Prof.DR.Dr.H.M.Thamrin Tanjjg p ()ung, Sp.OG(K)...

Dysfunctional Uterine BleedingDysfunctional Uterine Bleeding

Prof.DR.Dr.H.M.Thamrin Tanjung, Sp.OG(K)j g p ( )Dr.Muhammad Rusda, Sp.OG

Dept. of Obstetric & GynecologySchool of Medicine University of Sumatera Utara

Dysfunctional Uterine Bleedingy g

MOST COMMON MENSTRUAL DISORDER

CAN AFFECT ANY WOMEN FROM MENARCHEE TO MENOPAUSEMENARCHEE TO MENOPAUSE

OFTEN THE FIRST CLINICAL DIAGNOSIS FOR ANY EXCESSIVE MENSTRUAL BLEEDINGANY EXCESSIVE MENSTRUAL BLEEDING

DIAGNOSIS HAS TO BE CONFIRMED BY A PROCESS OF EXCLUSION OF PATHOLOGICAL CAUSES

Dysfunctional Uterine Bleedingy g

EXACT PATHOPHYSIOLOGY STILL NOT KNOWN

BASIS OF EXCESSIVE BLEEDING ISBASIS OF EXCESSIVE BLEEDING IS MOSTLY AN ENDOCRINE ABNORMALITY: -OESTROGEN PROGESTERONE IMBALANCEOESTROGEN - PROGESTERONE IMBALANCE (mostly estrogen dominance)

ALTERED PROSTAGLANDIN SYNTHESISALTERED PROSTAGLANDIN SYNTHESIS INFAVOUR OF E2 THAN E2α

Endocrine Abnormality In DUB

NORMALOVULATION : NORMAL OVULATION : -

SHORTENED FPPHASE CHANGE: -

ENDOMET.

NORMALHISTOLOGY: -

MENSTRUAL

POLYMENORRHOEA MENORHAGIA

MENSTRUAL

PATTERN: -

MENORHAGIA


NORMALOVULATION : NORMAL OVULATION : -

LONG F PPHASE CHANGE: -

ENDOMET.

NORMALHISTOLOGY: -

MENSTRUAL

OLIGOMENORRHOEA MENORHAGIA

MENSTRUAL

PATERN: -

MENORHAGIA


ABNORMAL COR LUTOVULATION : ABNORMAL COR.LUTOVULATION : -

SHORT L PPHASE CHANGE: -

ENDOMET.

DEFICIENT SEC. END.HISTOLOGY: -

MENSTRUAL

PRE MENS. SPOTTING MENORHAGIA

MENSTRUAL

PATTERN: -

MENORHAGIA


PERSISTENT COR LUTOVULATION : PERSISTENT COR. LUT.OVULATION : -

LONG L PPHASE CHANGE: -

ENDOMET.

WELL DEV. SEC. END.HISTOLOGY: -

MENSTRUAL

PROLONGED CYCLES

MENSTRUAL

PATTERN: -


ANOVULATIONOVULATION : ANOVULATION(Insufficient follicles)

OVULATION : -

SHORT CYCLESPHASE CHANGE: -

ENDOMET.

DEFICIENT PRO. END.HISTOLOGY: -

MENSTRUAL

POLYMENORRHAGIA MENORRHAGIA

MENSTRUAL

PATTERN: -

MENORRHAGIA


OVULATUION : ANOVULATIONOVULATUION : - ANOVULATION(Polycystic Ovaries)

PHASE CHANGE: -

ENDOMET.

PROL. CYCLES

HISTOLOGY: -

MENSTRUAL

PRO. / HYPERPLASTICMENSTRUAL

PATERN: - OLIGOMENORRHOEAMETROPATHIAMETROPATHIA HAEMORRHAGICA


OVULATION PHASE CHANGE

END. HIST MENSTRUAL PATTERN

NORMALNORMAL

NORMAL

SHORTENED F P

LONG F P

POLYMENORRHAGIAMENORRHAGIA

OLIGOMENORRHOEA

ABNORMAL COR LUT

SHORT L P DEFICIENT SEC END

PRE MENS. SPOTTING MENORHAGIA

NORMALLONG F P OLIGOMENORRHOEA MENORRHAGIA

PERSISTENT COR. LUT

LONG L P WELL DEV. SEC. END

PROLONGED CYCLES

COR.LUT SEC. END. MENORHAGIA

ANOVULATION PROL CYCLES PRO / OLIGOMENORRHOEA

ANOVULATION(Insufficient follicles)

DEFICIENT PRO. END.

SHORT CYCLES POLYMENORRHAGIAMENORRHAGIA

ANOVULATION(Polycystic Ovaries)

PROL. CYCLES PRO. / HYPERPLASTIC

OLIGOMENORRHOEAMETROPATHIA HAEMORRHAGICA

D U B - Management Optionsg p

CONSERVATIVE ← ← ← ← D & C ⇒ ⇒ ⇒ ⇒ MEDICAL↓ ⇓ ⇓

SPONTANEOUS CURE ⇓ ⇓SPONTANEOUS CURE ⇓ ⇓↓ ⇓ ⇓

RECURENCE → → → → D & C ⇐ ⇐ FAILURE /RECURENCE → → → → D & C ⇐ ⇐ FAILURE /RECURENCE

⇓ ⇓⇓ ⇓ ⇓⇓ ⇓ ⇓

-SURGERY-ENDOMETRIAL ABLATION / HYSTERCTOMY

Medical Treatment for DUB

HORMONES SECOND LINE & HORMONES Es+Pr mostly Adjuvant

NSAIDsProgestogensEstrogen

Mefenamic acidEthamsylateg

Androgens +Estrogen

Antifibrinolytics• EACA

EstrogenDanazol

• Tranexamic acid

R di th ?GnRha Radiotherapy ?

Medical Treatment for DUBProblems: -

Treatment has to be indivisualisedNot suitable for all ages gResponse is erratic and unpredictableSIDE EFFECTS - Discontinuation andSIDE EFFECTS Discontinuation and noncomplianceFailures are commonFailures are common Cost effectiveness ? Surgery is often resorted toSurgery is often resorted to

Surgical Treatment of DUB

ENDOMETRIAL ABLATION: -

HYSTEROSCOPIC METHODS: -

• TCRE – Tran Cervical Resection Of

Endometrium

• ELA – Endrometrial Laser Ablation

• HTEA – Hydrothermal Endrometrial Ablation


ENDOMETRIAL ABLATION: -

• RFEA – Radio Frequency Endometrial Ablation

NON HYSTREOSCOPIC METHODS: -q y

• TBEA – Thermal Balloon Endometrial Ablation• VSEA – Vestablate System Endometrial Ablationy• 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)


HYSTERECTOMY: -

• VAGINAL HYSTERECTOMY• LAPAROSCOPICALLY ASSISTED V H• Lap Hys.- Total / SubtotalLap Hys. Total / Subtotal • Abdominal / MINILAP Hysterectomy- Total /

SubtotalSubtotal


Curettage • HYSTERECTOMYProblems: -

CurettageMostly diagnosticNever gives a cure

HYSTERECTOMY• Invasive procedure• Not suitable at allNever gives a cure

Endometrial resection / ablation

• Not suitable at all ages

• Not without risksresection / ablationArray of methodsRecurrence is

• Not without risks• Costly• First option in 40+Recurrence is

commonAmenorrhoea gives

• First option in 40+ • DUB is the most common indicationcure common indication

Need of the Hour for the Treatment of DUBDUB

The ideal therapy should be a designer drugThe ideal therapy should be a designer drugwhich can block the action of Estrogen on

the Endometrium but not its beneficialthe Endometrium but not its beneficial actions on other tissues

“Selective Ostrogen Receptor Modulators”“D i O t ”“Designer Oestrogens”

Selective Ostrogen Receptor ModulatorsOestrogen Receptor

LigandE / SERM / ERD

Coregulatory Proteinsα / β AF 1 & 2

Oestrogen Receptor Li d C l

Gene Transcription

g y

Ligand Complex Transcription

DNA Oestrogen Response element

Tissue Response Agonistic & or

Mechanism of Tissue Response

pAntagonistic

Selective Ostrogen Receptor Modulators

E tDesigned to act in

Estrogens

SERMs

specific ways at each of the oestrogen receptor

SERMs sites in different tissues

3 ORMELOXIFENE3.ORMELOXIFENE

2.Raloxifene

iDroloxifeneToremifene

Anti Estrogens 1.TamoxifeneDroloxifene

The Ideal Selective Ostrogen Receptor Modulator Th S hModulator The Search goes on

The ideal SERM is one that has no

uterine stimulationuterine stimulation, prevents bone loss,

has no risk of breasthas no risk of breast cancer, a +ve effect

on lipids & cardiovascular system

and maintains iti f ti fcognitive function of the brain

Adopted from – Rita de Cassia M Dardes & V Craig Jordan

The Ideal Selective Ostrogen Receptor Modulator Th S hModulator The Search goes on

TISSUE Perfect Tamo Ralo Ormelo

Endometrium

B t

AE

AE

E

AE

AE

AE

AE a

AEaBreast

Vagina

AE

E

AE

AE

AE

AE

AE a

E a

Bone

Liver/CVS

E

E

E

E

E

?E+

E a

EaLiver/CVS

CNS

E

E

E

AE

?E+

E?

E a

E aE-Estrogenic, AE-Anti Estrogenic

ORMELOXIFENE

Chemical Name-

Trans -7-methyl-2-2-dimethyl-3-phenyl-4(4-(2-

pyroldinoethoxy)phenyl(-chroman hydrochloride)

The individual elements of the molecular structure give a tissue selectivity- different DNA transcriptions in y p

different tissues

Oestrogen agonist Oestrogen antagonist

ORMELOXIFENEAn optimally designed SERM with Varied Tissue

Responsep

It blocks the cytosol receptors by its competitive binding affinity over Estradiolbinding affinity over Estradiol.

It not only causes a slow build up of the receptors, y p p ,but also causes their prolonged retention.

Its action lasts long after the drug is withdrawnwithdrawn.


Responsep

Estrogen Antagonist in UTERUS & BREAST.

Mild Estrogenic action on Vagina, Bone mineral g g ,density, CNS and Serum Lipids.

No action on Hypothalamic Pituitary Ovarian function, Thyroid or Adrenal. No Progestational, , y g ,

Androgenic or Antiandrogenic properties


Responsep

INDICATED for the treatment of Dysfunctional Uterine BleedingDysfunctional Uterine Bleeding

at ANY AGE.

Offers additional advantage of relief of PMS i i lin peirmenopausal women.

Not suitable for women desiring pregnancy because of its contraceptive property.


Responsep

Women desiring contraception should use a barrier contraceptive for first two months

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

ORMELOXIFENEHas an excellent safety profile,very well tolerated & practically without any undesirable side effects

Precaution-

& practically without any undesirable side effects

• Menstrual cycles may be delayed in some users.users.• Is of no concern if tablets have been taken

regularlyregularly.

• However if it exceeds 15days rule out pregnancypregnancy.

ORMELOXIFENEHas an excellent safety profile,very well tolerated & practically without any undesirable side effects

Easy to administer-

& practically without any undesirable side effects

yTwo 60mg tablets twice a week ( for

l S d & W d d ) f 12example, Sunday & Wednesday) for 12 weeks followed by one tablet of 60mg twice a week for another 12 weeks


Responsep

Future possibility of use for-Fib•Fibromyoma,

•Adenomyosis•Endometriosis•Breast cancer (prevention & treatment)•Breast cancer (prevention & treatment)

•Osteoporosis (prevention & treatment)

•Menopause management.

ORMELOXIFENE

SummaryDysfunctional 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 differentdesired antirestrogenic and estrogenic action in different tissues.

ORMELOXIFENE

SummaryIt has a very good safety profile and well tolerated, being practically devoid of sidetolerated, being practically devoid of side effects.

It is easy to administer and cost effective.

However extensive large scale clinicalHowever extensive large scale clinical trials are needed to establish its effectiveness and safety

Prof.DR.Dr.H.M.Thamrin Tanjjg p ()ung, Sp.OG(K)...

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