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How to manage irregular bleeding or spotting after LNG-IUS PowerPoint PPT Presentation

How to manage irregular bleeding or spotting after LNG-IUS insertion

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How to manage irregular bleeding or spotting after LNG-IUS

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F ow to t r air age irregular bleeding or spotting after i g ius insert on

_-- :

F ow to t r air age irregular bleeding or spotting after i g ius insert on



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 ([email protected])



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


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.''


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].

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F ow to t r air age irregular bleeding or spotting after i g ius insert on



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


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-

F ow to t r air age irregular bleeding or spotting after i g ius insert on



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:.


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


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.


Smith MOP, Critchley HO. Progestogen only contraception and

endometrial breakthrough bleeding. Angiogenesis 2005; 7:


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


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:


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.


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.


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:


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.


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