Progesteronlu RİA : Kime ?

Prof.Dr.Umur Çolgar

THE LEVONORGESTREL INTRAUTERINE DEVICE

Steroid reservoir: Levonorgestrel 52mg Silicone rate-limiting membrane

T frame

Removal threads

32 mm

Mirena®: Levonorgestrel release 20 µg/24 hours

THE LEVONORGESTREL INTRAUTERINE SYSTEM

Mirena®

Levonorgestrel Intrauterine System

Multiple modes of action

Main: Prevention of

endometrial proliferation Thickening of utero-

cervical fluidMinor: Occasional prevention of

ovulation Foreign body reaction in

endometrium

Which Patient ?

Desire for contraceptionMenorrhagiaHRT programme for

perimenopausal and menopausal women

Barcelona1 7

Effects of LNG-IUD

Suppression of IGF-1 by abandoned production of IGFBP-1 causes inhibition of the IGF-1-mediated estrogen effects.Inhibition of angiogenesis.Hamptom et al Human Reprod. 20, 2653, 2005

Levonorgestrel concentration in plasma, fat myometrium, endometrial and oviduct tissues

Tissue LNG-IUS Oral**

Plasma(pg/ml) 202 559

Fat tissue * 1.23 4.41

Myometrium * 2.43 1.4

Endometrium* 808 3.5

Oviduct * 1.8 1.7

*ng/g wet weight** Oral administration of levonorgestrel

Clinical Endocrinology ,Nilsson et al 1982

LEVONORGESTREL IUS

Proliferative Secretory Inactive

Courtesy Dr E-M Rutanen, Helsinki

SEVERE PELVIC INFLAMMATION

12.5% risk of tubal infertility with first attack

33% risk with second attack

Weström 1980

Return to Fertility

No delay

Ovulation occurs within 2 weeks

& menstruation within 23 days

Rates of conception post removal

are normal

Definition

Regular heavy bleedingfrom a secretory endometriumexceeding 80 ml per cycle

Patient Selection for Menorrhagia Treatment

Organic factors should be diagnosed

Pathologies of the endometrium should be examined

Causes of menorrhagiaIdiopathic (no obvious cause)Fibroidsendometriosis / adenomyosisgenital infectionsendometrial polypshyperplasiamalignancycoagulation or endocrine

disordersmedications

Efficacy of Mirena® in menorrhagia

Mirena effectively reduces menstrual blood loss (MBL)

0

50

100

150

200

Beforeinsertion

3 6 12

Months of Mirena use

Med

ian

MB

L (m

L)

Andersson and Rybo. Br J Obstet Gynaecol. 1990; 97: 690-4

* * *

* p<0.001

─86%─97%─91%

% Reduction

(80mL MBL = menorrhagia)

Mirena® compared with flurbiprofen, and tranexamic acid

Mirena® is significantly more effective than flurbiprofen or tranexamic acid in reducing menstrual blood loss

-95.8

-20.7

-44.4

-100-90-80-70-60-50-40-30-20-10

0

Mirena Flurbiprofen

(FL)Tranexamicacid (TA)

Per

cent

age

chan

ge fr

om

base

line

in M

BL

Milsom et al. Am J Obstet Gynecol 1991; 164: 879-83

***

**

*

* P<0.05 (FL vs TA)

**P<0.01 (Mirena vs TA)

***P<0.001 (Mirena vs FL)

Mirena® compared with endometrial ablation/resection

Mirena has comparable efficacy with endometrial resection in reducing menstrual blood loss

Crosignani et al. Obstet Gynecol 1997; 90: 257-63

184.8203.2

38.823.5

0

50

100

150

200

250

Mirena Endometrialresection

Mea

n bl

eedi

ng s

core

Baseline

12 months

79% 89

%

LNG-IUS therapeutic effect on Fibroid uterus

The local direct endometrial suppression is the principal mechanism explaining the effect of the LNG-IUS on menstrual blood loss in cases of leiomyoma.

Single intramural fibroid less than 5 cm or multiple intramural fibroids < 3 cm in diameter and < 5 in number.

Submucousal extension less than 30% and not causing major distortion of uterine cavity.

Uterine length less than 10cm

Hysteroscopy, endometrial biopsy

liquid base cytology

Transvaginal ultrasound

Criteria of selection

ESH classification

X

XX

ESH Submucous Myoma Classification

TypeIntramural Extension

0 None

I  < 50%

II  > 50%

European Society for Hysteroscopy Classification

Changes in Uterine and Leimyoma Volume

Baseline(n=67)

3 months (n=56)

6 months (n=56)

12 months (n=61)

Uterine volume (mL)

138±72 131±68p<0.01

125±58 p<0.01

122±73p<0.01

Total leiomyoma volume (mL)

30±29 27±34p=0.10

19±21 p<0.001

19±21 p<0.001

Barcelona 2 23

Barcelona 2 26

Suvanto-Luukkonen et al Acta Obstet. Gynecol. Scand. 77, 758, 1998

Barcelona 2 27

Anderson et al Obstet. Gynecol. 79, 963, 1992

28

Mirena® combined with 2 mg oral estradiol valerate in postmenopausal women

At 6 and 12 month endometrial histology was nonproliferative.

The thickness of the endometrium was 3.6 mm.Conclusion: Mirena® protects against endometrial

hyperplasia. In most of the women it induces amenorrhea.

Varila et al Fert. Steril. 76,969,2001

Barcelona 2 29

Percutaneous gel (1.5 mgE2 daily) and Mirena®

1. Spotting was frequent during the first 6 month and declined thereafter.

2. At 1 one year 80 % of the women were amenorrheic

3. Endometrium morphology showed epithelial atrophy accompanied by decidual reaction of the stroma.

Suvanto-Luukkonen, Kauppila Fert. Steril. 72, 161, 1999

30

Levonorgestrel-IUD Mirena® with oral conjugated estrogens in perimenopausal women

n=82

Length of treatment

(month)

Nonproliverative endometrium

(%)

Propotion of amenorrhea

(%)

12 98,6 % 54,4

24 98,6 %

36 95,5 %

48 96,8 %

60 95,2 % 92,7

No endometrial hyperplasia was detected throughout the period of 60 month.

Hampton et al Human Reprod. 20, 2653, 2005

LNG-IUD in ERT-users1 Year Follow-Up

Raudaskoski et al. BritJ Obstet Gynaecol 2002;109:136

168 postmenopausal women in 4 Finish Menopause ClinicsAll did get oral 2mg E2-valeriate daily Randomised:

LNG-IUD 10 microgram per dayLNG-IUD 20 microgram per dayCyclic MPA: 5mg/day 14/30

Endometrial protectionAtrophia in both LNG-IUD18/47 had endometrial proliferation in MPA group

Serum lipid profileTotal cholesterol decreased in all 3 groupsHDL increased in MPA and LNG-IUD 10 micrograms per day

InsertionEasy: 70% for smaller versus 46% for larger (Mirena)Difficult: 4% for smaller versus 21% for larger (Mirena)

LNG-IUD – Beyond Contraception

Down regulation of ER/PRIncrease in apoptosis and decreased proliferationEndometrial glandular atrophy in 87%Endometrial stromal decidualisation in 96%Stromal inflammatory cell infiltrate in 79%Insuline-like growth factor 1 (IGF1-BP)Increase in impedance to blood flow to uterine a.Endometrial angiogenic growth factorsMany locally acting mediators of breakthrough

beeding: Interleukin-8, Cyclooxygenase-2

Barcelona1 33

Varma et al Obstet. Gynecol. in press

MIRENA and Endometriosis

StudyStudy size

Duration ResultsLNG IUS vs control

Vercellini et al (2003)

20 LNG IUS

20 surgery

only

12 months

10% vs 45% recurrence of dysmenorrhea

75% vs 50% satisfied with the treatment

Barcelona1 35

Petta et al Human Reprod. 20, 1993-1998, 2004

The nulliparous modern woman

Appropriate method NICE

Possible less PID Investment in fertility

◦ Less menorrhagia◦ Less dysmenorrhea

Switch off/Switch on contraception

Fit and forgetHigher continuation in 80%

compared to 73% for COC Suhonen, Contraception 2004;69:407

38

Meme Kanseri İnsidansı/100.000

Yaş Grupları 30-34 35-39 40-44 45-49 50-54

Mirena 27,2 74,0 120,3 203,6 258,5

Kontrol 25,5 49,2 122,4 232,5 272,6

BackmanT. ObstetGynecol 106:813,2005

40

Varma et al Obstet. Gynecol. in press