, Endurance, or Body Composition Adaptations to Combined Strength and Endurance Training in Women
Myllyaho, M. M., Ihalainen, J. K., Hackney, A. C., Valtonen, M., Nummela, A. T., Vaara, E. M., Häkkinen, K., Kyröläinen, H., & Taipale, R. S. (2018) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0000000000002713 · Cited by 31
“Hormonal contraceptives reduce the levels of total and free testosterone by inhibiting ovarian and adrenal androgen synthesis and by increasing levels of sex hormone-binding globulin (SHBG) (29, 37, 39).”
BackgroundInfluential
The effect of a drospirenone-containing combined oral contraceptive on female sexual function: a prospective randomised study
Čiaplinskienė, L., Žilaitienė, B., Verkauskienė, R., Žalinkevičius, R., Bumbulienė, Ž., Vanagienė, V., & Bitzer, J. (2016) · The European Journal of Contraception & Reproductive Health Care · doi:10.1080/13625187.2016.1217324 · Cited by 33
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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 31
Effects of oral contraceptives and natural menstrual cycling on environmental learning
Bianchini, F., Verde, P., Colangeli, S., Boccia, M., Strollo, F., Guariglia, C., Bizzarro, G., & Piccardi, L. (2018) · BMC Women s Health · doi:10.1186/s12905-018-0671-4 · Cited by 27
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Influence of Menstrual Cycle or Hormonal Contraceptive Phase on Energy Intake and Metabolic Hormones—A Pilot Study
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Polymorphisms and Haplotypes in the Cytochrome P 450 17A1, Prolactin, and Catechol- O -Methyltransferase Genes and Non-Hodgkin Lymphoma Risk
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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 35
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Clotting factor changes during the first cycle of oral contraceptive use
Westhoff, C. L., Eisenberger, A. B., Tang, R., Cremers, S., Liu, L. G., & Pike, M. C. (2015) · Contraception · doi:10.1016/j.contraception.2015.09.015 · Cited by 27
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Maintaining physiologic testosterone levels during combined oral contraceptives by adding dehydroepiandrosterone: II. Effects on sexual function. A phase II randomized, double-blind, placebo-controlled study
van Lunsen, R. H. W., Zimmerman, Y., Bennink, H. J. T. C., Termeer, H. M. M., Appels, N., Fauser, B. C. J. M., & Laan, E. T. M. (2018) · Contraception · doi:10.1016/j.contraception.2018.02.014 · Cited by 27
Modeling hormonal contraception in female rats: A framework for studies in behavioral neurobiology
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“…are comparable to those in men, but women have significantly lower cortisol responses when in the follicular phase or are taking oral contraceptives (Kirschbaum et al., 1999; Rohleder et al., 2001; Wolf et al., 2001), which appear to affect cortisol binding globulins (CBG) (Wiegratz et al., 2003).”
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Ethinylestradiol/Dienogest in Oral Contraception
Pérez-Campos, E. F. (2010) · Drugs · doi:10.2165/11536320-000000000-00000 · Cited by 27
Is There an Association Between Contraception and Sexual Dysfunction in Women? A Systematic Review and Meta-analysis Based on Female Sexual Function Index
Huang, M., Li, G., Liu, J., Li, Y., & Du, P. (2020) · The Journal of Sexual Medicine · doi:10.1016/j.jsxm.2020.06.008 · Cited by 26

Authors: Wiegratz, I., Kutschera, E., Lee, J. H., Moore, C., Mellinger, U., Winkler, U. H., & Kuhl, H.
Affiliations: Goethe University Frankfurt (DE)
Venue: Contraception
Publisher: Elsevier BV
Published: 2003-01
Volume: 67
Issue: 1
Pages: 25-32
ISSN: 0010-7824 (ISSN-L)
DOI: 10.1016/s0010-7824(02)00436-5
OpenAlex: W2002526921
Cited by: 239
References: 40
Citations by year: 2026: 6 · 2025: 10 · 2024: 10 · 2023: 10 · 2022: 12 · 2021: 10 · 2020: 13 · 2019: 14 · 2018: 9 · 2017: 8 · 2016: 13 · 2015: 13 · 2014: 10 · 2013: 12 · 2012: 13
FWCI: 7.11
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Contraception (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 › Reproductive Medicine › Ovarian function and disorders
Keywords: oral contraceptives, sex hormones, sex hormone-binding globulin, ethinyl estradiol, dienogest, estradiol valerate, levonorgestrel, free testosterone, dehydroepiandrosterone sulfate, prolactin, thyroxine-binding globulin, corticosteroid-binding globulin
MeSH terms: Adolescent, Adult, Contraceptives, Oral, Double-Blind Method, Estradiol, Ethinyl Estradiol, Female, Humans, Nandrolone, Reference Values, Sex Hormone-Binding Globulin, Gonadal Steroid Hormones, Testosterone, Thyroxine-Binding Proteins, Treatment Outcome, Levonorgestrel, Dehydroepiandrosterone Sulfate

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Effect of four different oral contraceptives on various sex hormones and serum-binding globulins

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