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

 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

 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.

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.

daily dose of hormone directly into the uterine cavity  Sustained for a number of years .AIM  Deliver a small predictable.

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  .


2. Progestasert Mirena Mirena MLS Fibroplant .TYPES 1. 4. 3.

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 .

 Bound to SHBG which protects from metabolism  Max levels in few hours.425 pg/ml at 1 month and 330 pg/ml at 6 months.  Mean systemic level of LNG following insertion. plateau after first few weeks .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.




systemic absorption of LNG IUS should be 50 mcg/24 hours.MECHANISM OF ACTION: OVARIAN FUNCTION  Effect on ovarian function –minimal  As for suppression of ovulation .  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 .

decidualisation of the stroma.atrophy of the endometrial glands.capillary thrombosis.ENDOMETRIAL EFFECTS  LNG IUS-profound changes in the hormonally non responsive decidua basalis  Endometrium undergoes uniform structural and histological changes  HISTOPATHOLOGICAL STUDIES show-thinning. and inflammatory cell infiltrate .


decrease in the subendometrial flow in the spiral arteries .ENDOMETRIAL EFFECTS (CONTD)  Thinning: Occurs in the first 3 months  Local blood flow gets altered development of thin walled blood vessels  Doppler studies show .

GROWTH FACTORS  Normal effect: Insulin like growth factors modulate the effect of estrogen  Endometrial stromal cells produce IGF and IGF BP   IGF 1STIMULATES ENDOMETRIUM TO PROLIFERATE IGF 2CAUSES AND MAINTAINS DIFFERENTIATION WITHIN THE ENDOMETRIUM .

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

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% .

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  Andersson and Rybo et al used LNG IUS in 20 women  Reduction in the menstrual blood loss by 85% at 3 months usage.

.  However larger trials are reqiured  With Progestasert reduction of 65% in 12 months.META ANALYSIS (CONTD)  RESULT:.74-97% REDUCTION IN MENSTRUAL LOSS IN WOMEN WITH CONFIRMED MENORRHAGIA.

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%) .

 Satisfaction rate-85% and 94% in the LNG IUS and TCRE group respectively. .with LNG IUS 79-90% reduction in the blood loss in 12 months.LNG IUS VERSUS SURGICAL MANAGEMENT  Reduction in menstrual loss by LNG IUS has decreased the demand for Hyterectomy and TCRE  Compared with TCRE .

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. however genital health and menstural pain decreased in both groups.ASSESSMENT OF LNG IUS  PICTORIAL BLOOD ASSESSMENT CHART(PBAC).  Sleeping problems noticed in TCRE group. .

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. .

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.  Costs higher with less pain in the hysterectomy group.  Health related quality of life(HRQoL) and psychological well being improved in both groups.RCT (Medical versus surgical)  Hurksainen et al. .

well tolerated.APPLICATIONS: (CONTD)  In overall: LNG IUS provides an effective. efficient. . 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.scanty and slight bloody dischargeinfrequent .  It induces atrophy and amenorrhoea in majority  SIDE EFFECTS.

LIPID AND LIPOPROTEIN METABOLISM  Generally postmenopausal women have different lipid profile  Serum cholesterol.cholesterol and LDL is decreased and HDL increased .LDL.high risk of cardiovascular disease  With estrogen replacement therapy-s.TG INCREASED  S.cholesterol and LDL.

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 .EFFECT ON LIPID METABOLISM:  Progestogens added.HDL increased .

 LNG achieves faster regression of endometrial hyperplasia greater efficacy of androgenic progestogens in achieving secretory transformation . protects against development of fibroids.Improvement in menorrhagia/ dysmenorrhoea.OTHER APPLICATIONS:  LNG IUS.

infection .embedment.DISADVANTAGES AND SIDE EFFECTS:  Hence adequate dilatation required  Adequate analgesia with NSAIDS/paracervical block/local analgesia  Asepsis important  Complications- preforation.expulsion.

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 .

STI’s  Pelvic Koch’s . anatomical abnormalities)  Current PID  Current purulent cervicitis.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.

 Used broadly as contraceptive agent with reversal of fertility following its removal within a year. and provides uterine protection during estrogen replacement therapy.  Forms the mainstay of treatment for idiopathic menorrhagia.TAKE HOME MESSAGE  According to NICE guidelines MIRENA is the first line of treatment for DUB along with the combined OCP’s. .

Janssens D. Zahradnik HP. 2005. Robertson DN. Nilsson CG. 2004. low-dose. Fertil Steril. Wildemeersch D. Riphagen FE. 2002. Colau JC. Lahteenmaki PL. frameless intrauterine levonorgestrel-releasing system for contraception and treatment: a review of initial clinical experience. Thiery M. 1986. Wildemeersch P. Rantala ML. device containing levonorgestrel.4(1):71–82.45(6):805–807 . Reprod Biomed Online.    . The acceptability of a small intrauterine progestogen-releasing system for continuous combined hormone therapy in early postmenopausal women. Sturdee D. Climacteric. Fertil Steril. Development of a miniature.REFERENCES:  Serum and peritoneal fluid levels of levonorgestrel in women with endometriosis.83(2):398–404. Schacht E. Luukkainen T. Sustained intrauterine release of levonorgestrel over five years.7(4):404–41.

Luukkainen T. 2002.REFERENCES (Contd)  French R. Rauramo I. The mirena levonorgestrel system. Cameron IT. 2001. Efficacy of the levonorgestrel intrauterine system in treating menorrhagia: actualities and ambiguities. Drugs Today. Pepra EF. 2000. The mirena levonorgestrel system.39(12):973–984 Ikomi A. Semin Reprod Med. Therapeutic use of the LNGIUS. Cochrane Database Syst Rev.39(12).28(2):99–100 Pakarinen P.65(10–11):693–697      . 2005. Cameron IT. Toivonen J. Hormonally impregnated intrauterine systems (IUSs) versus other forms of reversible contraceptives as effective methods of preventing pregnancy.1: McGavigan CJ. and counseling. J Fam Plann Reprod Health Care. Backman T. 2003. Drugs Today. 2003. McGavigan CJ.19(4):365–372 Lahteenmaki P. Steroids. The levonorgestrel intrauterine system in contraception.