CAPSULE: MIRENA AS TREATMENT OPTION IN DUB

Dr.NISHAT

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 LNG20 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. 2. 3. 4. Progestasert Mirena Mirena MLS 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

ENDOMETRIAL EFFECTS (CONTD)

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

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

MANAGEMENT OF MENORRHAGIA
Trend is towards endometrial destructive procedures It has lower complication rates and mortality High patient satisfaction Re operation rate of 11-40%

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% Reduction in menstrual blood loss by 87% with 3 cycles of nor ethisterone 76% wished to continue 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 dischargeinfrequent

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 STIs 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 STIs AIDs (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, STIs Pelvic Kochs

TAKE HOME MESSAGE

According to NICE guidelines MIRENA is the first line of treatment for DUB along with the combined OCPs. 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):398404. Nilsson CG, Lahteenmaki PL, Luukkainen T, Robertson DN. Sustained intrauterine release of levonorgestrel over five years. Fertil Steril. 1986;45(6):805807 . 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):40441. 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):7182.

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):973984 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):99100 Pakarinen P, Toivonen J, Luukkainen T. Therapeutic use of the LNGIUS, and counseling. Semin Reprod Med. 2001;19(4):365372 Lahteenmaki P, Rauramo I, Backman T. The levonorgestrel intrauterine system in contraception. Steroids. 2000;65(1011):693697

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