How to manage irregular bleeding or spotting after LNG-IUS

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2. REVIEW ARTICLES f{ow to tırıaIrıage irregular bleeding or spotting after I|üG-IUS insertİon Sezai Şahmay Department of Obstetrics and Gynaecology, Diaision of Reproductiae Endocrinology and lğertility, Cerrahpaşa Medical Faculty, lstanbul Uniııersity, Istanbul, Turkey (sahmay@yahoo.com) I Introduction The levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena@) is a long-term, progestogen-only method of contraception [1, 2]. Since its launch in Finland in 7990, it has become available in more than 100 countries and today is estimated to be used by more than 10 million women worldwide [2-4]. The LNG{US was developed primarily as a contra- ceptive device for up to 5 years of use [1, 5]. Its effects are local and hormonal, including prevention of endometrial proliferation. A low dose of levo- norgestrel is released into the uterine cavity, causing endometrial suppression and leading to endometrial atrophy, so that for many women its use is associated with little or no vaginal bleeding |1,,2, 4, 6f. The rate of adverse effects varies between studies: irregular bleeding or spotting is reported by 75-717o of women following insertion; progestogenic adverse effects by 24-61,%; and abdomino-pelvic pain by 1240%. The LNG-IUS must be fitted and removed by a qualified practitioner |1, 9, 12-1,5]. Causes of irregular bleeding The underlying mechanisms that cause irregular bleeding or spotting with progestogen-only contra- ception are not fully understood [3, 11] and may be explained by multiple factors I11,,74,76]. Bleeding in users of progestogen-only contracep- tives is usually related to estrogen deficiency. Insuffi- cient suppression of ovarian activity is another mech- anism for irregular bleeding. Fewer than half of cycles in LNG-IUS users are ovulatory 13, 6,73,77l. On the other hand, the long-term use of intrauterine levonorgestrel results in modulation of local media- tors regulating endometfial and vascular morphology and function. The histological changes begin to develop from the first month after insertion and persist until the device is removed. Endometrial exposure to levonorgestrel results in a marked downregulation of sex steroid receptors (progesterone, estrogen and androgen receptors) in all cellular components of the endometrium [18, 19]. 77!-Hydroxysteroid dehydrogenase type 2 (17P- HSD2) is expressed in endometrial glandular epithe- lium and is upregulated by progesterone. 17F-HSD2 converts potent estradiol to less potent estrone. The endometrial glands are exposed to higher levels of the weak estrogen (estrone), and thus the endometrium may develop a local intracellular estrogen-deficient environmen t 17 6, 1,8--20]. Over time, exposure of the endometrium to high concentrations of levonorgestrel results in marked atro- phy of the glandular and surface epithelium and heavy Occurrence of irregular bleeding Irregular bleeding or spotting is the most common unwanted adverse effect and reason for discontinua- tion, especially in the first few months following insertion [2, 4, 7-9]. The term 'spotting' refers to a small amount of vaginal bleeding that does not require the use of sanitary protection; the term 'vagi- nal bleeding' means that sanitary protection is required [5, 10-13]. lloııce the endometria7 efficts become .established, in the ınajoritg of woınen the bleeding pattern graduallg turns to oligomenowho e a or atnenoryhoe a usually within 6-12 ınonths after insertion.'' I Once the endometrial effects become established, in the majority of women the bleeding pattern gradually turns to oligomenorrhoea or amenorrhoea usually within 6-12 months after insertion [7, 9]. ö }ü] ] [,{ıdiııl iııı:ı: iııeııııiiıııı;i ('{nae.L]i.üı| İııııı !/ç|. ]ç, ı;*, ı. , ıül İ

4. ARTICLES REVIEW Figure 2: Mechanism of action of NSAIDs in reducing menstrual blood loss. Prostaglandin (PG) leaels are eleaated in women with menorrhagia. NSz{tDs inhibit PG synthesis by inhibiting the enzyme cyclo-oıygenase. NSdDs reduce both endometrial PG concentrations and blood loss. differences in clinical efficacy between individual prostaglandin inhibitors [6]. Treatment responses ale variable. For example, naProxen sodium requires twice-daily dosing, in contrast to ibuprofen, which is taken four times daily. A Cochrane review concluded that gastrointestinal side effects may be greater with naproxen than with mefenamic acid (in one study) [6]. There is no stan- dard dosage and duration of NSAID usage/ and indi- vidual NSAID treatment is convenient for reducing the amount of bleeding and severity of pain. Mefe- namic acid is the most'commonly studied agent, the usual dosage being 500 mg three times a day. The dosage for naproxen is 500 mg twice a day during the bleeding or spotting period. The dosage regimen for ibuprofen is 1200 mg pel day in divided doses 16,23l. NSAIDs should be considered a first-line therapy for bleeding and pain associated with IUD ııse I22, 23]. The optimal NSAID and regimen option is unclear, so the choice may be based on cost/ conveni- ence or side effects. Studies do not support prophy- lactic ibuprofen usage for the first six menses after IUD insertionI24]. p|ay an important role in endometrial vessel haemostasis. Thromboxane is a vasoconstrictor that facilitates platelet aggregation. Otherwise, prosta- cyclin chiefly prevents formation of the platelet plug and is also an effective vasodilator. All NSAIDs balance thromboxane and prostacyclin through prostaglandin synthase inhibition. Prostaglandin synthase inhibitors decrease menstrual bleeding by 50% (Figure 2). Most studies have shown that NSAIDs are effective therapy for irregular bleeding and pain related to the use of IUDs l1,4,22-24]. "Iwegular bleeding is redwced duing consecutiue use of the LNG-IUS, &nd *ome studİes encourage consecutİue use for contracepıtioıı or tha treatment of heavg menstrual bleeding. It is recoınmended to inseıi the second lNG-IUS imınediatelg after remouing the first." It has been shown that prostaglandin levels are elevated in women with excessive menstrual bleeding. NSAIDs reduce endometrial prostaglandin concentra- tions as well as the amount of blood loss [6,24l. NSAIDs include mefenamic acid, naproxen, ibupro- fery flurbiprofen, meclofenamic acid, diclofenac, indomethacin and acetylsalicylic acid. There are no Tranexamic acid Plasminogen acüvators are a group of enzymes that cause fibrinolysis (the dissolution of clots). Women with bleeding problems have high levels of plasmino-

6. REVIEW ARTICLES 10. Gemzell-Danielsson K, Inki P, Boubli L, et al. Bleeding pattern and safety of consecutive use of the levonorgestrel-releasing intrauterine system (LNG-IUS) - a multicentre prospective sfudy. Hum Reprod 2070;25: 354-9. 11. Mansour D, Bahamondes L, Critchley H, et al. The manage- ment of unacceptable bleeding patterns in etonogestrel-releas- ing contraceptive implant users. Contraception 2011,; 83:. 202-10. 12. Hidalgo M, Bahamondes L, Perrotti M, et al. Bleeding patterns and clinical performance of the levonorgestrel releasing intrauterine system (Mirena@) up to two years. Contraception 2002;65:129-32. 13. Backrnan T, Huhtala S, Blom T, et al. Length of use and s;.mp- toms associated with premafure removal of the levonorgestrel intrauterine system: a nation-wide study of 17,360 users. Br J Obstet Gynaecol 2000; 1,07:335-9. 14. Abdel-Aleem H, d'Arcangues C, Vogelsong KM, Gulmezoglu AM. Treatment of vaginal bleeding irregularities induced by progestin only contraceptives. Cochrane Database Syst Rev 2007;4: CD003449. 15. Ewies AAA. Levonorgestrel-releasing intrauterine system - the discontinuing story. Gynecol Endocrinol 2009 ; 25: 668-73. 16. Guttinger A, Critchley HO. Endometrial effects of intrauterine levonorgestrel. Contraception 2007;75 (6 suppl): 593-8. 17. Şahmay S. Menstrual cycle and dysfunctional uterine bleeding [in Turkish]. Istanbul: Esin Ofset,2007. 18. Burton K, Henderson TA, Hillier SG, et a1. Local levonorgestrel regulation of androgen receptor and l7P-hydroxysteroid dehy- drogenase type 2 expression in human endometrium. Hum Reprod 2003; 18: 261,0-17. 19. Critchley HO, Wang H, Kelly RW, et al. Progestin receptor isoforms and prostaglandin dehydrogenase in the endometrium of women using a levonorgestrel-releasing intrauterine system. Hum Reprod 7998; 73: 1210,1,7. 20. Smith MOP, Critchley HO. Progestogen only contraception and endometrial breakthrough bleeding. Angiogenesis 2005; 7: 1-10. Heikinheimo O, Inki R Kunz M, Gemzell-Danielsson K. Predic- tors of bleeding and user satisfaction during consecutive use of the levonorgestrel-releasing intrauterine system. Hum Reprod 2010;25:7423-7. 22. Şahırıay S, Erfungealp E, Arvas M, Atasu T. Antiprostaglandins in therapy for side effects of intrauterine contraceptive devices [in Turkish]. Cerrahpaşa Tıp Fakii-ltesı Dergisı1987;18: 75-83. 23. Şahmay S, Kaleli S, Oral E, et al. Effect of different types of intrauterine devices on intrauterine activity. Int J Fertil Women's Med 1999; 44:'],50-5. 24. Grimes DA, Hubacher D,,Lopez LM, Schulz KF, Non-steroidal anti-inflaınmatory drugs for heavy bleeding or pain associated with intrauterine-device use. Cochrane Database Syst Rev 2006; 4: CD006034. 25. Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev 2000; 4: CD000249. 26. Phihpp CS. Antifibrinolytics in women with menorrhagia. Thromb Res 2011; 727 (sıpp| 3): 5113-15. 27. Milsorn I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am I Obstet Glmecol 1997;764: 879-a3. Warner et al. [4] studied the use oi CDB-291,4 50 mg/day orally for 3 consecutive days, with separate treatments starting 27,49 and77 days after LNG-IUS insertion. The effect of CDB-2914 on bleeding/spot- ting was initially beneficial but by the third treatment period was less advantageous than placebo. conclusion NSAIDs and tranexamic acid offer simple and effec- tive therapies and should be considered as first-line therapy options in LNG-IUS-related bleeding/spot- ting and pain. Tranexamic acid is more effective than NSAIDs in decreasing bleeding. If bleeding is associated with pain, NSAIDs should be considered as first-line therapy. Tianexamic acid is suitable in cases with only bleeding/spotting, since it offers no pain relief. References 1. National Collaborating Centre for Women's and Children's Health, National Institute for Health and Clinical Excellence. Heavy rnenstrual bleeding. Clinical guideline 44. London: RCOG Press, 2007. Available at: http://guidance.nice. ory.ıık / CG44 / Guidance /pdf / English. Accessed 1 5 July 2011. 2. Endrikat J, Vilos G, Muysers C, et al. The levonorgestrel-releas- ing intrauterine system provides a reliable, long-term treatment option for women with idiopathic menorrhagia. Arch Gynecol Obstet 2011; Apr 8 [Epub ahead of print]. 3. Inki P. Long-term use of the levonorgestrel-releasing intrauter- ine system. Contraception 2007;75 (suppl 6): 5767-6. 4. Warner P, Guttinger A, Glasier AF, et al. Randomized placebo- controlled trial of CDB-2914 in new users of a levonorgestrel- releasing intrauterine system shows only short-lived amelio- ration of unscheduled bleeding. Hum Reprod 201,0; 25: 345_53, 5. Jensen Jl Nelson AL, Costales AC. Subject and clinician experi- ence with the levonorgestrel-releasing intrauterine system. Contraception 2008; 77 : 22-9. 6. Lethaby A, Augood C, Duckitt K, Farquhar C. Nonsteroidal anti-inflammatory drugs for heaılı menstrual bleeding. Cochrane Database Syst Rev 2007; 4: CD000400. 7. ESHRE Capri Workshop Group. Intrauterine devices and intrauterine systems. Hum Reprod Update 2008; 74: 1,97 -208. 8. Lal S, Kriplani A, Kulshrestha V, et al. Eihcacy of mifepristone in reducing intermenstrual vaginal bleeding in users of the levonorgestrel intrauterine system. Int J Gynecol Obstet 2010; 109: 128-30. 9. Chi C, Huq FY, Kadir RA. Levonorgestrel-releasing intrauterine system for the management of heaıy menstrual bleeding in . women with inherited bleeding disorders: long-term follow- up. Contraception 2011; 83:242-7. 27. l:ı.,ıı.:*r;iıÇ! jiııı;ı 1ı'ı:i. :Ç- fuı. ı , ]ii ] O İ*j] lİt{il-ıi ıı)l*ı,: iıicıı;İ;.ıı: