aub.prof.salah roshdy

AUB Salah Roshdy,M.D

Professor of Obstetrics

&Gynecology

2015

Objectives

• Definitions & Diagnosis

• The evidence base for recommended management

• What tests are necessary & when

• Treatment

– Medical & Surgical

– Indications & Options

– Risks & Side Effects

Normal Menstrual Cycle

• Menstration is a cyclic physiological phenomena

• starting at the age of Menarche (11-14years) till establishment of Menopause (45-55 yrs).

• It is regulated by hypothalmo-pituitary- ovarian hormones secreted in pulsatile and cyclic pattern.

• Volume of blood flow is assessed by number of pads / tampons used whether the pads are fully/ partially soaked , presence of clots. It can be better assessed by pictorial charts--

Pad Area Soaked 1st day 2nd Day

3rd Day 4th Day 5th day

6th Day

7th Day

X 1 // / /

X 5 /// //

X20 ///

Total Points 89(<1oo)- Normal

blood Loss

Tampons soaked X1

// // / /

x 5

///

D X 15 Total Points

////// 111 Excessive

Arrest of Menstrual bleeding

1 Haemostasis by platelet plug and clot formation – starts soon the bleeding starts and open BV are plugged .once Blood vessels are plugged , fibrin deposition occurs ---Fibrinolysis also go hand in hand to balance and keep the blood loss fluid.

Arrest of Menstrual bleeding

• 2.Prostaglandin Mediation – Archadonic acid and Pg synthetase enzyme produce PGs ---pge2 –vasodilator, PGf2a--- vasoconstrictor and Thromboxane – vasoconstrictor. Estrogen produce PGE2 and PGF2a in ratio of 1:1 in proliferative phase ; while Progesterone produce PGE2 and PGF2a + thromboxane in 1: 2 ratio in premenstrual phase so balance is shifted towards vasoconstriction which help in control of bleeding.

Arrest of Menstrual bleeding --

3. Tissue Repair --- starts from the mouths of open endometrial glands in the denuded areas , endothelium out grows and covers the raw area under the influence of Epithelial Growth Factor ( EGF) and blood vessels regrow due to Vascular endothelial Growth Factor (VEGF).

Thus the raw area of remaining basal endometrium is completely epithelized under Estrogen effect.

Why do we have to know about AUB??

• Abnormal uterine bleeding affects 10 to 30 percent of reproductive-aged women and up to 50 percent of perimenopausal women

• It is a common reason for gynecologic consultation.

• Responsible for over one third of hysterectomies.

Terms abandoned in the FIGO nomenclature system

• Dysfunctional uterine bleeding

• Functional uterine bleeding

• Hypermenorrhea

• Hypomenorrhea

• Menorrhagia (all usages: essential

menorrhagia, idiopathic menorrhagia,

Terms abandoned in the FIGO nomenclature system

primary menorrhagia, functional menorrhagia, ovulatory menorrhagia,anovulatory menorrhagia).

• Metrorrhagia

• Metropathica hemorrhagica. • Oligomenorrhea • Polymenorrhagia

• Polymenorrhea • Uterine hemorrhage

Frasier I, Fertility and Sterility 2007; 87:466-76

The “New Normal”: Proposed Terms for Vaginal Bleeding

FIGO terminology system • Acute AUB

Is now defined as “an episode of bleeding in a woman of reproductive age, who is not pregnant, that, is of sufficient quantity to require immediate intervention to prevent further blood loss

FIGO terminology system

• Chronic AUB

is" bleeding from the uterine corpus that is

abnormal in duration, volume, and/or frequency

and has been present for the majority of the last 6 months

Heavy Menstrual Bleeding

• The term HMB is used to describe the woman’s perspective of increased menstrual volume, regardless of regularity, frequency, or duration

National Institute of Health and Clinical Excellence

guidelines • “HMB should be defined as excessive

menstrual blood loss which interferes with the woman’s physical, emotional, social and material quality of life, and which can occur alone or in combination with other symptoms

Intermenstrual bleeding

When a woman experiences episodes of bleeding that occur between normally timed menstrual periods.

• Such bleeding can be cyclic and predictable,

such as that often associated with ovulation.

FIGO System for AUB, 2011

AUB: Structural Conditions

• P: Endometrial polyp

– IMB or PCB in 30-50 year old woman

• A: Adenomyosis

– Dysmenorrhea, dyspareunia, chronic pelvic pain, sometimes menorrhagia

• L: Leiomyoma

– Submucous myoma

– Menorrhagia; rarely IMB; never metrorrhagia

AUB: Structural Conditions

• M: Malignancy and hyperplasia

– Adenomatous hyperplasia (AH) atypical AH endometrial carcinoma

• Post-menopausal bleeding

• Recurrent perimenopausal metrorrhagia

• Chronic anovulator (PCOS) with metrorrhagia

– Leiomyosarcoma

• Post-menopausal bleeding

COEIN: Coagulopathy

• Clotting factor deficiency or defect – Liver disease

– Congenital (Von Willebrands Disease)

• Platelet deficiency (thrombocytopenia) with platelet count <20,000/mm3 – Idiopathic thrombocytopenic purpura (ITP)

– Aplastic anemia

• Platelet function defects

COEIN: Coagulopathy Screen for underlying disorder of hemostasis if any of • Heavy menstrual bleeding since menarche • One of the following

– Post-partum hemorrhage – Bleeding associated with surgery – Bleeding associated with dental work

• Two or more of the following – Bruising 1-2 times per month – Epistaxis 1-2 times per month – Frequent gum bleeding – Family history of bleeding symptoms

Munro M, Int J Gynecol Obstet (2011)

COEIN: Ovulatory

• Anovulation

–Age: peri-menarche and perimenopuse

–PCOS

– Stress

• Hypothyroidism

• Luteal phase defects

COEIN: Ovulatory

• Mainly due to anovulatory bleeding

– Age-related: peri-menarche, perimenopause

– Estrogenic: unopposed exogenous or endogenous estrogen

– Androgenic: PCOS; CAH, acute stress

– Systemic: Renal disease, liver disease

• Diagnosis of exclusion

– Menometrorrhagia not due to by anatomic lesion, medications, pregnancy

COEIN: Ovulatory

• Hyperthyroidism or hypothyroidism

– Bleeding can be excessive, light, or irregular

– Only severe, uncorrected thyroid disease causes abnormal bleeding patterns

– Normal pattern when corrected to euthyroid

– 1o hypothyroidism assoc. with 2o amenorrhea

Low T4 high TRH high TSH normal T4

high PRL amenorrhea + galactorrhea

COEIN: Ovulatory

• Luteal Phase Defect (LPD)

– Luteal phase lasts 7-10 days (vs. 14 days) or inadequate peak luteal phase progesterone (P)

• Diagnosis

– Polymenorrhea (“periods every 2 weeks”)

– Mid-luteal phase P level between 4-8 ng/ml

– Endometrial biopsy >2 days out of phase

COEIN: Endometrial

• Idiopathic – Unexplained menorrhagia

• Endometritis

– Post-partum

– Post-abortal endometritis

– Endometritis component of PID

• In teens, PID commonly presents with abnormal bleeding (menorrhagia, IMB), not pelvic pain

– Any teen with abnormal bleeding + pelvic pain requires bimanual exam to evaluate for PID

COEIN: Iatrogenic Conditions

• Anticoagulants

– Over-anticoagulation: menorrhagia

– Therapeutic levels will not cause bleeding problems

• Chronic steroids, opiates

• Progestin-containing contraceptives

• Intrauterine Contraception (IUC)

– "Normal" side effect menorrhagia

– PID, pregnancy (IUP or ectopic),

perforation, expulsion

COEIN: Not Classified

• Chronic endometritis

• AVM

• Myometrial hypertrophy

FIGO classification system for causes of abnormal uterine bleeding in the reproductive years

Diagnostic management

• History • Any known uterine disease, induced vaginal

bleeding.

• Risk factors for hypothyroidism and any personal or family history of disorders of hemostasis must be sought with specific questions(Grade B)

• Age • Age at menarche. • Parity. • Menstrual History—regularity, frequency,

duration of bleeding , Volume of blood loss. • Post coital bleeding ? • Dysmenorrhoea – spasmodic / congestive . • Dyspareunia. • O.H.---fertility / infertility/ gravidity / parity etc. • Associated Vaginal Discharge . • Recent Abortion / delivery / ectopic pregnancy . • IUCD insertion , ocs, hormone therapy/ drugs.

Clinical Examination • A complete clinical examination is

recommended, including checking for signs of anemia, abdominal palpation, and a cervical examination, both digital and with a speculum , except for virgins or adolescents.

• When the history suggests nothing relevant, the pictogram is normal, the clinical examination is normal and no sign of anemia is present, no diagnostic investigation is recommended (Grade C).

laboratory Investigations

• CBC

• Blood coagulation profile

• TFT if there is any risk factors

• B HCG

Imaging examinations

• Pelvic ultrasound:

both abdominal and transvaginal, is recommended as a first-line procedure for the etiological diagnosis of AUB (Grade A).

• Doppler ultrasonography provides additional information useful for characterizing endometrial and myometrial abnormalities (Grade B).

Hysteroscopy or SIS

• Uterine exploration: Hysteroscopy or SIS can be suggested as a second-line procedure when ultrasound suggests an intrauterine abnormality or if medical treatment fails after

3–6 months (Grade B).

Endometrial biopsy

• An endometrial biopsy must be performed in the case of any risk factor for endometrial cancer and for all patients older than 45 years (Grade C).

• A biopsy sample should be obtained with a polypropylene endometrial suction curette (Pipelle de Cormier)during the diagnostic hysteroscopy (Grade B)

• Diagnostic curettage under general anesthesia is not recommended as a first-line treatment (Grade A).

• Hysteroscopic directed biopsies .

Which Test?

What is the Evidence?

• Systematic Review of TVS (10 studies), Saline I Sonography (SIS, 11 studies) and Hysteroscopy (3 studies) for the identification of any pathology

• TVS – Sensitivity 48 – 100%

– Specificity 12 – 100%

• SIS – Sensitivity 85 – 100%

– Specificity 50– 100%

• Hysteroscopy – Sensitivity 90 – 97%

– Specificity 62 – 93%

• Ultrasound better for the identification of fibroids

• SIS and Hysteroscopy better for the identification of polyps

Treatment A. General

1.Treatment of iron deficiency anemia

B. Medical I. Hormonal:

1.Progestagen

2.Oestrogen

3.COCP

4.Danazol

5.GnRh agonist

6.Levo-nova (Mirena)

II. Non –hormonal

1.Prostaglandin synthetase inhibitors (PSI)

2.Antifibrinolytics

3.Ethamsylate

C. Surgical 1. Endometrial ablation

2. UAE

3. Hysterectomy

Tranexamic acid Competitive inhibitor of plasminogen activator -antifibrinolytic agents

Menorrhagia -Reduced breakdown of fibrin preformed clot in spiral endometrium arterioles reduce MBL

Reduce MBL by 34-59% Cost effective when compared with other NSAIDS and no treatment -not when compared with LNG-IUS However,

-not reduce dysmenorrhea -not a contraceptive -not regulate cycles

Dosage: 1g ( 2 tablets) 3-4x daily from onset of bleeding up to 4 days

Mechanism of action: The endometrium possess an active fibrinolytic

system, & the fibrinolytic activity is higher in

menorrhagia. Effect: Greater reduction of menstrual bleeding than other

therapies (PSI, oral luteal phase progestagen &

ethamsylate)(Cochrane library,2002).

Tranexamic acid is effective in treating menorrhagia

associated with IUCD.

Side effects: is dose related. Nausea , vomiting, diarrhea, dizziness. Rarely: transient color vision disturbance, intracranial thrombosis. But, no evidence that tranxemic acid increases the risk in absence of past or family history of thrombophilia. (Cochrane library,2002).

NSAIDs Reduce prostaglandin synthesis by inhibiting COX

Prostaglandin: - Inflammatory response - Pain pathways - Uterine cramps - Uterine bleeds

Reduces MBL 20-49% but tranexamic acid and danazol reduces MBL greater -better AE profile than danazol Less cost effective than LNG and tranexamic acid

Treatment of dysmenorrhea

However, - Not contraceptions - Not to be used in bleeding

disorders

Cyclooxygenase Pathway

Arachidonic Acid

Prostaglandins

Thromboxane Prostacyclin*

cyclic endoperoxides are inhibited, therefore this step is blocked

X

*Causes vasodilation and inhibits platelet aggregation

Mechanism; the endometrium is a rich source of PGE2 & PGF2œ &

its concentrations are greater in menorrhagia. PSI

decreases endometrial PG concentrations.

Effect: PSI decreased menstrual blood by 24% &

norethisterone by 20%.

The beneficial effect of mefenamic acid on MBL

& other symptoms e.g. dysmenorrhea, headache, nausea, diarrhea & depression

persists for several months.

Dose: Mefenamic acid 500 mg tds during menses. Side effects: nausea, vomiting, gastric discomfort,

diarrhea, dizziness. Rarely: haemolytic

anemia, thrombocytopenia. The degree of

reduction of MBL is not as great as it is with

tranxamic acid but PSI have a lower side

effect profile.

Ethamsylate: Mechanism of action:

maintain capillary integrity, anti-

hyalurunidase activity & inhibitory effect

on PG

Dose:

500 mg qid, starting 5 days before

anticipated onset of the cycle &

continued for 10 days

Effect:

20% reduction in MBL.

There is no conclusive evidence of

the effectivness of ethamsylate in

reducing menorrhgea (Grade A)

Side effects:

headache, rash, nausea

Summary of Non-Hormonal Drugs • Tranexemic acid is more effective than NSAIDs

• But both can be used together

• And either can be continued long term if benefit is obtained

• But should be stopped if there is no response after 3 cycles

• Neither are contraceptive or cycle regulating

• NSAID is the drug of 1st choice when there is concomitant dysmenorrhoea

• All of the trials excluded women with fibroids so their role in menorrhagia with fibroids is uncertain

Systemic progestagens: Norethisterone & medroxyprogesterone acetate

Ovulatory DUB: not effective if given at low dose for

short duration (5-10 days) in the luteal phase.

Effective if NEA is given at higher dose for 3 w out of

4 w (5 mg tds from D5 to 26)

Anovulatory DUB: useful

Side effects:

weight gain, nausea, bloating, edema, headache,

acne, depression, exacerbation of epilepsy &

migraine, loss of libido

Progestins: Mechanisms of Action

• Inhibit endometrial growth

– Inhibit synthesis of estrogen receptors

–Promote conversion of estradiol estrone

– Inhibit LH

• Organized slough to basalis layer

• Stimulate arachidonic acid formation

Progesterone Cyclooxygenase Pathway

Arachidonic Acid

Prostaglandins PGF2α*

Thromboxane Prostacyclin *Net result is increased PGF2α/PGE ratio

Progestational Agents

• Cyclic medroxyprogesterone 2.5-10mg daily for 10-14 days

• Continuous medroxyprogesterone 2.5-5mg daily

• Progesterone in oil, 100mg every 1 week

• DepoProvera® 150mg IM every 3 months

• Levonorgestrel IUD (5 years)

LNG-IUS

Vertical stem: release daily doses of 20 micrograms of LNG

Effects: -prevent endometrial proliferation -thicken cervical mucus -suppress ovulation

Cost effective when compared with other hormonal and non hormonal treatments

Reduction of MBL between 71-96% -benefit seen after 6 months

Effect; 1.Comparable to endometrial

resection for management of AUB. 2.Superior to PSI & antifibrinolytics

3.May be an alternative to

hysterectomy in some patients

Side effects;

1.BTB in the first cycles

2.20% develop amenorrhea within 1 yr

3.Functional ovarian cysts

Special indications:

1. Intractable bleeding associated

with chronic illness

2. Ovulatory heavy bleeding

Meta-Analysis: Mirena® vs. Ablation for AUB

• No difference between rates of treatment failures

–21.2% LNG-IUS vs. 17.9% endometrial ablation

• Both methods resulted in similar improvements in quality of life

• Less need for analgesia/anesthesia in LNG-IUS group

• Ablation requires additional effective contraception

Kaunitz, et al. OG. 2009 May;113(5):1104-16b.

The Mirena IUS for AUB

What is the Evidence?

• Systematic Review of 10 RCT’s that compare Mirena with other hormonal methods of treatment, endometrial ablation & hysterectomy

• Reduces mean menstrual loss by 71 – 96%

• Up to 50% of patients amenorrhoeic after 6m depending on age

• ≈ 85% patients are satisfied (and continuation rate)

• ≈ 1% rate of troublesome hormonal side effects

When compared to endometrial ablation (EA).

The Mirena IUS for AUB

What is the Evidence?

– Mean reduction in blood loss is greater with EA

– But overall satisfaction equal

– And Mirena better in the longer term (1 small study)

• When compared to hysterectomy

– Overall satisfaction rates are equal

– But Mirena is half the cost even when up to 40% of patients go on to hysterectomy

COCP Contain estrogen and progestogen in combinations

Act on HPO axis to suppress ovulation and fertility Endometrial suppresion -cause withdrawal bleeding

Reduces MBL by 43 -50 % - Greater than naproxen - Lesser than danazol and tranexamic

acid

Less benefit

COCP

Mechanism of action:

endometrial suppression Side effects; headache, migraine, weight gain, breast tenderness, nausea, cholestatic jaundice,

hypertension, thrombotic episodes,

Oral Hormones for AUB

What is the Evidence?

• Only one RCT of 45 patients for Combined oral contraceptive (COC)

• Mean blood loss (MBL) was reduced by 43-50%

• Better than Danazol and one NSAID but not another trialled

• Risks in older women and smokers plus side effects limit its use

• Progestin e.g. Norethisterone 5 mg TDS from Day 5 to 26 of a cycle is effective in reducing (MBL)

– Luteal phase progestins are not effective

• Not as effective as NSAIDs and Tranexamic acid

• But MBL was reduced by 83% with long term use in 44 women CF Mirena (94%) and this difference is not significant

• Side effects are limiting – weight gain, headaches, acne, mood changes, mastalgia

GnRH-analogues

Synthetic peptide that act like a natural GnRH but with longer biological half life

Action 1. Flare effect -increase FSH and LH 2. Profoung hypogonadal effect - after 10 days downregulation

No follicular development, estrogen production, no ovulation, no progeterone, no menses

Treatment 1. Hormonal sensitive cancer -breast cancer, prostate cancer 2. Estrogen dependant lesion - leiomyoma, endometriosis

Reduces MBL but with high adverse effects

GnRH analog Side effects;

hot flushes, sweats, headache,

irritability, loss of libido, vaginal

dryness, lethargy, reduced bone

density.

GnRH analogues for AUB

• Most studies have been directed at the reduction of uterine size with these agents that induce a “reversible menopause”

• Reductions in uterine size up to 75% over 6m can occur

• And up to 90% of patients achieve amenorrhea

• This can be very useful prior to hysterectomy

• Oestrogen-deficiency symptoms i.e. hot flushes, vaginal atrophy and bone loss are limiting

• But these can be overcome with add-back therepy using small doses of oral oestrogen, COC, progestin or tibilone

• GnRH are currently very expensive drugs

RECOMMENDATION FOR PHARMACEUTICAL APPROACH

Recommendations

• Considered in - no structural or histological abnormalities - fibroid <3 cm that not distort uterus • Choices depends on wish to conceive

• If either can, follow order 1. LNG-IUS 2. Tranexamic acid or COCP 3. Oral Progestogen

• If treatment is needed during investigations or before definite treatment

- tranexamic acid or NSAIDs • If coexist with dysmenorrhea NSAIDs

• Stop NSAIDs and tranexamic acid if no improvement

after 3 cycles

• GnRH-a -recommended prior to surgery -other treatments of uterine fibroids (UAE, surgery) is contraindicated

• Not to be used as AUB treatment

-Danazol

- Oral progestogen during luteal phase

Surgical treatment Endometrial ablation

Methods: I.Hysteroscopic:

1. Laser

2. Electrosurgical: a. Roller ball

b. Resection II.Non-hysteroscopic:

1. Thermachoice

2. Microwave.

Indications:

1. Failure of medical treatment

2. Family is completed

3. Uterine cavity <10 cm

4. Submucos fibroid <5 cm

5. Endometrium is normal or low

risk hyperplasia.

Complications of

hysteroscopic methods

1. Uterine perforation

2. Bleeding

3. Infection.

4. Fluid overload

5. Gas embolism

Uterine artery embolization (UAE)

Indications - Heavy bleeding - Large fibroids

How it works? - Small particles introduced into artery supply to the uterus

fibroid shrinks Adverse outcomes - Persistent vaginal discharge - Post-embolisation syndrome: pain, nausea, vomiting and fever - Need additional surgery - Premature ovarian failure - hematoma

Fertility

maintained!

Hysterectomy Indications:

1. Failure of medical treatment

2. Family is completed Routes:

1. Abdominal

2. Vaginal

3. Laparoscopic

Advantages:

1. Complete cure 2. Avoidance of long term medical treatment 3. Removal of any missed pathology Disadvantages:

1.Major operation

2.Hospital admission

3.Mortality & morbidity

Endometrial Ablation or Hysterectomy

What is the Evidence? • Systematic review 1999 of 5 RCTs with 706 patients

• Hysterectomy reduced MBL more (OR 0.12, CI 0.06 – 0.25)

• Greater patient satisfaction at 12m & 24m (OR 0.46, CI 0.24 – 0.88)

• Less pelvic pain on follow up (p<0.007)

• Better social functioning (p<0.007)

• Endometrial ablation had shorter hospital stay

• Fewer adverse outcomes

• More likely to require further surgery (OR 7.33, CI 4.18 – 12.86) (1:5 patients go on to hysterectomy)

• As a result hysterectomy is as cost effective as EA

• But is associated with ↑rate of long term urinary symptoms

Uterine Artery Embolisation (UAE) or

Hysterectomy?

• 5 RCT’s 157+ patients showed that UAE better than hysterectomy in terms of: – Procedure time (Mean 16min less)

– Less blood loss (minimal with UAE CF av. 400 ml for hysterectomy )

– Fewer blood transfusions

– Shorter hospital stay (Mean 3.3 days less)

– Quicker return to normal duties (Mean 27 days less)

– Cheaper (UAE costs 65% those of hysterectomy)

• No difference between UAE and hysterectomy in terms of: – Patient satisfaction

– Complication rates

• But UAE result in more readmissions (OR 6.00, CI 1.14 -31.53)

• And 13 – 30% UAE patients require further surgery

NICE Recommendations on Surgical Options

• Endometrial resection by a 2nd generation technique be offered to all women with HMB provided that they have completed their family

• If the uterus is <10w in size and or fibroids < 3 cm diameter

• A hysteroscopic technique is used when there are submucous fibroids

• Practitioners and institutions be trained and competent for EA

• Hysterectomy, uterine artery embolisation or myomectomy be considered for fibroids >4 cm or uterus >10w size

Summary • AUB is a common problem

• Mirena is offered as first line treatment and has reduced need for hysterectomies significantly

• For women wanting to conceive in short term – tranexamic acid and mefenamic acid appropriate

• For others COCP, norethisterone, Depo-provera can be effective

• Surgical and radiological interventions available in secondary care setting