2. Dysfunctional Uterine Bleeding Prof.DR.Dr.H.M.Thamrin Tanjung, Sp.OG(K) Dr.Muhammad Rusda, Sp.OG Dept. of Obstetric & Gynecology School of Medicine University of Sumatera Utara

3. Dysfunctional Uterine Bleeding  MOST COMMON MENSTRUAL DISORDER  CAN AFFECT ANY WOMEN FROM MENARCHEE TO MENOPAUSE  OFTEN THE FIRST CLINICAL DIAGNOSIS FOR ANY EXCESSIVE MENSTRUAL BLEEDING  DIAGNOSIS HAS TO BE CONFIRMED BY A PROCESS OF EXCLUSION OF PATHOLOGICAL CAUSES

4. Dysfunctional Uterine Bleeding  EXACT PATHOPHYSIOLOGY STILL NOT KNOWN  BASIS OF EXCESSIVE BLEEDING IS  MOSTLY AN ENDOCRINE ABNORMALITY: - OESTROGEN - PROGESTERONE IMBALANCE (mostly estrogen dominance)  ALTERED PROSTAGLANDIN SYNTHESIS INFAVOUR OF E2 THAN E2 

5. NORMAL SHORTENED FP NORMAL POLYMENORRHOEA MENORHAGIA Endocrine Abnormality In DUB w OVULATION : - w PHASE CHANGE: - w ENDOMET. HISTOLOGY: - w MENSTRUAL PATTERN: -

6. NORMAL LONG F P NORMAL OLIGOMENORRHOEA MENORHAGIA Endocrine Abnormality In DUB w OVULATION : - w PHASE CHANGE: - w ENDOMET. HISTOLOGY: - w MENSTRUAL PATERN: -

7. ABNORMAL COR.LUT SHORT L P DEFICIENT SEC. END. PRE MENS. SPOTTING MENORHAGIA Endocrine Abnormality In DUB w OVULATION : - w PHASE CHANGE: - w ENDOMET. HISTOLOGY: - w MENSTRUAL PATTERN: -

8. PERSISTENT COR. LUT. LONG L P WELL DEV. SEC. END. PROLONGED CYCLES Endocrine Abnormality In DUB w OVULATION : - w PHASE CHANGE: - w ENDOMET. HISTOLOGY: - w MENSTRUAL PATTERN: -

9. ANOVULATION (Insufficient follicles) SHORT CYCLES DEFICIENT PRO. END. POLYMENORRHAGIA MENORRHAGIA Endocrine Abnormality In DUB w OVULATION : - w PHASE CHANGE: - w ENDOMET. HISTOLOGY: - w MENSTRUAL PATTERN: -

10. w OVULATUION : - w PHASE CHANGE: - w ENDOMET. HISTOLOGY: - w MENSTRUAL PATERN: - ANOVULATION (Polycystic Ovaries) PROL. CYCLES PRO. / HYPERPLASTIC OLIGOMENORRHOEA METROPATHIA HAEMORRHAGICA Endocrine Abnormality In DUB

11. OVULATIONPHASE CHANGE END. HISTMENSTRUAL PATTERN ANOVULATION (Polycystic Ovaries) PROL. CYCLESPRO. / HYPERPLASTIC OLIGOMENORRHOEA METROPATHIA HAEMORRHAGICA ANOVULATION (Insufficient follicles) DEFICIENT PRO. END. SHORT CYCLES POLYMENORRHAGIA MENORRHAGIA PERSISTENT COR. LUT LONG L P WELL DEV. SEC. END PROLONGED CYCLES ABNORMAL COR.LUT SHORT L PDEFICIENT SEC. END. PRE MENS. SPOTTING MENORHAGIA NORMAL SHORTENED F P LONG F P POLYMENORRHAGIA MENORRHAGIA OLIGOMENORRHOEA MENORRHAGIA

12. D U B - Management Options CONSERVATIVE     D & C     MEDICAL    SPONTANEOUS CURE       RECURENCE     D & C   FAILURE /  RECURENCE       -SURGERY- ENDOMETRIAL ABLATION / HYSTERCTOMY

13.  HORMONES  Es+Pr  Progestogens  Estrogen  Androgens + Estrogen  Danazol  GnRha  SECOND LINE & mostly Adjuvant  NSAIDs  Mefenamic acid  Ethamsylate  Antifibrinolytics EACA Tranexamic acid  Radiotherapy ? Medical Treatment for DUB

14.  Treatment has to be indivisualised  Not suitable for all ages  Response is erratic and unpredictable  SIDE EFFECTS - Discontinuation and noncompliance  Failures are common  Cost effectiveness ?  Surgery is often resorted to Medical Treatment for DUB Problems: -

15. ENDOMETRIAL ABLATION: - TCRE – Tran Cervical Resection Of Endometrium ELA – Endrometrial Laser Ablation HTEA – Hydrothermal Endrometrial Ablation  HYSTEROSCOPIC METHODS: - Surgical Treatment of DUB

16. RFEA – Radio Frequency Endometrial Ablation TBEA – Thermal Balloon Endometrial Ablation VSEA – Vestablate System Endometrial Ablation MWEA – Microwave Endometrial Ablation ERA – Endometrial Resection and Ablation With a Specialised Tissue Aspiration Resectoscope (STAR) TUMA – Total Uterine Mucosa Ablation by a Calibrated Uterine Resection Tool (CURT) ENDOMETRIAL ABLATION: -  NON HYSTREOSCOPIC METHODS: - Surgical Treatment of DUB

17. VAGINAL HYSTERECTOMY LAPAROSCOPICALLY ASSISTED V H Lap Hys.- Total / Subtotal Abdominal / MINILAP Hysterectomy- Total / Subtotal HYSTERECTOMY: - Surgical Treatment of DUB

18.  Curettage  Mostly diagnostic  Never gives a cure  Endometrial resection / ablation  Array of methods  Recurrence is common  Amenorrhoea gives cure HYSTERECTOMY Invasive procedure Not suitable at all ages Not without risks Costly First option in 40+ DUB is the most common indication Problems: -

19. Need of the Hour for the Treatment of DUB The ideal therapy should be a designer drug which can block the action of Estrogen on the Endometrium but not its beneficial actions on other tissues “Selective Ostrogen Receptor Modulators” “Designer Oestrogens”

20. Mechanism of Tissue Response Oestrogen Receptor Ligand Complex Oestrogen Receptor Ligand E / SERM / ERD DNA Oestrogen Response element Gene Transcription Tissue Response Agonistic & or Antagonistic Coregulatory Proteins  /  AF 1 & 2 Selective Ostrogen Receptor Modulators

21. Estrogens Anti Estrogens SERMs Designed to act in specific ways at each of the oestrogen receptor sites in different tissues 3.ORMELOXIFENE 1.Tamoxifene 2.Raloxifene Droloxifene Toremifene

22. The Ideal Selective Ostrogen Receptor Modulator The ideal SERM is one that has no uterine stimulation, prevents bone loss, has no risk of breast cancer, a +ve effect on lipids & cardiovascular system and maintains cognitive function of the brain The Search goes on Adopted from – Rita de Cassia M Dardes & V Craig Jordan

23. The Ideal Selective Ostrogen Receptor Modulator The Search goes on TISSUE Endometrium Breast Vagina Bone Liver/CVS CNS Perfect AE E E-Estrogenic, AE-Anti Estrogenic Tamo E AE E AE Ralo AE E ?E+ E? Ormelo AE  E 

24. ORMELOXIFENE The individual elements of the molecular structure give a tissue selectivity- different DNA transcriptions in different tissues Oestrogen agonist Oestrogen antagonist Chemical Name- Trans -7-methyl-2-2-dimethyl- 3-phenyl-4(4-(2- pyroldinoethoxy)phenyl(- chroman hydrochloride)

25. An optimally designed SERM with Varied Tissue Response It blocks the cytosol receptors by its competitive binding affinity over Estradiol. It not only causes a slow build up of the receptors, but also causes their prolonged retention. Its action lasts long after the drug is withdrawn. ORMELOXIFENE

26. An optimally designed SERM with Varied Tissue Response Estrogen Antagonist in UTERUS & BREAST. Mild Estrogenic action on Vagina, Bone mineral density, CNS and Serum Lipids. No action on Hypothalamic Pituitary Ovarian function, Thyroid or Adrenal. No Progestational, Androgenic or Antiandrogenic properties ORMELOXIFENE

27. An optimally designed SERM with Varied Tissue Response INDICATED for the treatment of Dysfunctional Uterine Bleeding at ANY AGE. Offers additional advantage of relief of PMS in peirmenopausal women. Not suitable for women desiring pregnancy because of its contraceptive property. ORMELOXIFENE

28. An optimally designed SERM with Varied Tissue Response Women desiring contraception should use a barrier contraceptive for first two months ORMELOXIFENE

29. Has an excellent safety profile,very well tolerated & practically without any undesirable side effects Few contraindications- H/O Liver dysfunction or clinical jaundice PCOD Cervical Dysplasia, Chronic Cervicitis H/O Hypersensitivity to the drug Nursing mothers(6months). Allergic conditions Chronic illness renal disease & TB ORMELOXIFENE

30. Precaution- Menstrual cycles may be delayed in some users. Is of no concern if tablets have been taken regularly. However if it exceeds 15days rule out pregnancy. ORMELOXIFENE Has an excellent safety profile,very well tolerated & practically without any undesirable side effects

31. Easy to administer- Two 60mg tablets twice a week ( for example, Sunday & Wednesday) for 12 weeks followed by one tablet of 60mg twice a week for another 12 weeks ORMELOXIFENE Has an excellent safety profile,very well tolerated & practically without any undesirable side effects

32. An optimally designed SERM with Varied Tissue Response Future possibility of use for- Fibromyoma, Adenomyosis Endometriosis Breast cancer (prevention & treatment) Osteoporosis (prevention & treatment) Menopause management. ORMELOXIFENE

33. Summary  Dysfunctional Uterine Bleeding is a very common disorder at all ages from menarche to menopause.  Though its pathophysioology is still unclear, Estrogen- Progesterone imbalance is usually the basis of bleeding.  Available medical treatment modalities are far from satisfactory.  Ormeloxifene, the latest Selective Estrogen Receptor Modulator, is closest to the perfect SERM, having the desired antirestrogenic and estrogenic action in different tissues. ORMELOXIFENE

34.  It has a very good safety profile and well tolerated, being practically devoid of side effects.  It is easy to administer and cost effective.  However extensive large scale clinical trials are needed to establish its effectiveness and safety ORMELOXIFENE Summary