mirena updated
TRANSCRIPT
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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