Noncontraceptive benefits of the estradiol valerate/dienogest combined oral contraceptive: a review of the literature

Figures & data

Table 1 Primary efficacy outcomes* used in two identically designed, double-blind, placebo-controlled, randomized controlled studies with estradiol valerate/dienogest, in women with heavy and/or prolonged menstrual bleeding without organic pathology

Efficacy condition	Definition (per 90-day period)
1	No bleeding episodes lasting >7 days
2	No more than four bleeding episodes
3	No bleeding episodes with a blood loss volume of ≥80 mL
4	No more than one bleeding episode increase from baseline
5	Total number of bleeding days ≤24
6	No increase from baseline in total number of bleeding days
7	Decrease of ≥2 days between maximum duration during run-in phase and efficacy phase (if enrolled with prolonged bleeding)
8	Blood loss volume associated with each episode <80 mL and decreased by 50% or more from the average of the qualifying bleeding episodes (where the qualifying bleeding episodes are those with a blood loss volume ≥80 mL per episode) that occurred during the run-in phase (if enrolled with excessive bleeding)

Notes:

* Fraser et al¹⁵ and Jensen et al¹⁶ had to use these outcomes as mandated by the US Food and Drug Administration.⁶² The primary efficacy outcome was the proportion of women who had a complete response (ie, restoration of “normal menstruation”) during a 90-day efficacy interval versus the 90-day run-in interval. A complete response was defined as a composite of up to eight individual criteria defined in the table.

Figure 1 Bleeding reduction after 6 months of treatment with selected medical therapies, measured using the alkaline hematin method (data from randomized control trial unless otherwise stated).^{15,16,47,50,58–61}

Notes: ^b10 mg daily from day 16 to 25 of cycle; ^aEE 30 μg/LNG 150 μg in a 21/7 regimen after 12 months; ^c1.3 g TID on days 1 to 5 of cycle; ^dnonrandomized trial; ^eMBL reduction between 90-day run-in phase and 90-day efficacy phase.
Abbreviations: DNG, dienogest; E₂V, estradiol valerate; EE, ethinyl estradiol; LNG–IUS, levonorgestrel-releasing intrauterine system; LNG, levonorgestrel; MBL, menstrual blood loss; MPA, medroxyprogesterone acetate; TID, three times daily.

Figure 2 Change from baseline to cycle 6 in the average of the three highest VAS values on cycle days 22–28, for the hormone withdrawal-associated symptoms of headache or pelvic pain, in women who received treatment with E₂V/DNG compared with (A) triphasic EE/NGM and (B) EE/LNG.

Notes: (A) Reproduced from Jensen JT, Parke S, Mellinger U, et al, Eur J Contracept Reprod Health Care, 2013;18(4):274–283, Copyright © 2013, Informa Healthcare. Reproduced with permission of Informa Healthcare.¹⁷ (B) Reproduced from Macìas G, Merki-Feld GS, Parke S, et al, J Obstet Gynaecol, 2013;33(6):591–596, Copyright © 2013, Informa Healthcare. Reproduced with permission of Informa Healthcare.³¹
Abbreviations: DNG, dienogest; E₂V, estradiol valerate; EE, ethinyl estradiol; LNG, levonorgestrel; NGM, norgestimate; SD, standard deviation; VAS, visual analog scale.

Figure 3 Scores of the Female Sexual Function Index subdomains, for E₂V/DNG and EE/LNG, at baseline and cycle 6, and the change from baseline.

Note: Reproduced from Change to either a nonandrogenic or androgenic progestin-containing oral contraceptive preparation is associated with improved sexual function in women with oral contraceptive-associated sexual dysfunction. Davis SR, Bitzer J, Giraldi A, et al. J Sex Med. 2013;10(12):3069–3079. Copyright © 2013 International Society for Sexual Medicine.³⁴
Abbreviations: DNG, dienogest; E₂V, estradiol valerate; EE, ethinyl estradiol; FSFI, Female Sexual Function Index, LNG, levonorgestrel.

FraserISRömerTParkeSEffective treatment of heavy and/or prolonged menstrual bleeding with an oral contraceptive containing estradiol valerate and dienogest: a randomized, double-blind Phase III trialHum Reprod201126102698270821784734

 PubMed Web of Science ®Google Scholar

JensenJTParkeSMellingerUMachlittAFraserISEffective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trialObstet Gynecol2011117477778721422847

 PubMed Web of Science ®Google Scholar

Center for Drug Evaluation and ResearchApplication number: 22-252, Original 1 Statistical Review(s)http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022252_Orig-1_StatR.pdfU.S. Department of Health and Human Services, Food and Drug Administration2010Accessed July 7, 2014

 Google Scholar

KaunitzAMBissonnetteFMonteiroILukkari-LaxEMuysersCJensenJTLevonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: a randomized controlled trialObstet Gynecol2010116362563220733445

 PubMed Web of Science ®Google Scholar

TangGWLoSSLevonorgestrel intrauterine device in the treatment of menorrhagia in Chinese women: efficacy versus acceptabilityContraception19955142312357796588

 PubMed Web of Science ®Google Scholar

MilsomIAnderssonKAnderschBRyboGA comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagiaAm J Obstet Gynecol199116438798831900665

 PubMed Web of Science ®Google Scholar

LukesASMooreKAMuseKNTranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trialObstet Gynecol2010116486587520859150

 PubMed Web of Science ®Google Scholar

JensenJTParkeSMellingerUSerraniMMabeyRGHormone withdrawal-associated symptoms: comparison of oestradiol valerate/dienogest versus ethinylestradiol/norgestimateEur J Contracept Reprod Health Care201318427428323638631

 PubMed Web of Science ®Google Scholar

MacìasGMerki-FeldGSParkeSMellingerUSerraniMEffects 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 studyJ Obstet Gynaecol201333659159623919857

 PubMedGoogle Scholar

DavisSRBitzerJGiraldiAChange to either a nonandrogenic or androgenic progestin-containing oral contraceptive preparation is associated with improved sexual function in women with oral contraceptive-associated sexual dysfunctionJ Sex Med201310123069307924034466

 PubMed Web of Science ®Google Scholar