Hormonal and metabolic responses across phases of combined oral contraceptive use and menstrual cycle in young elite female athletes

European Journal of Applied Physiology https://doi.org/10.1007/s00421-025-05745-x ORIGINAL ARTICLE Hormonal and metabolic responses across phases of combined oral contraceptive use and menstrual cycle in young elite female athletes Katia Collomp1,2,3,4 · Agnès Olivier5 · Caroline Teulier1,2 · Juliette Bonnigal5 · Nathalie Crépin4 · Corinne Buisson4 · Magnus Ericsson4 · Emmanuelle Duron6 · Eric Favory5 · Mathieu Zimmermann7 · Virgile Amiot7 · Carole Castanier1,2 Received: 26 September 2024 / Accepted: 18 February 2025 © The Author(s) 2025 Abstract Purpose Despite the significant number of female athletes using combined oral contraceptives (COCs), there is scant literature on their hormonal and metabolic effects across different phases. Methods In order to contribute to a wider knowledge of COC-action mechanisms involved in athletes’ performance and health, we therefore examined the effects of low-dose monophasic COC (ethinylestradiol/levonorgestrel) intake on sex hormones (estradiol, progesterone, sex hormone binding protein (SHBG)) as well as on a large number of pituitary (LH, TSH, prolactin) and peripheral (triiodothyronine, cortisol, DHEA, DHEA-S, aldosterone, osteocalcin, 25(OH)D) basal hormone levels in nine young elite female athletes, across COC administration (first and second half of active hormone intake, washout phases), compared to eleven female athletes without hormonal contraception across their normal menstrual cycle (NMC, i.e., early follicular, end follicular/peri-ovulatory, mid-luteal phases). Results COC vs. NMC increased SHBG (p < 0.01), TSH, cortisol and 25(OH)D (p < 0.05), and decreased DHEA and DHEAS (p < 0.05) concentrations. Across COC and NMC phases, higher estradiol and aldosterone concentrations (p < 0.05) were observed during the washout and mid-luteal phases, respectively. Conclusion In highly trained female athletes, COC vs. NMC induced several hormonal alterations, irrespective of the phases, leading to potential ergogenic and clinical repercussions that merit clarification. In NMC athletes, the impact of endogenous sex hormone fluctuations on the parameters studied appeared limited, perhaps mitigated by intense physical training, with only aldosterone change. Given the high prevalence of vitamin D insufficiency, it seems warranted to monitor this parameter, not yet routinely considered in female athletes, taking into account COC intake. Trial registration : ID-RCB:2020-A02965-34, France Communicated by Fabio Fischetti. * Katia Collomp 1 CIAMS, Université d’Orléans, Pôle STAPS, Orléans, France 2 CIAMS, Université Paris-Saclay, Orsay, France 3 Fédération SAPREM, Université d’Orléans, Orléans, France 4 LADF, Université Paris-Saclay, Orsay, France 5 IFCE, Cadre Noir, Saint‑Hilaire‑Saint‑Florent, Saumur, France 6 Hôpital Brousse, AP‑HP, Equipe INSERM MOODS-CESP, Villejuif, Kremlin‑Bicêtre, France 7 Médecine du Sport, CHU Orléans, Orléans, France Vol.:(0123456789) European Journal of Applied Physiology Graphical Abstract Keywords Ethinylestradiol/levonorgestrel · Sex-hormone status · Highly trained · TSH · Aldosterone · 25(OH)D Abbreviations ALD Aldosterone ANOVA Analyse of variance CBP Cortisol-binding protein COC Combined oral contraceptive COC0 Washout period (inactive hormone intake) COC1 First half of active hormone intake COC2 Second half of active hormone intake COR Cortisol DHEA Dehydroepiandrosterone DHEA-S Dehydroepiandrosterone-sulphate EE Ethinylestradiol E2 Estradiol FEI Free estradiol index FSH Follicle-stimulating hormone FT3 Free triiodothyronine HPG Hypothalamo-pituitary–gonadal LH Luteinizing hormone LVN Levonorgestrel NMC Normal menstrual cycle NMP1 Early follicular phase NMP2 End follicular/peri-ovulatory phase NMP3 Mid-luteal phase OST Osteocalcin PG Progesterone PRL Prolactin SEM Standard error of the mean SHBG Sex hormone binding protein TSH Thyroid-stimulating hormone 25(OH) D Calcidiol (25-hydroxyvitamin D) Introduction Between 20 and 70% of elite female athletes use hormonal contraception (Larsen et al. 2020; Martin et al. 2018; Oxfeldt et al. 2020), with a large majority opting for 2nd-generation combined oral contraceptives (COCs). These COCs, whether mono-, bi- or triphasic, contain synthetic estrogens and progestins, typically ethinylestradiol (EE) as the estrogen at concentrations between 20 and 50 μg per pill and levonorgestrel (LVN) as the progestin at concentrations of 50 to 150 μg (Castanier et al. 2021). They are administered for 21 days followed by a 7 day break (i.e., washout phase), with or without inactive non-hormonal pills, to mimic the menstrual cycle but without the peaks of estradiol (E2) and progesterone (PG), thus stabilising hormone levels through inhibition of the hypothalamo-pituitary-gonadal (HPG) axis and suppression of gonadotropin secretion produced by the pituitary gland, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). European Journal of Applied Physiology While COCs are known to significantly decrease E2 and PG, free and total blood testosterone, as well as dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEA-S), with a parallel increase in sex hormone-binding protein (SHBG) concentrations in healthy women (Coelingh Bennink et al. 2017; Enea et al. 2009; Knutsson et al. 2023), the literature on a female athlete population or on the other COC hormonal effects is sparse and lacking consensus. Indeed, few studies, most of which were carried out on nonphysically trained women and/or with higher COC doses, reported during the active hormonal pill phase an increase or not in prolactin (PRL), thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), cortisol (COR), aldosterone (ALD), osteocalcin (OST) and calcidiol (25(OH)D) (Aden et al. 1998; Kuhl et al. 1985a, 1985b; Özcan et al. 2023; Raps et al. 2014; Sawin et al. 1978; Weeke and Hansen 1975; Wiegratz et al. 2003). As these hormones directly or indirectly regulate metabolism, COC-induced changes may play a role in athletes' performance and health. Moreover, even fewer studies have explored potential modifications in hormonal and metabolic status during the COC washout phase (Aden et al. 1998; Ihalainen et al. 2021; Kuhl et al. 1985a; Martin et al. 2021; Rechichi et al. 2008; Weeke and Hansen 1975) and across the intake period, despite LVN concentrations only reaching a steady state in the second half of each active hormone intake treatment cycle (Kuhnz et al. 1992). In order to contribute to a wider knowledge of COCaction mechanisms in highly trained female athletes, we therefore aimed to examine the effects of low-dose monophasic COC (i.e. EE/LVN) intake on various pituitary and peripheral hormone secretions and metabolic responses in young elite female athletes, taking into account the phase of COC administration (first and second half of active hormone intake, and washout phases), compared to female athletes with a normal menstrual cycle ( (...truncated)