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Expert Opinion on Pharmacotherapy Volume 16, 2015 - Issue 18
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Reviews

An update on new orally administered contraceptives for women

Anita L NelsonObstetrics and Gynecology, David Geffen School of Medicine at UCLA, Manhattan Beach, CA, USACorrespondence[email protected]
, MD
Pages 2759-2772 | Published online: 29 Oct 2015

Bibliography

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*** A must read article for all clinicians to remind us what constitutes evidence that should change practice.

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** Well-written introduction of the potential of estradiol in oral contraceptives.

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  • Strowitzki T, Marr J, Gerlinger C, et al. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Hum Reprod. 2010;25(3):633–641.
  • Momoeda M, Harada T, Terakawa N, et al. Long-term use of dienogest for the treatment of endometriosis. J Obstet Gynaecol Res. 2009;35(6):1069–1076.
  • Takenaka M, Yano R, Hiraku Y, et al. Exploratory study of pre-surgical medications with dienogest or leuprorelin in laparoscopic cystectomy of endometrial cysts. J Obstet Gynaecol Res. 2015;41(8):1234–1239.
  • Angioni S, Nappi L, Pontis A, et al. Dienogest. A possible conservative approach in bladder endometriosis. Results of a pilot study. Gynecol Endocrinol. 2015;31(5):406–408.
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  • Endrikat J, Parke S, Trummer D, et al. Pituitary, ovarian and additional contraceptive effects of an estradiol-based combined oral contraceptive: results of a randomized, open-label study. Contraception. 2013;87(2):227–234.
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  • Blode H, Zeun S, Parke S, et al. Evaluation of the effects of rifampicin, ketoconazole and erythromycin on the steady-state pharmacokinetics of the components of a novel oral contraceptive containing estradiol valerate and dienogest in healthy postmenopausal women. Contraception. 2012;86(4):337–344.
  • Bitzer J, Parke S, Roemer T, et al. Endometrial safety of an oral contraceptive Containing estradiol valerate and dienogest. Int J Womens Health. 2011;3:127–132.
  • Nelson A, Parke S, Makalova D, et al. Efficacy and bleeding profile of a combined oral contraceptive containing oestradiol valerate/dienogest: a pooled analysis of three studies conducted in North America and Europe. Eur J Contracept Reprod Health Care. 2013;18(4):264–273.
  • Nelson A, Parke S, Mellinger U, et al. Efficacy and safety of a combined oral contraceptive containing estradiol valerate/dienogest: results from a clinical study conducted in North America. J Womens Health (Larchmt). 2014;23(3):204–210.
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*** Insightful article identifying the causes of the “Pearl creep” in more modern clinical times.

  • Ahrendt HJ, Makalová D, Parke S, et al. Bleeding pattern and cycle control with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial of estradiol valerate/dienogest and ethinyl estradiol/levonorgestrel. Contraception. 2009;80(5):436–444.
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  • Jensen JT, Parke S, Mellinger U. et al. Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trial. Obstet Gynecol. 2011;117(4):777–787.

* Well-written description of the impact of heavy menstrual bleeding and the studies done to test oral contraceptives as therapy.

  • Fraser IS, Parke S, Mellinger U, et al. Effective treatment of heavy and/or prolonged menstrual bleeding without organic cause: pooled analysis of two multinational, randomised, double-blind, placebo-controlled trials of oestradiol valerate and dienogest. Eur J Contracept Reprod Health Care. 2011;16(4):258–269.
  • Rafie S, Borgelt L, Koepf ER, et al. Novel oral contraceptive for heavy menstrual bleeding: estradiol valerate and dienogest. Int J Womens Health. 2013;5:313–321.

* Nice summary article.

  • Wasiak R, Filonenko A, Vanness DJ, et al. Impact of estradiol valerate/dienogest on work productivity and activities of daily living in women with heavy menstrual bleeding. J Womens Health (Larchmt). 2013;22(4):378–384.
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  • Petraglia F, Parke S, Serrani M, et al. Estradiol valerate plus dienogest versus ethinylestradiol plus levonorgestrel for the treatment of primary dysmenorrhea. Int J Gynaecol Obstet. 2014;125(3):270–274.
  • Macìas G, Merki-Feld GS, Parke S, et al. Effects of a combined oral contraceptive containing oestradiol valerate/dienogest on hormone withdrawal-associated symptoms: results from the multicentre, randomised, double-blind, active-controlled HARMONY II study. J Obstet Gynaecol. 2013;33(6):591–596.
  • Jensen JT, Parke S, Mellinger U, et al. Hormone withdrawal-associated symptoms: comparison of oestradiol valerate/dienogest versus ethinylestradiol/norgestimate. Eur J Contracept Reprod Health Care. 2013;18(4):274–283.
  • Nappi RE, Terreno E, Sances G, et al. Effect of a contraceptive pill containing estradiol valerate and dienogest (E2V/DNG) in women with menstrually-related migraine (MRM). Contraception. 2013;88(3):369–375.
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  • Grandi G, Xholli A, Napolitano A, et al. Pelvic pain and quality of life of women with endometriosis during quadriphasic estradiol valerate/dienogest oral contraceptive: a patient-preference prospective 24-week pilot study. Reprod Sci. 2015;22(5):626–632.
  • Stanczyk FZ. Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception. Rev Endocr Metab Disord. 2002;3(3):211–224.

* Classic study describing the multifaceted impacts of progestogens.

  • Ruan X, Seeger H, Mueck AO. The pharmacology of nomegestrol acetate. Maturitas. 2012;71(4):345–353.
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  • Coutinho EM, De Souza JC, Athayde C, et al. Multicenter clinical trial on the efficacy and acceptability of a single contraceptive implant of nomegestrol acetate, Uniplant. Contraception. 1996;53(2):121–125.
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  • Dinger J, Minh TD, Buttmann N, et al. Effectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen. Obstet Gynecol. 2011;117(1):33–40.
  • Lello S. Nomegestrol acetate: pharmacology, safety profile and therapeutic efficacy. Drugs. 2010;70(5):541–559.
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  • Sitruk-Ware R, Nath A. Metabolic effects of contraceptive steroids. Rev Endocr Metab Disord. 2011;12(2):63–75.

* Excellent review of the topic.

  • Gerrits MG, Schnabel PG, Post TM, et al. Pharmacokinetic profile of nomegestrol acetate and 17β-estradiol after multiple and single dosing in healthy women. Contraception. 2013;87(2):193–200.
  • Chabbert-Buffet N, Chassard D, Ochsenbein E, et al. Inhibition of ovulation by NOMAC/E2, a novel monophasic oral contraceptive combining nomegestrol acetate and 17β-oestradiol: a double-blind, randomised, dose-finding pilot study. Eur J Contracept Reprod Health Care. 2011;16(2):76–84.
  • Christin-Maitre S, Serfaty D, Chabbert-Buffet N, et al. Comparison of a 24-day and a 21-day pill regimen for the novel combined oral contraceptive, nomegestrol acetate and 17β-stradiol (NOMAC/E2): a double-blind, randomized study. Hum Reprod. 2011;26(6):1338–1347.
  • Westhoff C, Kaunitz AM, Korver T, et al. Efficacy, safety, and tolerability of a monophasic oral contraceptive containing nomegestrol acetate and 17β-estradiol: a randomized controlled trial. Obstet Gynecol. 2012;119(5):989–999.

* Good summary of the US and Canadian clinical trial using modern criteria.

  • Mansour D, Verhoeven C, Sommer W, et al. Efficacy and tolerability of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in a 24/4 regimen, in comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a 21/7 regimen. Eur J Contracept Reprod Health Care. 2011;16(6):430–443.
  • Ågren UM, Anttila M, Mäenpää-Liukko K, et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism. Eur J Contracept Reprod Health Care. 2011;16(6):444–457.
  • Ågren UM, Anttila M, Mäenpää-Liukko K, et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in comparison to one containing levonorgestrel and ethinylestradiol on markers of endocrine function. Eur J Contracept Reprod Health Care. 2011;16(6):458–467.
  • Sørdal T, Grob P, Verhoeven C. Effects on bone mineral density of a monophasic combined oral contraceptive containing nomegestrol acetate/17β-estradiol in comparison to levonorgestrel/ethinylestradiol. Acta Obstet Gynecol Scand. 2012;91(11):1279–1285.
  • Gaussem P, Alhenc-Gelas M, Jl T, et al. Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17β-estradiol, compared with those of evonorgestrel/ethinyl estradiol. A double-blind, randomised study. Thromb Haemost. 2011;105(3):560–567.

* Important initial study of the potential for reduced VTE risk with E2.

  • Duijkers IJ, Klipping C, Grob P, et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17 beta-oestradiol on ovarian function in comparison to a monophasic combined oral contraceptive containing drospirenone and ethinylestradiol. Eur J Contracept Reprod Health Care. 2010;15(5):314–325.
  • Witjes H, Creinin MD, Sundström-Poromaa I, et al. Comparative analysis of the effects of nomegestrol acetate/17 β-estradiol and drospirenone/ethinylestradiol on premenstrual and menstrual symptoms and dysmenorrhea. Eur J Contracept Reprod Health Care. 2015;20(4):296–307.
  • Sulak PJ, Scow RD, Preece C, et al. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95(2):261–266.

** Classic study demonstrating the suffering women have with scheduled bleeding with oral contraceptives.

  • Sulak P, Willis S, Kuehl T, et al. Headaches and oral contraceptives: impact of eliminating the standard 7-day placebo interval. Headache. 2007;47(1):27–37.
  • Sulak PJ, Kuehl TJ, Coffee A, et al. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195(4):935–941.
  • Coutinho EM, Segal SJIS. Is menstruation obsolete? New York (NY): Oxford University Press; 1999.

*** A must read for anyone in women’s health. This should be the basis for all conversations with women.

  • Edelman A, Lew R, Cwiak C, et al. Acceptability of contraceptive-induced amenorrhea in a racially diverse group of US women. Contraception. 2007;75(6):450–453.

* Provides good insights into the beliefs 9and knowledge gaps) women hold.

  • Sulak PJ. Ovulation suppression of premenstrual symptoms using oral contraceptives. Am J Manag Care. 2005;11(16 Suppl):S492–7.
  • Snow R, Hardy E, Kneuper E, et al. Women’s responses to menses and nonbleeding intervals in the USA, Brazil and Germany. Contraception. 2007;76(1):23–29.
  • 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(5):359–363.
  • Szarewski A, Von Stenglin A, Rybowski S. Women’s attitudes towards monthly bleeding: results of a global population-based survey. Eur J Contracept Reprod Health Care. 2012;17(4):270–283.
  • Kaunitz AM, Portman DJ, Hait H, et al. Adding low-dose estrogen to the hormone-free interval: impact on bleeding patterns in users of a 91-day extended regimen oral contraceptive. Contraception. 2009;79(5):350–355.
  • Reape KZ, DiLiberti CE, Hendy CH, et al. Effects on serum hormone levels of low-dose estrogen in place of placebo during the hormone-free interval of an oral contraceptive. Contraception. 2008;77(1):34–39.
  • Anderson FD, Feldman R, Reape KZ. Endometrial effects of a 91-day extended-regimen oral contraceptive with low-dose estrogen in place of placebo. Contraception. 2008;77(2):91–96.
  • Kroll R, Reape KZ, Margolis M. The efficacy and safety of a low-dose, 91-day, extended-regimen oral contraceptive with continuous ethinyl estradiol. Contraception. 2010;81(1):41–48.
  • Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68(2):89–96.
  • Jensen JT, Garie SG, Trummer D, et al. Bleeding profile of a flexible extended regimen of ethinylestradiol/drospirenone in US women: an open-label, three-arm, active-controlled, multicenter study. Contraception. 2012;86(2):110–118.
  • Darwish M, Bond M, Ricciotti N, et al. A comparison of the pharmacokinetic profile of an ascending-dose, extended-regimen combined oral contraceptive to those of other extended regimens. Reprod Sci. 2014;21(11):1401–1410.
  • Portman DJ, Kaunitz AM, Howard B, et al. Efficacy and safety of an ascending-dose, extended-regimen levonorgestrel/ethinyl estradiol combined oral contraceptive. Contraception. 2014;89(4):299–306.
  • Klipping C, Duijkers I, Fortier MP, et al. Long-term tolerability of ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen: results from a randomised, controlled, multicentre study. J Fam Plann Reprod Health Care. 2012;38(2):84–93.
  • Klipping C, Duijkers I, Fortier MP, et al. Contraceptive efficacy and tolerability of ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen: an open-label, multicentre, randomised, controlled study. J Fam Plann Reprod Health Care. 2012;38(2):73–83.
  • Strowitzki T, Kirsch B, Elliesen J. Efficacy of ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen in women with moderate-to-severe primary dysmenorrhoea: an open-label, multicentre, randomised, controlled study. J Fam Plann Reprod Health Care. 2012;38(2):94–101.
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