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Commentary| Volume 94, ISSUE 2, P104-108, August 2016

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The elusive minimum threshold concentration of levonorgestrel for contraceptive efficacy

      Progestins, either alone or in combination with ethinyl estradiol (EE), are a critical component of hormonal contraceptives. Levonorgestrel (LNG) has been extensively studied over decades and is considered to be a safe and highly effective progestin [
      • Ellertson C.
      History and efficacy of emergency contraception: beyond coca-cola. Journal [serial on the Internet].
      ]. However, the minimum threshold level of circulating LNG required for contraceptive efficacy is still uncertain.
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      References

        • Ellertson C.
        History and efficacy of emergency contraception: beyond coca-cola. Journal [serial on the Internet].
        Date: 1996
        (Date [cited 2014 8/14/2014]; 28(2): Available from:)
        • Croxatto H.B.
        NORPLANT: levonorgestrel-releasing contraceptive implant.
        Ann Med. 1993; 25: 155-160
        • Primiero F.M.
        • Benagiano G.
        Long-acting contraceptives.
        Raven Press, Ltd., New York1994
        • Bardin C.
        • Sivin I.
        Sitruk-Ware R. Bardin C. Norplant: the first implantable contraceptive. Mercel Dekker Inc., New York1992
        • Robertson D.N.
        • Sivin I.
        • Nash H.A.
        • Braun J.
        • Dinh J.
        Release rates of levonorgestrel from silastic capsules, homogeneous rods and covered rods in humans.
        Contraception. 1983; 27: 483-495
        • Olsson S.E.
        • Odlind V.
        • Johansson E.D.
        • Nordstrom M.L.
        Plasma levels of levonorgestrel and free levonorgestrel index in women using NORPLANT implants or two covered rods (NORPLANT-2).
        Contraception. 1987; 35: 215-228
        • Ohshima T.
        • Hasegawa T.
        • Johno I.
        • Kitazawa S.
        Variations in protein binding of drugs in plasma and serum.
        Clin Chem. 1989; 35: 1722-1725
        • El-Migdadi F.
        • Qaw F.
        Serum and plasma levels of total and free testosterone and of sex hormone binding globulins in rats growing in the below sea level environment of the jordan valley. Journal [serial on the Internet].
        Date: 2008
        (Date; 5(2): Available from:)
        • Croxatto H.B.
        • Diaz S.
        • Miranda P.
        • Elamsson K.
        • Johansson E.D.
        Plasma levels of levonorgestrel in women during long-term use of Norplant.
        Contraception. 1981; 23: 197-209
        • Stanczyk F.Z.
        • Roy S.
        Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids.
        Contraception. 1990; 42: 67-96
        • Stanczyk F.Z.
        • Hiroi M.
        • Goebelsmann U.
        • Brenner P.F.
        • Lumkin M.E.
        • Mishell Jr., D.R.
        Radioimmunoassay of serum d-norgestrel in women following oral and intravaginal administration.
        Contraception. 1975; 12: 279-298
        • Victor A.
        • Edqvist L.E.
        • Lindberg P.
        • Elamsson K.
        • Johansson E.D.
        Peripheral plasma levels of d-norgestrel in women after oral administration of d-norgestrel and when using intravaginal rings impregnated with dl-norgestrel.
        Contraception. 1975; 12: 261-278
      1. Measuring total plasma levonorgestrel (LNG) levels among users of contraceptive implants: a comparison of radioimmunoassay and mass spectrometry methods.
        in: Callahan R. Stanczyk F. Taylor D. Steiner M. Kopf G. Dorflinger L. Fertility control club hormonal contraception methods: from basic research to clinical practice. 2015 ([Barcelona, Spain])
        • Cherala G.
        • Edelman E.
        • Thornburg K.
        Traditional assay methodology, drug species, and perinatal growth: a perfect storm for oral contraceptive failure among obese women.
        J Womens Health. 2014; 23: 855
        • Stanczyk F.Z.
        • Clarke N.J.
        Advantages and challenges of mass spectrometry assays for steroid hormones.
        J Steroid Biochem Mol Biol. 2010; 121: 491-495
        • Smith D.A.
        • Di L.
        • Kerns E.H.
        The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery.
        Nat Rev Drug Discov. 2010; 9: 929-939
        • Thomson A.H.
        Introduction to clinical pharmacokinetics.
        Paediatr Perinat Drug Ther. 2000; 4: 3-11
        • Buccafusco J.J.
        • Letchworth S.R.
        • Bencherif M.
        • Lippiello P.M.
        Long-lasting cognitive improvement with nicotinic receptor agonists: mechanisms of pharmacokinetic-pharmacodynamic discordance.
        Trends Pharmacol Sci. 2005; 26: 352-360
        • Westhoff C.L.
        • Torgal A.H.
        • Mayeda E.R.
        • Pike M.C.
        • Stanczyk F.Z.
        Pharmacokinetics of a combined oral contraceptive in obese and normal-weight women.
        Contraception. 2010; 81: 474-480
        • Edelman A.B.
        • Carlson N.E.
        • Cherala G.
        • Munar M.Y.
        • Stouffer R.L.
        • Cameron J.L.
        • et al.
        Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic–pituitary–ovarian activity.
        Contraception. 2009; 80: 119-127
        • Edelman A.B.
        • Cherala G.
        • Munar M.Y.
        • Dubois B.
        • McInnis M.
        • Stanczyk F.Z.
        • et al.
        Prolonged monitoring of ethinyl estradiol and levonorgestrel levels confirms an altered pharmacokinetic profile in obese oral contraceptives users.
        Contraception. 2013; 87: 220-226
        • Edelman A.B.
        • Cherala G.
        • Munar M.Y.
        • McInnis M.
        • Stanczyk F.Z.
        • Jensen J.T.
        Correcting oral contraceptive pharmacokinetic alterations due to obesity: a randomized controlled trial.
        Contraception. 2014; 90: 550-556
        • Goldzieher J.W.
        • Stanczyk F.Z.
        Oral contraceptives and individual variability of circulating levels of ethinyl estradiol and progestins.
        Contraception. 2008; 78: 4-9
        • Garcia-Becerra R.
        • Cooney A.J.
        • Borja-Cacho E.
        • Lemus A.E.
        • Perez-Palacios G.
        • Larrea F.
        Comparative evaluation of androgen and progesterone receptor transcription selectivity indices of 19-nortestosterone-derived progestins.
        J Steroid Biochem Mol Biol. 2004; 91: 21-27
        • Hammond G.L.
        • Wu T.S.
        • Simard M.
        Evolving utility of sex hormone-binding globulin measurements in clinical medicine.
        Curr Opin Endocrinol Diabetes Obes. 2012; 19: 183-189
        • Xita N.
        • Tsatsoulis A.
        Genetic variants of sex hormone-binding globulin and their biological consequences.
        Mol Cell Endocrinol. 2010; 316: 60-65
        • Pugeat M.
        • Nader N.
        • Hogeveen K.
        • Raverot G.
        • Dechaud H.
        • Grenot C.
        Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome.
        Mol Cell Endocrinol. 2010; 316: 53-59
        • Stone J.
        • Folkerd E.
        • Doody D.
        • Schroen C.
        • Treloar S.A.
        • Giles G.G.
        • et al.
        Familial correlations in postmenopausal serum concentrations of sex steroid hormones and other mitogens: a twins and sisters study.
        J Clin Endocrinol Metab. 2009; 94: 4793-4800
        • Brache V.
        • Alvarez-Sanchez F.
        • Faundes A.
        • Tejada A.S.
        • Cochon L.
        Free levonorgestrel index and its relationship with luteal activity during long-term use of Norplant implants.
        Adv Contracept. 1992; 8: 319-326
        • Rinaldi S.
        • Geay A.
        • Dechaud H.
        • Biessy C.
        • Zeleniuch-Jacquotte A.
        • Akhmedkhanov A.
        • et al.
        Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations.
        Cancer Epidemiol Biomarkers Prev. 2002; 11: 1065-1071
        • Stanczyk F.Z.
        Diagnosis of hyperandrogenism: biochemical criteria.
        Best Pract Res Clin Endocrinol Metab. 2006; 20: 177-191
        • Buscher B.
        • Laakso S.
        • Mascher H.
        • Pusecker K.
        • Doig M.
        • Dillen L.
        • et al.
        Bioanalysis for plasma protein binding studies in drug discovery and drug development: views and recommendations of the European Bioanalysis Forum.
        Bioanalysis. 2014; 6: 673-682
        • Trivedi A.
        • Lee R.E.
        • Meibohm B.
        Applications of pharmacometrics in the clinical development and pharmacotherapy of anti-infectives.
        Expert Rev Clin Pharmacol. 2013; 6: 159-170
        • Kenna L.A.
        • Labbe L.
        • Barrett J.S.
        • Pfister M.
        Modeling and simulation of adherence: approaches and applications in therapeutics.
        AAPS J. 2005; 7: E390-E407
        • Dorlo T.P.
        • Balasegaram M.
        • Lima M.A.
        • de Vries P.J.
        • Beijnen J.H.
        • Huitema A.D.
        Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine.
        J Antimicrob Chemother. 2012; 67: 1996-2004