Dr.NISHAT

CAPSULE: MIRENA AS TREATMENT OPTION IN DUB

INDEX

History Aim Basic structure Types Pharmacokinetics Ovarian function Endometrial effects Role in menorrhagia Meta analysis Applications/Benefits Disadvantages/ Side effects

HISTORY

Most significant development of gynecological management of 20th century

MIRENA was first launched in 1990 in Finland and Licensed in the UK in May 1995.

FDA approved since 2000

INTRODUCTION

The only brand currently available is the T-frame LNG-20 IUS, marketed as Mirena Coil, releases 20 mcg of LNG/ day over a period of 5 years.

Two newer lower LNG devices are under development, Fibroplant- LNG (frameless device) and MLS system releasing 14 and 10 mcg of LNG/day.

INTRODUCTION: (contd)

License awarded: In 1995, as contraceptive agent.

In 2001, treatment of menorrhagia

In 2005, in use with estrogen replacement therapy in peri and postmenopausal women to provide uterine protection.

AIM

Deliver a small predictable, daily dose of hormone directly into the uterine cavity

Sustained for a number of years

MIRENA (LNG IUS) Currently marketed in Europe/US/Asia

T shaped frame 32mmx32mmm

Made of polyethylene surrounded by elastomer sleeve

Sleeve-1:1 mixture of levonorgesterol and polymethylsiloxane

Controlled release of 20 mcg daily for over 5 years

After 5 years-15 mcg/day

At 7 years-12 mcg/day

BASIC STRUCTURE

TYPES

1. Progestasert

2. Mirena

3. Mirena MLS

4. Fibroplant

PROGESTASERT(PIPS)

First progesterone releasing system

T shaped polymeric platform

Drug reservoir of 38 mg

Daily release of 65 mcg /day

For 18-24 months

Received FDA approval in 1976

Contraceptive use for 1 year,bioavailability of 2 years

MIRENA MLS

Low dose IUS

Delivering 10 mcg/day

Under trial to evaluate the effectiveness for progestogenic opposition in HRT

FIBROPLANT

Frameless delivery system, also under trial

3 or 4cm long

1.2 mm wide reservoir

Sustained release (10 or 14 mcg)

Bound to fibrous flexible stem

Duration 3 years

PHARMACOKINETICS OF LNG IUS

Absorption: Levonorgestrel directly released into the uterine cavity absorbed into capillaries systemic circulation

Shelf life: 3 years

Detected in plasma within 15 minutes of insertion.

Mean systemic level of LNG following insertion- 425 pg/ml at 1 month and 330 pg/ml at 6 months.

Bound to SHBG which protects from metabolism

Max levels in few hours, plateau after first few weeks

MIRENA IN SITU

BASIC MECHANISM OF ACTION

MECHANISM OF ACTION: OVARIAN FUNCTION

Effect on ovarian function –minimal

As for suppression of ovulation - systemic absorption of LNG IUS should be 50 mcg/24 hours.

Over 85% have ovulatory cycles

With anovulatory cycles plasma levels higher than ovulatory cycles

Effect is maximum in the first year of use declines ovulation returns after removal

ENDOMETRIAL EFFECTS LNG IUS-profound changes in the hormonally non

responsive decidua basalis

Endometrium undergoes uniform structural and histological changes

HISTOPATHOLOGICAL STUDIES show-thinning,atrophy of the endometrial glands,decidualisation of the stroma,capillary thrombosis, and inflammatory cell infiltrate

HISTOPATHOLOGICAL CHANGES

Thinning: Occurs in the first 3 months Local blood flow gets altered development of thin

walled blood vessels

Doppler studies show - decrease in the subendometrial flow in the spiral arteries

ENDOMETRIAL EFFECTS (CONTD)

GROWTH FACTORS Normal effect: Insulin like growth factors modulate the

effect of estrogen

Endometrial stromal cells produce IGF and IGF BP

IGF 1STIMULATES ENDOMETRIUM TO PROLIFERATE IGF 2CAUSES AND MAINTAINS DIFFERENTIATION

WITHIN THE ENDOMETRIUM

WITH LNG IUS….. Increase in IGF BP1 and decrease in IGF 1 Rise in concentration of IGF 2 RESULTS IN WEAK PROLIFERATION OF THE ENDOMETRIUM

OTHER EFFECTS:

Ki 67 gene -abundant in women with menorrhagia

Decreased in women with LNG IUS

Endometrial plasminogen activator inhibitor induced with LNG IUS

This decreases menstrual blood flow

BIOCHEMICAL FACTORS:

The biochemical mediators cause increase in Apoptosis and gene down regulation.

Gene codes for thrombin(protease activated receptor-1)

Alteration in the expression of this receptor-affects growth and haemostatic activity

CHANGES ARE REVERSIBLE EVEN AFETR LONG TERM USE AND NORMAL MENSTRATION RESTORED IN 1 MONTH

MENORRHAGIA

Experienced by 30% of the reproductive age group

60% due to menstrual dysfunction

12% of gynec referrals

Cause of IDA in 20-25% of healthy women

1 out of 20 women in the 30-50 year age group consult with

menorrhagia

STUDD 16

ROLE OF MANAGEMENT IN MENORRHAGIA

60% likely to have hysterectomy

Though hysterectomy is the definitive cure-morbidity and mortality

rates are high

With abdominal hysterectomy: 42%

With vaginal hysterectomy: 24%

STUDD 16

Trend is towards endometrial destructive procedures

It has lower complication rates and mortality

High patient satisfaction

Re operation rate of 11-40%

MANAGEMENT OF MENORRHAGIA

META ANALYSIS

Andersson and Rybo et al used LNG IUS in 20 women

Reduction in the menstrual blood loss by 85% at 3

months usage, 97% at 12 months usage

Also ferritin increased by 47% in 1st year

Side effects-spotting common in 1st 3 months and

amenorrhoea by 1 year

META ANALYSIS (CONTD)

RESULT:- 74-97% REDUCTION IN MENSTRUAL LOSS IN

WOMEN WITH CONFIRMED MENORRHAGIA.

However larger trials are reqiured

With Progestasert reduction of 65% in 12 months.

RCT

In another study by Wildermeersch and Schacht-

Fibroplant was inserted in 32 women

Reduction in menstrual blood loss by 80% in 1-23

months

APPLICATIONS:LNG VERSUS MEDICAL THERAPIES

Reduction in menstrual

blood loss by 94%

76% wished to continue

Reduction in menstrual

blood loss by 87% with 3

cycles of nor ethisterone

22% wished to continue

Mean menstrual blood loss higher with LNG IUS(96%)

LNG IUS VERSUS SURGICAL MANAGEMENT

Reduction in menstrual loss by LNG IUS has decreased

the demand for Hyterectomy and TCRE

Compared with TCRE - with LNG IUS 79-90% reduction in

the blood loss in 12 months.

Satisfaction rate-85% and 94% in the LNG IUS and TCRE

group respectively.

ASSESSMENT OF LNG IUS

PICTORIAL BLOOD ASSESSMENT CHART(PBAC); Menstrual

blood loss is measured

success rate of 67% in the LNG IUS and 90% in the resection

group

VISUAL ANALOGUE SCALE ASSESSMENT (VAS) CHART;

Sleeping problems noticed in TCRE group, however genital

health and menstural pain decreased in both groups.

OTHER STUDIES:

SMART study(Satisfaction with MIRENA and ablation: A

RANDOMISED TRIAL)

To assess satisfaction and amount of heaviness at 12

months post treatment

Study terminated due to poor recruitment rate owing to

high reluctance to be randomised to the LNG IUS group.

RCT (Medical versus surgical) Hurksainen et al- conducted a trial of cost effectiveness of LNG

IUS versus hysterectomy in 236 women with menorrhagia

After 12months: 20% of the women with LNG IUS-underwent

hysterectomy,68% continued to use and 69% experienced

minimal bleeding or amenorrhea.

Health related quality of life(HRQoL) and psychological well

being improved in both groups.

Costs higher with less pain in the hysterectomy group.

APPLICATIONS: (CONTD)

In overall: LNG IUS provides an effective, efficient, well

tolerated, cost effective alternative to other medical and

surgical management of menorrhagia.

OTHER BENEFITS:

Endometrial suppression also achieved by IUS delivering

10 mcg/day

Histological non proliferation of the endometrium after

12 months.

LOWER DOSE MIRENA

LOWER dose of LNG mirena MLS-10 mcg or 10-14 mcg

with fibroplant safe and effective for suppression of

endometrium during ERT in perimenopausal/post

menopausal women.

It induces atrophy and amenorrhoea in majority

SIDE EFFECTS- scanty and slight bloody discharge-

infrequent

LIPID AND LIPOPROTEIN METABOLISM

Generally postmenopausal women have different lipid

profile

Serum cholesterol,LDL,TG INCREASED

S.cholesterol and LDL- high risk of cardiovascular disease

With estrogen replacement therapy-s.cholesterol and

LDL is decreased and HDL increased

EFFECT ON LIPID METABOLISM:

Progestogens added- the lipid and lipoprotein profile gets

adversely altered in dose and duration dependent manner

Recent study with 2mg of oestradiol valerate and

MIRENA/oral MDPA- HDL was maintained at baseline levels

However with lower 10mcg LNG IUS - HDL increased

OTHER APPLICATIONS:

LNG IUS- Improvement in menorrhagia/ dysmenorrhoea,

protects against development of fibroids.

LNG achieves faster regression of endometrial

hyperplasia greater efficacy of androgenic progestogens

in achieving secretory transformation

DISADVANTAGES AND SIDE EFFECTS:

Hence adequate dilatation required

Adequate analgesia with NSAIDS/paracervical block/local

analgesia

Asepsis important

Complications-

preforation,embedment,expulsion,infection

OTHER USES OF LNG IUS (CONTD)

As contraceptive agent, prevention of ectopic

Treatment of early endometrial cancer (stage I a)

Helps in prevention of PID by preventing from STI’s transmission

As part of estrogen replacement therapy

Prevention of tamoxifen induced endometrial hyperplasia

Reduction in pain and dymenorrhoea in endometriosis

SIDE EFFECTS

Ovarian cyst formation: Function ovarian cysts

commoner with LNG-1.2/100 women years

Cysts are symptomless/small/and spontaneous

resolution(94%)

Fitting the system: Necessitates a wider insertion tube

and prior cervical dilatation.

SIDE EFFECTS (CONTD)

Unscheduled vaginal bleeding

Irregular vaginal bleeding and spotting in the first 3 – 6

months

Amenorrhoea at the end of 1st year in 35% of women

Prior intrauterine pathology to be excluded

SIDE EFFECTS ( CONTD)

Progestogenic side effects

Edema

Wt gain

Hirsuitism

Acne

Headache

Metabolic side effects

CONTRA INDICATIONS RELATIVE

Postpartum between 48hrs to 4weeks (↑expulsion rates)

Current DVT or Pulmonary embolus

Benign trophoblastic disease Past H/O breast carcinoma Ovarian carcinoma Exposure to gonorrhea or

Chlamydia STI’s AID’s (unless clinically well

on anti-retroviral therapy) Active liver disease (acute

viral hepatitis, severe decompensate cirrhosis, benign or malignant liver tumors)

ABSOLUTE

Pregnancy Postpartum puerperal sepsis Immediately post-septic

abortion Malignant GTD Cervical carcinoma (awaiting

treatment) Endometrial carcinoma Distortion of uterine cavity

(fibroids, anatomical abnormalities)

Current PID Current purulent cervicitis,

STI’s Pelvic Koch’s

TAKE HOME MESSAGE

According to NICE guidelines MIRENA is the first line of

treatment for DUB along with the combined OCP’s.

Used broadly as contraceptive agent with reversal of

fertility following its removal within a year.

Forms the mainstay of treatment for idiopathic

menorrhagia, and provides uterine protection during

estrogen replacement therapy.

REFERENCES: Serum and peritoneal fluid levels of levonorgestrel in women with

endometriosis, device containing levonorgestrel. Fertil Steril. 2005;83(2):398–404.

Nilsson CG, Lahteenmaki PL, Luukkainen T, Robertson DN. Sustained intrauterine release of levonorgestrel over five years. Fertil Steril. 1986;45(6):805–807 .

Sturdee D, Rantala ML, Colau JC, Zahradnik HP, Riphagen FE. The acceptability of a small intrauterine progestogen-releasing system for continuous combined hormone therapy in early postmenopausal women. Climacteric. 2004;7(4):404–41.

Wildemeersch D, Schacht E, Wildemeersch P, Janssens D, Thiery M. Development of a miniature, low-dose, frameless intrauterine levonorgestrel-releasing system for contraception and treatment: a review of initial clinical experience. Reprod Biomed Online. 2002;4(1):71–82.

REFERENCES (Contd) French R. Hormonally impregnated intrauterine systems (IUSs) versus other

forms of reversible contraceptives as effective methods of preventing pregnancy. Cochrane Database Syst Rev. 2005;1:

McGavigan CJ, Cameron IT. The mirena levonorgestrel system. Drugs Today. 2003;39(12).

McGavigan CJ, Cameron IT. The mirena levonorgestrel system. Drugs Today. 2003;39(12):973–984

Ikomi A, Pepra EF. Efficacy of the levonorgestrel intrauterine system in treating menorrhagia: actualities and ambiguities. J Fam Plann Reprod Health Care. 2002;28(2):99–100

Pakarinen P, Toivonen J, Luukkainen T. Therapeutic use of the LNG-IUS, and counseling. Semin Reprod Med. 2001;19(4):365–372

Lahteenmaki P, Rauramo I, Backman T. The levonorgestrel intrauterine system in contraception. Steroids. 2000;65(10–11):693–697

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