Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills?

Odlind, Viveca; Milsom, Ian; Persson, Ingemar; Victor, Arne

doi:10.1034/j.1600-0412.2002.810603.x

Cited by 71 publications

(81 citation statements)

References 55 publications

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“…SHBG increases have been suggested as a marker of VTE risk, an unsettled association [28–34]. In the present study, we found little association between SHBG or CBG increases and changes in the hemostatic variables or the systemic EE2 exposure.…”

Section: Discussioncontrasting

confidence: 80%

Clotting factor changes during the first cycle of oral contraceptive use

et al. 2016

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Objectives The risk of venous thromboembolism (VTE) is highest during the initial months of oral contraceptive (OC) use. We sought to evaluate the extent of hemostatic variable changes during the initial OC cycle and if such changes are related to systemic ethinyl estradiol (EE2) exposure. Study Design Participants provided multiple blood samples during a 21-day OC cycle (30 mcg EE2; 150 mcg levonorgestrel) and after a single dose following a wash-out period. Analytes included D-dimer, factor VIII activity, protein C total antigen and the hepatic proteins corticosteroid- and sex-hormone-binding globulins (CBG and SHBG). EE2 pharmacokinetic analyses related to the 24 hours after the first OC tablet (OC1) and at steady state (OC21). Results Seventeen women completed the study. D-dimer more than doubled by OC6 (p = 0.013) and remained elevated at OC21 (p=0.012). D-dimer levels within women varied widely from day-to-day. Factor VIII increased 27% by OC2 (p < 0.001), but declined to a 9% increase by OC21. Protein C increased only 6%. EE2 steady-state area-under-the-curve ranged from 488 to 1103 pg·h/mL; higher levels were not correlated with greater increases in clotting variables. CBG and SHBG increased significantly, but were not significantly correlated with levels of EE2 or with the hemostatic variables. Conclusions D-dimer increases during the first OC cycle were at least as great as increases seen with longer OC use. These results provide support for the increased VTE risk during initial OC use. The extreme variability in D-dimer levels may be an important component of this risk.

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Section: Discussioncontrasting

confidence: 80%

Clotting factor changes during the first cycle of oral contraceptive use

et al. 2016

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“…However, COCs containing other progestins produced much greater increases. The average increase in SHBG associated with COCs was 200–300% for those containing DSG or gestodene, 150% for those including norgestimate, 250–300% for those containing drospirenone or DNG, and 300–400% for cyproterone acetate-based COCs 23 . Although changes in SHBG levels in our study were similar between cyclic and extended LNG/EE regimens, a study comparing continuous 90 μg LNG/20 μg EE versus cyclic 100 μg LNG/20 μg EE reported greater SHBG rises with continuous LNG/EE than with cyclic LNG/EE 24 .…”

Section: Discussionmentioning

confidence: 99%

“…Among the secondary endpoints in our study, changes in SHBG levels with COCs are of particular interest given that they can be used to measure total oestrogenicity, which may predict VTE risk 23 . Odlind and colleagues analysed data retrieved from a non-systematic literature review plus data from EMA application files to investigate the relationship between the risk of VTE with COCs and their impact on SHBG levels 23 .…”

Section: Discussionmentioning

confidence: 99%

“…Odlind and colleagues analysed data retrieved from a non-systematic literature review plus data from EMA application files to investigate the relationship between the risk of VTE with COCs and their impact on SHBG levels 23 . In their study, VTE risk was estimated using an EMA assessment of VTE risk in COC users, which was based on an expert review of published reports.…”

Section: Discussionmentioning

confidence: 99%

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Multinational, multicentre, randomised, open-label study evaluating the impact of a 91-day extended regimen combined oral contraceptive, compared with two 28-day traditional combined oral contraceptives, on haemostatic parameters in healthy women

Nappi

Paoletti

Volpe

et al. 2014

The European Journal of Contraception & Reproductive Health

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ObjectivesTo evaluate the impact of a 91-day extended regimen combined oral contraceptive (150 μg levonorgestrel [LNG]/30 μg ethinylestradiol [EE] for 84 days, followed by 10 μg EE for seven days [Treatment 1]) compared with two traditional 21/7 regimens (21 days 150 μg LNG/30 μg EE [Treatment 2] or 150 μg desogestrel [DSG]/30 μg EE [Treatment 3], both with seven days’ hormone free), on several coagulation factors and thrombin formation markers.MethodsRandomised, open-label, parallel-group comparative study involving healthy women (18–40 years). The primary endpoint was change from baseline in prothrombin fragment 1 + 2 (F1 + 2) levels over six months.ResultsA total of 187 subjects were included in the primary analysis. In all groups, mean F1 + 2 values were elevated after six months of treatment. Changes were comparable between Treatments 1 and 2 (least squares mean change: 170 pmol/L and 158 pmol/L, respectively) but noticeably larger after Treatment 3 (least squares mean change: 592 pmol/L). The haemostatic effects of Treatment 1 were comparable to those of Treatment 2 and noninferior to those of Treatment 3 (lower limit of 95% confidence interval [− 18.3 pmol/L] > − 130 pmol/L).ConclusionsThe LNG/EE regimens had similar effects on F1 + 2. Noninferiority was demonstrated between extended regimen LNG/EE and DSG/EE.

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“…Therefore, the free drug concentration and distribution of GSD were known to be influenced by SHBG 23. Furthermore, it was found that COCs containing desogestrel or GSD cause an average SHBG increase of 200%–300%, which further complicates the disposition of GSD 24. Accordingly, it was reported that the concentrations of GSD during multiple dosing could not be predicted on the basis of single-dose pharmacokinetics 25.…”

Section: Discussionmentioning

confidence: 99%

An open-label, two-period comparative study on pharmacokinetics and safety of a combined ethinylestradiol/gestodene transdermal contraceptive patch

Zhang¹,

Li²,

Xiong³

et al. 2017

DDDT

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We investigated the pharmacokinetics and safety profiles of a newly developed combined ethinylestradiol (EE)/gestodene (GSD) transdermal contraceptive patch after a single-dose administration and compared with the market available tablet formulation in healthy adult subjects. An open-label, two-period comparative study was conducted in 12 healthy women volunteers. A single dose of the study combined EE/GE transdermal contraceptive patch and oral tablet (Milunet®) were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) assay method was developed in this study to determine the plasma concentrations of EE and GSD. Compared to the tablet, the study patch had a significantly decreased maximum plasma concentration (Cmax), extended time to reach the Cmax and half-life, as well as increased clearance and apparent volume of distribution. The half-lives of EE and GSD of the patch were 3.3 and 2.2 times, respectively, than the half-life of the tablet. The areas under the plasma concentration–time curve (AUCs) of EE and GSD of the patch were 8.0 and 16.2 times, respectively, than the AUC of the tablet. No severe adverse event was observed during the whole study, and the general safety was acceptable. In conclusion, compared to the oral tablet Milunet, the study contraceptive patch was well tolerated and showed potent drug exposure, significant extended half-life and stable drug concentrations.

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Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills?

Cited by 71 publications

References 55 publications

Clotting factor changes during the first cycle of oral contraceptive use

Clotting factor changes during the first cycle of oral contraceptive use

Multinational, multicentre, randomised, open-label study evaluating the impact of a 91-day extended regimen combined oral contraceptive, compared with two 28-day traditional combined oral contraceptives, on haemostatic parameters in healthy women

An open-label, two-period comparative study on pharmacokinetics and safety of a combined ethinylestradiol/gestodene transdermal contraceptive patch

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