Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives

Giuseppe Benagiano, Sabina Carrara, Valentina Filippi, Giuseppe Benagiano, Sabina Carrara, Valentina Filippi

Abstract

The progestational steroid norgestrel was synthesized and tested between 1960 and 1965 through an international cooperation between Wyeth, USA and Schering, Berlin. It is a mixture of two "enantiomers," with only one form (designated as levonorgestrel) biologically active. When taken orally, it is rapidly absorbed, not subjected to a "first-pass" effect and is approximately 90% bioavailable, with a circulating half-life around 15 hours. Its contraceptive action is exerted at the central (hypothalamic) and peripheral (cervical mucus and endometrium) levels. Levonorgestrel (LNG), alone or in combination with ethinyl estradiol (EE), is the most widely employed contraceptive progestin: it is used in combined oral contraceptives, progestogen-only pills, long-acting contraceptive implants, intrauterine contraceptive systems and in emergency contraception. It is also the steroid of choice for new oral contraceptive regimens aimed at reducing the frequency of bleeding episodes. This novel approach, already tried more than 30 years ago, gained interest around the year 2000 when surveys of women's attitudes toward monthly menstrual bleeding started to show a major change: more and more women declared that they would welcome a hormonal contraceptive method that reduced bleeding episodes to 4, 2 or even 1 per year. At this point, while the debate on the significance and "usefulness" of menstruation went on, attention focused on new regimens. The first new modality consisted of changing the 7-day medication-free interval, either shortening it to fewer than 7 days, or by the administration of low-dose estrogens during the interval between packages. Then, continuous administration regimens started to be investigated. This, however, did not happen suddenly, since, in specific situations, doctors had for years empirically utilized various continuous administration regimens. The first extended-cycle oral contraceptive regimen introduced in clinical practice is an 84-day regimen that results in bleeding only 4 times a year. A commercial product specifically packed for continuous use is now available in Europe and contains 30 mug EE and 150 mug LNG. In a variation of this regimen, after administration of the same combination for 84 days, women are given 7 pills containing 10 mug EE. A 6-monthly regimen has also been tested in a small study using EE 20 mug plus LNG 100 mug taken with and without a hormone-free interval. Women in the continuous group reported significantly fewer bleeding days requiring protection and were more likely to have amenorrhea; in addition they also reported significantly fewer days of bloating and menstrual pain. A yearly regimen is now being developed. Each pill of this novel formulation contains EE 20 mug and LNG 90 mug to be taken continuously for 364 days (13 cycles) per year. A phase III trial has now evaluated safety, efficacy and menses inhibition. At the end of the 1-year trial amenorrhea was present in 58.7% of the women and a complete absence of bleeding in 79.0%. Overall, the number of bleeding and spotting days per pill pack declined with time and adverse events and discontinuations were comparable to those reported for cyclic oral contraceptive regimens.

Keywords: amenorrhea; continuous administration; levonorgestrel; menstruation; oral contraceptive.

Figures

Figure 1
Figure 1
Norgestrel: 8R,9S,10R,13S,14S,17S-13-ethyl-17-ethynyl-17-hydroxy- 1, 2, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16-dodecahydrocyclopenta[a]phenanthren-3-one.
Figure 2
Figure 2
The “Progestogen Tree.” Abbreviations: CMA, chlormadinone acetate; CPA, cyproterone acetate; DNG, dienogest; DRSP, drospirenone; DSG, desogestrol; GST, gestodenes; MGA, megestrol acetate; LNG, levonorgestrol; MPA, medroxyprogesterone acetate; NETA; norethindrone acetate; TMG, trimegestone Courtesy Prof. A Genazzani, University of Pisa, Italy.
Figure 3
Figure 3
Percentage of subjects reporting no bleeding in each treatment cycle. Asterisks indicate significant difference (p = 0.05) within a cycle. Reproduced with permission from Kwiecien M, Edelman A, Nichols MD, Jensen JF. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose oral contraceptive: a randomized trial. Contraception. 2003;67:9–13. Copyright © 2003 Elsevier.

References

    1. Goldzieher JW, Rudel HW. How the oral contraceptives came to be developed. J Am Med Assoc. 1974;230:421–425.
    1. Diczfalusy E. The contraceptive revolution. Caserton Hall: The Parthenon Publishing Group; 1997.
    1. Benagiano G, Isidori C. Le basi razionali per l’utilizzazione clinica di una associazione estro-progestinica contenente Gestodene. In: Fioretti P, Melis GB, editors. Aggiornamenti in scienze ginecologiche ed ostetriche. Roma: CIC Edizioni Internazionali; 1987. pp. 295–304.
    1. Benagiano G, Farris M, Primiero FM. Clinical profile of contraceptive progestins. Eur J Contracept Reprod Health Care. 2004;9:182–193.
    1. Ware RS. New progestagens for contraceptive use. Hum Reprod Update. 2006;2:169–178.
    1. Smith CL, O’Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 2004;25:45–71.
    1. Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM. Selective progesterone receptor modulators and progesterone antagonist: mechanism of action and clinical applications. Hum Reprod Update. 2005;11(3):293–307.
    1. Spitz IM, Chwalisz K. Progesterone receptor modulators and progesterone antagonists in women’s health. Steroids. 2000;65:807–815.
    1. Chwalisz K, Perez MC, DeManno D, Winkel C, Schubert G, Elger W. Selective Progesterone Receptor Modulator. Development and Use in the Treatment of Leiomyomata and Endometriosis. Endocrine Rev. 2005;26:423–438.
    1. Spitz IM, Croxatto HB, Robbins A. Antiprogestins: mechanism of action and contraceptive potential. Annu Rev Pharmacol Toxicol. 1996;36:47–81.
    1. Schering AG. Hormonal Contraception. 3rd Ed. London: Butler & Tanner; 2001. p. 109.
    1. Stanczyk FZ, Roy S. Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids. Contraception. 1990;42:67–96.
    1. Sanchez-Borregol R, Balasci J. Ethinyl oestradiol plus dl-norgestrel or levonorgestrel in the Yuzpe method for post-coital contraception: results of an observational study. Hum Reprod. 1996;11:2449–2453.
    1. Fotherby K, Caldwell ADS. New progestogens in oral contraception. Contraception. 1994;49:1–31.
    1. Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas. 2003;(46 Suppl 1):S7–S16.
    1. Stanczyk FZ. Structure-function relationships, potency, and pharmacokinetics of progestogens. In: Lobo RA, editor. Treatment of the postmenopausal woman: basic and clinical aspects. New York: Raven Press; 1994. pp. 69–89.
    1. Scleusser E, Broeckner T, Brautigam J, Michaels W. Influence of two low dose oral contraceptives on possible gonadotropin secretion. Gynecol Endocrinol. 2001;15:259–264.
    1. Anderson FD, Hait H, Hsiu J, Thompson-Graves AL, Wilborn WH, Williams RF, et al. Endometrial microstructure after long-term use of a 91-day extended-cycle oral contraceptive regimen. Contraception. 2005;71:55–59.
    1. Guttinger A, Critchley HO. Endometrial effects of intrauterine levonorgestrel. Contraception. 2007;(75 Suppl 6):S93–S98.
    1. Luukkainen T. Levonorgestrel-releasing intrauterine device. Ann NY Acad Sci. 1991;626:43–49.
    1. Dunson TR, Blumenthal PD, Alvarez F, et al. Timing of onset of contraceptive effectiveness in Norplant implant users. Changes in cervical mucus. Fertil Steril. 1998;69:258–266.
    1. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. Lancet. 1995;346:1575–1582.
    1. Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thromboembolism. BMJ. 2001;323:1–9.
    1. Sartwell PE, Masi AP, Arthes G, et al. Thromboembolism and oral contraceptives: an epidemiologic case-control study. Am J Epidemiol. 1969;90:365–380.
    1. Martínez F, Avecilla A. Combined hormonal contraception and venous thromboembolism. Eur J Contracept Reprod Health Care. 2007;12:97–106.
    1. Endrikat J, Hite R, Bannemerschult R, Gerlinger C, Schmidt W, et al. Multicenter, comparative study of cycle control, efficacy and tolerability of two low-dose oral contraceptives containing 20 mcg ethinylestradiol/100 mcg levonorgestrel and 20 mcg ethinylestradiol/500 mcg norethisterone. Contraception. 2001;64:3–10.
    1. Reisman H, Martin D, Gast MJ. A multicenter randomized comparison of cycle control and laboratory findings with oral contraceptive agents containing 100 mcg levonorgestrel with 20 mcg ethinyl estradiol or triphasic norethindrone with ethinyl estradiol. Am J Obstet Gynecol. 1999;181:45–52.
    1. Chavez A, DelConte A. A comparison of cycle control with monophasic levonorgestrel/ethinylestradiol 100 micrograms/20 micrograms versus triphasic norethindrone/ethinylestradiol 500–750–1000 micrograms/35 micrograms: a multicenter, randomized, open label study. Eur J Contracept Reprod Health Care. 1999;4:75–83.
    1. Pincus G. Control of fertility. New York and London: Academic Press; 1965. p. 219.
    1. The ESHRE Capri Workshop Group. Apter D, Baird DT, Collins J, et al. Report prepared by Collins J, Crosignani PG. Endometrial bleeding. Hum Reprod Update. 2007;13:421–431.
    1. Finn CA. Implantation, menstruation and inflammation. Biol Rev. 1986;61:313–328.
    1. Lin K, Banhart K. The clinical rationale for menses-free contraception. J Womens Health (Larchmt) 2007;16:1171–1180.
    1. Drife JO. Menstruation: a cultural and historical perspective. In: Cameron IT, Fraser IS, Smith SK, editors. Clinical disorders of the endometrium and the menstrual cycle. Oxford and London: Oxford University Press; 1998. p. 312.
    1. O’Grady K.Canadian Women’s HealthAvailable from:
    1. Coutinho EM, Segal SJ. Is menstruation obsolete? New York: Oxford University Press; 1999.
    1. Berkowitz B. Cultural aspects in the care of the orthodox Jewish woman. J Midwifery Womens Health. 2008;53:62–67.
    1. Dhami S, Sheikh A. The Muslim family: predicament and promise. West J Med. 2000;173:352–356.
    1. Profet M. Mestruation as a defence against pathogen transported by sperm. Q Rev Biol. 1993;68:335–386.
    1. Sulak PJ. Continuous oral contraception: changing times. Best Pract Res Clin Obstet Gynaecol. 2007;20:1–20.
    1. Strassmann BI, Gillespie B. Life-history theory, fertility and reproductive success in humans. Proc R Soc Lond B. 2002;262:553–562.
    1. Houppert K. The curse: confronting the last unmentionable taboo: Menstruation. New York: Ferrar, Straus and Giroux; 1999.
    1. Strassmann BI. The Evolution of endometrial cycle and menstruation. Q Rev Biol. 1996;71:181–220.
    1. Strassmann BI. Energy economy in the evolution of menstruation. Evol Anthropol. 1997;5:158–164.
    1. Eaton SB, Wood JW, Pike MC, et al. Women’s reproductive cancers in evolutionary context. Quart Rev Biol. 1994;69:353–367.
    1. Segal SJ. Is menstruation obsolete? New York: Oxford University Press; 1999. Preface to Coutinho EM, Segal SJ; p. XIII.
    1. Martin E. The woman in the body: a cultural analysis of reproduction. Boston: Beacon Press; 1987.
    1. Garside D, Gann PH, Gapstur SM, et al. the effects of a low-fat/high-fiber diet on sex hormone levels and menstrual cycling in pre-menopausal women. Wiley InterScience. 2004;98:1870–1879.
    1. Pincus G, Garcia CR, Rock J. Effects of certain 19-nor-steroids on the normal human menstrual cycle. Science. 1956;124:891–893.
    1. World Health Organisation Task Force on Psychosocial Research in Family Planning . Geneva: WHO; 1981.
    1. Pardthaisong T, McDaniel EB, Gray RH. Acceptance and use of Depo Provera in Chieng Mai. IPPF Med Bull. 1975;9:1–3.
    1. Edelman A, Lew R, Cwiak C, Nichols M, Jensen J. Acceptability of contraceptive-induced amenorrhea in a racially diverse group of US women. Contraception. 2007;75:450–453.
    1. Kaunitz AM. Menstruation: choosing whether ... and when. Contraception. 2000;62:277–284.
    1. Glasier AF, Smith KB, van der Spuy ZM, et al. Amenorrhea associated with contraception-an international study on acceptability. Contraception. 2003;67:1–8.
    1. Snow R, Hardyb E, Kneuperc E, et al. Women’s responses to menses and non-bleeding intervals in the USA, Brazil and Germany. Contraception. 2007;76:23–29.
    1. Tonkelaar I, Oddens BJ. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraception use, and hormone replacement therapy use. Contraception. 1999;59:357–362.
    1. SOFRES Reproduction Humaine et Hormones, Symptômes liés au cycle: doivent-ils rester une fatalité? Résultat d’une grande enquête miroir TNS Sofres, Médecins/patientes sur l’attitude vis à vis des règles et la prise en charge des symptômes liés aux cycles. SOFRES Survey. 2006;19(8 Spécial):1–11.
    1. Ferrero S, Abbamonte LH, Giordano M, et al. What is the desired menstrual frequency of women without menstruation-related symptoms. Contraception. 2006;73:537–541.
    1. Wiegratz I, Hommel HH, Zimmermann T, Kuhl H. Attitude of German women and gynecologists towards long-cycle treatment with oral contraceptives. Contraception. 2004;69:37–42.
    1. Sánchez-Borrego R, García-Calvo C. Spanish women’s attitudes towards menstruation and use of a continuous, daily use hormonal combined contraceptive regimen. Contraception. 2008;77:114–117.
    1. Abraham S, Fraser I, Gebski V, et al. Menstruation, menstrual protection and menstrual cycle problems. The knowledge, attitudes and practices of young Australian women. Med J Aust. 1985;142:247–251.
    1. Loudon NB, Foxwell M, Potts DM, Guild AL, Short RV. Acceptability of an oral contraceptive that reduces the frequency of menstruation: the tri-cycle pill regimen. Br Med J. 1977;2:487–490.
    1. Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 μg) and ethinyl estradiol (15 μg) on ovarian activity. Fertil Steril. 1999;72:115–120.
    1. Bachman G, Sulak PJ, Sampson-Landers C, et al. Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3mg drospirenone. Contraception. 2004;70:191–198.
    1. Nakajima ST, Archer DF, Ellman H. Efficacy and safety of a new 24-day oral contraceptive regimen of norethindrone acetate 1mg/ethinyl estradiol 20 mg (Loestrin-24 Fe) Contraception. 2007;75:16–22.
    1. Thomas SL, Ellertson C. Nuisance or natural healthy: should monthly menstruation be optional for women. Lancet. 2000;355:922–924.
    1. Andrist LC, Arias RD, Nucatola D, et al. Women’s and providers’ attitudes toward menstrual suppression with extended use of oral contraceptives. Contraception. 2004;70:359–363.
    1. Benagiano G, Pera A, Bianchi P. Management of endometriosis: Historical background and rationale for the use of steroid hormones. In: Lemay A, Maheux R, editors. Understanding and managing endometriosis Advances in research and practice. New York: Parthenon Publishing; 1999. pp. 211–218.
    1. Vercellini P, De Giorgi O, Mosconi P, Stellato G, Vicentini G, Crosignani PG. Cyproterone acetate versus a continuous monophasic oral contraceptive in the treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis. Fertil Steril. 2002;77:52–61.
    1. MacGregor A. Migraine associated with menstruation. Funct Neurol. 2000;15:143–153.
    1. Martin-Johnston MK, Okoji OY, Armstrong A. Therapeutic amenorrhea in patients at risk for thrombocytopenia. Obstet Gynecol Surv. 2008;63:395–402.
    1. Miller L. Continuous administration of 100 mcg levonorgestrel and 20 mcg ethinyl estradiol for elimination of menses: a randomized trial. Obstet Gynecol. 2001;97:S16.
    1. Kaunitz AM. Beyond the pill: New data and options in hormonal and intrauterine contraception. Am J Obstet Gynecol. 2005;192:998–1004.
    1. Anderson FD, Hait H, The Seasonale-301 Study Group A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68:89–96.
    1. Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92–96.
    1. Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended regimen oral contraceptive utilizing continous low-dose ethinyl estradiol. Contraception. 2006;73:229–234.
    1. De Berardis D, Serroni N, Salerno RM, Ferro FM. Treatment of premenstrual dysphoric disorder (PMDD) with a novel formulation of drospirenone and ethinyl estradiol. Ther Clin Risk Manag. 2007;3:585–590.
    1. Fenton C, Wellington K, Moen-Robinson DM. Drospirenone/ethi-nylestradiol 3 mg/20 microg (24/4 day regimen): a review of its use in contraception, premenstual dysphoric disorder and moderate acne vulgaris. Drugs. 2007;67:1749–1765.
    1. Association of Reproductive Health Professionals Extended regimen oral contraceptivesHarris Poll, June14–172002
    1. den Tonkelaar I, Odden BJ. Preferred frequency and characteristics of menstrual bleeding in relation to reproductive status, oral contraceptive use, and hormone therapy replacement use. Contraception. 1999;59:357–362.
    1. Omar H, Kives S, Allen L. Extended use of the oral contraceptive pill – is it an acceptable option for the adolescent. J Pediatr Adolesc Gynecol. 2005;18:285–288.
    1. Sulak PJ, Buckley T, Kuehl TJ. Attitudes and prescribing preferences of health care professionals in the United States regarding use of extended-cycle oral contraceptives. Contraception. 2006;73:41–45.
    1. Schwartz JL, Creinen MD, Pymar HC. The trimonthly combination oral contraceptive regimen: is it cost effective. Contraception. 1999;60:263–267.
    1. Kwiecien M, Edelman A, Nichols MD, Jensen JF. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose oral contraceptive: a randomized trial. Contraception. 2003;67:9–13.
    1. Miller L, Hughes JP. Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: a randomized trial. Obstet Gynecol. 2003;101:653–661.
    1. Archer DF, Jensen JT, Johnson JV, Borisuted H, Grubb GS, Constantine GD. Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 study results. Contraception. 2006;74:439–445.
    1. Johnson JV, Grubbs GS, Constantine GD. Endometrial histology following 1 year of a continuous daily regimen of levonorgestrel 90 microg/ethinyl oestradiol 20 microg. Contraception. 2007;75:23–26.
    1. Kaiser Daily Women’s Health Policy Report 5/22/2007
    1. Edelman A, Gallo MF, Nichols MD, Jensen JT, Schulz KF, Grimes DA. Continuous versus cyclic use of combined oral contraceptives for contraception: systematic Cochrane review of randomized controlled trials. Hum Reprod. 2006;21:573–578.
    1. Steinauer J, Autry AM. Extended cycle combined hormonal contraception. Obstet Gynecol Clin North Am. 2007;34:43–55.

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