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F.I.G.O. Guideline
&
Medical Mx Of A. U. B.
( FOCUS ON PROGESTERONE )
Dr. Shashwat Jani
M. S. ( Obs – Gyn ), F.I.A.O.G.
Diploma in Advance Laparoscopy.
Consultant Assistant Professor,
Smt. N.H.L. Municipal Medical College.
Sheth V. S. General Hospital , Ahmedabad.
Mobile : 99099 44160.
E-mail : drshashwatjani@gmail.com
Abnormal Uterine Bleeding…
Most common complaint in Gynecological and
Family practice.
It accounts for 70% of all Gynaecologic Consults.
Affects 1/3 of women at some stage in their life.
Key to management include:
• establishing cause
• instituting appropriate therapy
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
2
Epidemiology
▶ The estimated worldwide prevalence of subjective,
self-defined AUB varies greatly, from 4 to 52%
▶ Abnormal uterine bleeding is a common condition
affecting women of reproductive age that has
significant social and economic impact.
▶ India - Prevalence is about 17.9%
F1000Prime Rep. 2015; 7: 33.
https://www.nhp.gov.in/disease/gynaecology-and-obstetrics/abnormal-uterine-bleeding
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
3
4
Many terms
Menorrhagia
Hypermenorrhea Metrorrhagia
Menometorrhagia
Amenorrhea
Polymenorrhea Oligomenorrhea
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
Back To Basics…
• Polymenorrhoea: frequent (<21 d) menstruation,
at regular intervals
• Oligomenorrhea: infrequent menstruation (>35 d)
• Menorrhagia: Excessive (>80 ml) & / or prolonged
menstruation, at regular intervals
• Metrorrhagia: Excessive (>80 ml) & / or prolonged
menstruation at irregular intervals.
• Menometrorrhagia: both.
• Intermenstual bleeding: episodes of uterine
bleeding between regular menstruations
• Hypomenorrhoea: scanty menstruation.
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
5
Etiology Of AUB
Neonatal
period
Prepubertal
period
Adolescence Reproductive years Peri-
menopause
Post-
menopause
Estrogen
withdrawal
Foreign body
Infection
Blood dyscrasia
Hypothalamic
Anovulation (central,
intermed, gonadal)
Carcinoma
(uterus, cervix)
Atrophic
vaginitis
Sarcoma immaturity Functional (blood
dyscrasia, hypothyroid,
Climacteric Carcinoma
(uterus,
botryoides
Ovarian tumor
Inadequate
luteal function
luteal dysfunction)
Iatrogenic
(contraception,
Polyps ovarian)
Estrogen
Trauma Psychogenic
(including
anorexia,
bulemia)
anticoagulation,
hemodialysis)
Pregnancy (abortion,
ectopic, RPOC, GTD)
replacement
Uterine
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
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7
We need a mnemonic..!!!
• HELPERR
• CHADSVASc
• SIGECAPS
• O BATMAN!
• I GET SMASHED
• ABCDEFGH
• PPPPPPP
Etiology
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
WAVES OF CHANGE…!!!
 In 2006, FIGO identified as the appropriate
body to provide supervision & international
credibility to the ongoing evaluation of new
terminology
 In 2009, FIGO Menstrual Disorders Group was
formed. FIGO World Congress of Gynecology and
Obstetrics , accepted the new terminology.
 In 2011, the PALM-COEIN Classification
System created.
 In 2012, PALM-COEIN system was endorsed by
ACOG.
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
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If I Had A Coin In My Palm
For
Every Women With AUB…
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
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+91 99099 44160.
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FIGO Classification System for Causes of
Abnormal Uterine Bleeding
in the Reproductive Years
Structural abnormality No structural abnormality
Polyp
Adenomyosis
Leiomyoma
Malignancy & Hyperplasia
Coagulopathy
Ovulatory Dysfunction
Endometrial
Iatrogenic
Not Yet Classified
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+91 99099 44160.
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Terminology abandoned by FIGO
Munro et al. Int J Gynecol Obstet 2011; 113: 3-13
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Dr Shashwat Jani.
+91 99099 44160.
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What’s Normal ? ( FIGO 2011 )
Character Descriptive term Normal limits
Frequency of menses, days
Frequent
Normal
Infrequent
<21
21-38
>38
Regularity of menses: cycle-
to-cycle variation over 12
months, days
Absent
Regular
Irregular
No Bleeding
Variation ± 2-20
Variation >20
Duration of flow, days
Prolonged
Normal
Shortened
>8
3-8
<3
Volume of monthly blood
loss, mL
Heavy
Normal
Light
>80
5-80
<5
1 normally soaked “regular” product is approximately 5mL of blood, a “super” or “maxi” size
holds 10mL
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
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28-Aug-18
Dr Shashwat Jani.
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Structural Abnormalities
• P – Polyps – scored as Present or Absent
• A – Adenomyosis - scored as Present or Absent
• L – Leiomyoma
Primary level – Present or Absent
Secondary level – Distinguish between
submucosal (SM) & others (O)
Tertiary level – Detail location/size of uterine
fibroids
• M – Malignancy & hyperplasia
28-Aug-18
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AUB – P ; POLYPS ( 8 – 35 %)
• Diagnosis: US, SIS, hysteroscopy
• Further sub-classification: Dimensions, location &
number
Pre-menopausal polyps:
64 – 88% have symptoms
Present with HMB, AUB, IMB, or post-coital bleeding
Symptoms do NOT correlate with number, diameter & site
Post-menopausal polyps:
Most are symptom free
Cause for 21-28% of PMP bleeding
Associated with cervical polyps in 24-27%
Incidence of carcinoma varies between 0–4.8%
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
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Polyp
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AUB – A ; ADENOMYOSIS
• Ectopic endometrial glands & stroma within the
myometrium.
• Hypertrophy & hyperplasia of surrounding
myometrium.
• Usual presentation: HMB, uterine enlargement,
& dysmenorrhea.
28-Aug-18
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+91 99099 44160. 18
AUB – L ; Leiomyoma
• 1ry level: AUB-L
• 2ry level:
Submucosal – AUB- L SM
Other – AUB – L O
• 3ry level: Types 0 - 8
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
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The 3 stage Classification
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AUB – M ;
Malignancy & Hyperplasia
• Detected based upon results of office biopsy or
curettage
• FIGO AUB Staged only as present or absent
• Use existing WHO and FIGO categorization
• Up to 40% of patients with a biopsy diagnosis of
complex hyperplasia with atypia will have a
concomitant endometrial adenocarcinoma
present.
28-Aug-18
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+91 99099 44160.
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28-Aug-18
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Non - structural Abnormalities
• C – Coagulopathy
• O – Ovulatory Dysfunction
• E – Endometrial
• I – Iatrogenic
• N – Not yet classified
28-Aug-18
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+91 99099 44160.
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AUB – C ; COAGULOPATHY
• Prevalence: 3% of women presenting with HMB
• Etiologies:
Von Willebrand’s disease (10%)
Platelet Dysfunction
Factor XI deficiency
Factor X deficiency
Category includes patient’s taking anticoagulants
28-Aug-18
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+91 99099 44160.
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AUB – O ; OVULATORY DYSFUNCTION
Etiology:
 Polycystic Ovarian Syndrome (PCOS)
 Hypothyroidism
 Hyper- prolactinemia
 Mental stress
 Obesity
 Anorexia
 Weight loss
 Extreme exercise
 Adolescence
 Menopausal transition
28-Aug-18
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+91 99099 44160.
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AUB – E , ENDOMETRIAL
It is diagnosed by exclusion
Etiology:
• Deficiencies of local production of vasoconstrictors
Endothelin-1
Prostaglandin F2a
• Excessive production of plasminogen activators
• Increased local production of vasodilators
Prostaglandin E2
Prostacyclin I2
• Disorders of endometrial repair (inflammation)
• Chlamydia
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
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AUB – I ; IATROGENIC
Etiology:
Breakthrough bleeding (BTB) using gonadal steroids is
the major component of AUB-I :
• Oral contraceptives
• Continuous or cyclic progesterone
• IUD or implant related bleeding
Cigarette smoking : reduces the level of steroids because
of enhanced hepatic metabolism
Systemic agents that interfere with dopamine
metabolism :
• Serotonin uptake inhibitors
28-Aug-18
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+91 99099 44160.
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AUB – N ; NOT YET CLASSIFIED
Disorders that would be identified or defined only
by biochemical or molecular biology assays…
• Arterio-venous malformations
• Myometrial hypertrophy
• Category for new etiologies
• Pathological conditions of lower genital tract ??
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
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Acc. To FIGO Classification…
• Abnormal Uterine Bleeding (AUB): quantity,
regularity and/or timing.
• Acute AUB: episode of heavy bleeding that
is of sufficient amount to require immediate
intervention to prevent further blood loss.
• Chronic AUB: AUB present for most of
previous 6 months.
Acute AUB can be spontaneous or in context of
chronic AUB.
28-Aug-18
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• Intermenstrual bleeding (IMB): bleeding
between clearly defined cycles.
• Heavy menstrual bleeding (HMB): excessive
menstrual blood loss affecting quality of life –
physical, emotional, social.
Objective HMB: blood loss > 80ml/ cycle. 60% of
these women will have evidence of iron deficiency
anaemia.
Subjective HMB: 50% of women presenting with
heavy menses will have measured blood loss within
normal limits , but must still be considered
abnormal, and investigated accordingly.
28-Aug-18
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+91 99099 44160.
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AUB Patterns
▶ Ovulatory AUB
▶ Ovulatory bleeding may be heavy and can be associated with
typical premenstrual symptoms and painful periods.
▶ Anovulatory AUB
▶ Found more frequently during the perimenopause, is often
linked to prolonged periods, heavier flow and an irregular
cycle.
▶ If prolonged (e.g. in PCOS or associated with obesity),
anovulatory bleeding has a stronger link to endometrial cancer
and endometrial hyperplasia .
Am Fam Physician. 2012 Jan 1;85(1):35-4328-Aug-18
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NOTATION FOR AUB
• A patient may be found to have more than one
potential entity contributing to symptoms of AUB.
• A notation approach has been designed to enable
categorization.
For example, if a patient is found to have endometrial
hyperplasia and ovulation dysfunction with no other
abnormalities, she would be
Categorized as follows:
• AUB P0 A0 L0 M1 - C0 O1 E0 I0 N0
• May be abbreviated as : AUB – M,0
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Notation: Each Case Has 1 Identified
Abnormality
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Notation: >1 Positive Category
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Hormonal imbalance and AUB
28-Aug-18Dr Shashwat Jani.
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28-Aug-18
Dr Shashwat Jani.
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Algorithm for evaluation of
women with HMB
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
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Uterine Evaluation
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Diagnosis: H&P
• History
1. Acute vs Chronic
2. Characterize bleeding pattern
3. Menstrual bleeding hx (incl. severity and assoc pain)
4. FamHx: AUB/ bleeding disorders
5. Meds: warfarin, heparin, NSAID, OCP, ginkgo, ginseng,
motherwort
• Physical
1. PCOS: obesity, hirsutism, acne
2. Thyroid dysfunction: cold/heat intolerance, dry skin, lethargy,
proptosis
3. DM: acanthosis nigricans
4. Bleeding disorder: petechiae, pallor, signs of hypovolemia
5. Pelvic exam
◦ Is it from the uterus?!
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42
Diagnosis: Labs and Imaging
• Labs
1. Pregnancy test (Strong recommendation)
2. CBC (Strong recommendation)
3. Targeted screening for bleeding disorder (when indicated)
4. TSH
5. Gonorrhea/Chlamydia in high risk patients
• Imaging:
1. TVUS
2. Sonohysterography
3. Hysteroscopy
4. MRI
• Endometrial biopsy
28-Aug-18
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+91 99099 44160.
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Common Differential by Age
13-18 19-39 40-Menopause
• Anovulation
• OCP
• Pelvic infection
• Coagulopathy
• Tumor
• Pregnancy
• Structural Lesions
(leiomyoma, polyp)
• Anovulatory cycles
(PCOS)
• OCP
• Endometrial hyperplasia
• Endometrial cancer (less
common)
• Anovulatory bleeding
• Endometrial
hyperplasia/ carcinoma
• Endometrial atrophy
• Leiomyoma
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Management
Medical management should be initial
treatment for most patients.
Need for surgery is based on various factors
(stability of patient, severity of bleed,
contraindications to med management,
underlying cause)
 Type of surgery dependent on above + desire for
future fertility .
 Long term maintenance therapy after acute
bleed is controlled.
28-Aug-18
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Continue…
• Determine acute vs. chronic
• If acute, signs of hypovolemia/hemodynamic
instability?
– If yes, IV access with 1 to 2 large bore IV;
prepare for transfusion and clotting factor
replacement
• Once stable, evaluate etiology (PALM-COEIN)
• Determine Treatment
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Before selecting the best
treatment consider following
▶ Treat patients with dignity and respect
▶ The need for current or future fertility
▶ Facilitate informed decision making of the
women seeking treatment
▶ Allowing the woman to choose the
treatment most appropriate for her
28-Aug-18
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Medical treatment
⦿ HORMONES
› Es+Pr (COCP)
› Progestogens
› LNG IUS
› GnRHa
› Estrogen
⦿ PRM
› Ulipristal acetate
⦿ SERMS
› Ormeloxifene
⦿ ANTIFIBRINOLYTICS
› TRANEXAMIC ACID
(TA)
⦿ NSAIDs
› Mefenamic acid (MA)
› Naproxen, Ibuprofen,
Aspirin
⦿ Radiotherapy ??
BMJ. 2007 May 26; 334(7603): 1110–1111.
RCOG. National evidence-based clinical guidelines.
The initial management of menorrhagia London: RCOG, 1998.
BMJ. 2007 May 26; 334(7603): 1110–1111.
RCOG. National evidence-based clinical guidelines.
The initial management of menorrhagia London: RCOG, 1998
28-Aug-18
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Non-steroidal Inflammatory drugs
▪ Ideal NSAID would be a selective inhibitor of vasodilating PGs,
permitting the vasoconstrictor PGs to inhibit the excessive
menstrual blood loss
▪ Such a selective inhibitor is not yet available
▪ NSAIDs reduce blood loss by 25–30%, but not all women respond
similarly
▪ Commonly used are mefenamic acid and naproxen but are less
effective than tranexamic acid
▪ NSAIDS have shown only minimal effect in anovulatory
menorrhagia
▪ Side-effects include minor gastrointestinal disturbance and
headaches
1. Non-Invasive Management of Gynecologic Disorders. pp: 65-66
2. Medscape General Medicine. 1996;1(1).28-Aug-18
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Tranexamic acid
• Reduces blood loss by 50%
▶ However, many women remain
menorrhagic and many are non-
compliant due to daily dosing
▶ Large doses of tranexamic acid are
required
▶ Incidence of GI side-effects,
intermenstrual bleeding are relatively high
▶ Risk of thrombogenic disorders is a
concern 1. Clinical Gynecologic Endocrinology and Infertility. pp: 564–565.
2. J. Obstet. Gynaecol. Res. Vol. 35, No. 4: 746–752, August 2009.28-Aug-18
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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 .
28-Aug-18
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LNG-IUS
▶ A progestogen releasing intrauterine device is an
effective treatment for menorrhagia
▶ Its main advantages are relief of dysmenorrhoea,
effective contraception, and long-term control of
menorrhagia following insertion
▶ The main disadvantages are intermenstrual
bleeding and breast tenderness in the first few
months following insertion.
▶ Contraindicated in pregnancy, unexplained
vaginal bleeding and uterine sepsis
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GnRH Agonists
▶ Utility should really be for short-term use
▶ Particularly useful in the treatment of leiomyoma,
which can reduce considerably in size when ovarian
hormone levels are suppressed
▶ May be used prior to surgical intervention in women
with fibroids, or for those in whom surgery is not
suitable or desirable
▶ Studies have demonstrated excellent efficacy, with an
amenorrhea rate of up to 90% with GnRH agonist use
▶ Danazol is not frequently used because of its
androgenic and long-term lipid profile side-effects
1. Friedman et al. 1991
2. Takeuchi H et al. 200028-Aug-18
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Oral Contraceptives
▪ Action is probably mediated through endometrial
atrophy. OCPs suppress pituitary gonadotropin release,
thus inhibiting ovulation
▪ High doses of estrogen are associated with an
increased risk of thromboembolism
▪ These should be avoided in women with thrombosis or a
family history of idiopathic venous thromboembolism
▪ The most common side-effects include weight gain,
abdominal discomfort, and mid-cycle breakthrough
bleeding
▪ Not suitable in patients desiring pregnancy
1. Medscape General Medicine. 1996;1(1).
2. Clinical Gynecologic Endocrinology and Infertility. pp: 560–561.
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Injectable progestogens
▶ Depot medroxyprogesterone acetate [DMPA] can
induce amenorrhea in up to 50% of users after 1 year
and 80% after 5 years
▶ Injections are usually given every 12 weeks to maintain
progestogen exposure and ensure contraceptive
efficacy
▶ Side effects can limit compliance and include weight
gain, greasy skin and hair, acne and bloating
1. Best Practice & Research Clinical Obstetrics & Gynaecology. 2014; 28(6): 795-806
2. Obstet Gynecol. 2013; 28(6): 795-806
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Progestin therapy
▪ Most commonly used hormonal therapy given during
luteal phase.
▪ Norethisterone is the most commonly used oral
progestogen in the treatment of HMB.
▪ Older women with hypertension or diabetes or who
smoke are not good candidates
▪ “ Progestins modulate the effect of estrogen on
target cells and metabolism of estrogen, the
endometrium is maintained in a state of antimitosis
and antigrowth. “
1. Clinical gynecologic endocrinology and infertility. pp: 564–565.
2. J Midwifery Womens Health. 2003;48.
3. 3. Clinical gynecologic endocrinology and infertility. pp: 560–561.
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Hormonal therapy vs Non hormonal treatment
(When hormonal therapy??)
▶ Non-hormonal treatment is effective mainly in the
setting of heavy menstrual bleeding when the
timing of bleeding is predictable.
▶ Irregular or prolonged bleeding is most effectively
treated with hormonal options that regulate cycles,
decreasing the likelihood of unscheduled and
potentially heavy bleeding episodes
J Obstet Gynaecol Can. 2018 May;40(5):e391-e413
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Surgical Management Options
D&C
Endometrial Ablation
Uterine Artery Embolization
Hysterectomy
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Endometrial Ablation or Resection
▪ An alternative to hysterectomy; cost is a limiting factor
▪ About 20–30% have no improvement and up to 10% need
hysterectomy
▪ These procedures are less effective in women aged under 35
years, where pain is a significant associated symptom or when
the uterus is enlarged
▪ Contraindicated if future fertility is desired
▪ Younger women who use tobacco products, and have
menometrorrhagia are more likely to fail hydrothermal ablation
1. J. Obstet. Gynaecol. Res. Vol. 35, No. 4: 746–752, August 2009.
2. . Oxford American Handbook of Obstetrics and Gynecology. pp 468–469. 3.
3. Am J Obstet Gynecol. 2010 Jun;202(6):622.e1–e6.
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Medical Therapy or Hysterectomy??
▪ Success with first-generation ablative procedures varies from 80
to 97%, but they require skill for hysteroscopy
▪ Second-generation procedures take less time to perform and are
technically easier to conduct, but are expensive
▪ In low-resource settings, hot Foley catheters have been
developed with no reported complications to reduce the cost of
second-generation balloon devices, but the use of boiling saline
has its own risks
J. Obstet. Gynaecol. Res. Vol. 35, No. 4: 746–752, August 2009.
Thus, drug therapy should be the first-line treatment before recourse to
surgery
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Consideration of Medication Therapy
▶ A recent study showed 38% of women less than 40 years of
age have unsupported pathology at the time of hysterectomy
performed for AUB, uterine fibroids, endometriosis, or pelvic pain
▶ In addition, overall up to 38 % of the women who underwent a
hysterectomy were never offered an alternative treatment
option.
▶ Therefore, it is crucial to review the medical options available and
to reduce the reliance on major surgical interventions, when
possible
J Obstet Gynaecol Can. 2018 May;40(5):e391-e413
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• 17-a-hydroxy-progesterone derivatives have substitutions at C17 that slow hepatic
metabolism : medroxyprogesterone (MPA)
• 19-nor testosterone derivatives display primarily progestational rather than androgenic
activity : norethindrone
• Replacement of the 13-methyl group of norethindrone with a 13-ethyl substituent are
more potent progestins and less androgenic: norgestrel, nomegestrol
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Related to
Progesterone Related to
Testosterone
Related to
Spironolactone
✓ 17alpha-
hydroxyprogesterone
derivatives
Cyproterone acetate,
Chlormadinone acetate,
Medroxyprogesterone
acetate,
Megestrol acetate
✓ 19-norprogesterone
derivatives
Nomegestrol,
Promegestone,
Trimegestone, Nesterone
✓ 19-nortestosterone
derivatives
Norethisterone,
Levonorgestrel,
Lynestrenol,
Desogestrel,
Gestodene,
Norgestimate,
Dienogest
Drospirenone
CLASSIFICATION OF PROGESTINS
(Synthetic Derivatives Of Progesterone)
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Norethisterone
Norethisterone (or norethindrone) is a molecule used in some
combined oral contraceptive pills, progestogen only pills and
is also available as a stand-alone drug.
Used to treat PMS, painful periods, AUB, irregular periods,
menopausal syndrome (in combination with oestrogen), or to
postpone a period.
It is also commonly used to help prevent uterine hemorrhage in
complicated non-surgical or pre-surgical gynecologic cases
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Norethindrone Acetate
(NETA):
▶ Norethisterone acetate (NA) is the acetic acid ester of
norethisterone and is about twice as potent as
norethisterone
▶ Therapeutic uses of Norethindrone acetate (NETA) have been
longstanding and widely accepted
▶ It requires less frequent dosing
▶ Dose: 2.5 to 10 mg (may be given daily for 5 to 10 days) for the
treatment of AUB
The Obstetrician & Gynaecologist 2006;8:229–
234
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Mechanism of actions of NETA
• Mitotic activity
• Decreased growth of endometrium.
• Prevents or reversal of the hyperplastic process
Progesterone account for the diminished
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Side Effects ( Rare )
• Edema,
• Nausea ,
• breast tenderness,
• irregular menstrual cycle,
• breakthrough bleeding,
• spotting,
• weight change, and
• Headache .
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
66
Clinical
Evidences:
NETA
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
67
International Journal of Basic & Clinical Pharmacology 2012 ;1 (3) :191-195
Norethisterone acetate
was more effective and
better
tolerated compared to
COC
N= 60 young girls from age of
menarche to 19 years with
menorrhagia
Norethisterone Acetate Vs. COC Pills
In puberty menorrhagia.
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
68
NETA vs Drospirenone/
Ethinyl Estradiol
▶ N= 38 patients with dysmenorrhea
▶ Study type: Prospective, open-label study
▶ Treatment: Continuous NETA 5 mg daily or cyclical COC for 6 months
▶ Results:
❑ Both drugs were effective in suppressing dysmenorrhea
❑ Participants in the NETA group were less likely to use pain killers
A continuous NETA regimen is well tolerated, effective, and
inexpensive option for dysmenorrhea treatment and was as good
as COC
J Pediatr Adolesc Gynecol 29 (2016) 143e147
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
69
Efficacy of NETA as compared to MPA in
the treatment of peri-menopausal DUB
N=60 women with perimenopausal DUB
Group 1 : NETA
Group 2: MPA
Duration: Treatment was given for 20 days each cycle ( 3 treatment
cycles)
Group Cured Markedly
effective
Effective Total effective
rate (%)
NETA (30 cases) 14 11 3
93.33%
MPA (30 cases) 5 9 10 80%
Study results
• Norethisterone was more effective than MPA in controlling irregular vaginal
bleeding
• Treatment with NETA significantly improved the quality of life of patients
Open Access Library Journal 2017, Volume 4, e4136
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
70
Progestin Estrogenic activity Glucocorticoid activity
NETA slight No
MPA No Yes
Biological activities of NETA & MPA
Progestogenic effectivity on level of endometrium
Progestin Dose (mg per cycle) for secretory transformation
of endometrium
NETA 30–60
MPA 80
A.E. Schindler et al. / Maturitas 46S1 (2003) S7–S16
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
71
Norethisterone 15 mg vs LNG-IUS in
idiopathic menorrhagia
Objective: To compare the efficacy of
norethisterone vs LNG-IUS for the
treatment of idiopathic menorrhagia
Study Type: Randomized comparative
parallel group study
*LNG-IUS: Levonorgestrel intrauterine system
*MBL: Menstrual blood loss
Patient profile: Women with heavy
regular periods and a measured MBL
exceeding 80 ml
Method: N= 44 women
▶ Group 1: N=22 women treated with
LNG-IUS, inserted within the first 7
days of menses
▶ Group 2: N= 22 women received
norethisterone 15 mg (5 mg 3 times
daily) from day 5 to day 26 of the
cycle for three cycles.
British Journal of Obstetrics and Gynaecology June 1998, Vol. 105, pp. 592-598
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
72
Study Results
▶ Both regimen were effective in reducing menstrual blood loss
▶ Oral norethisterone reduced mean MBL by 87%
▶ Norethisterone at a dose of 15 mg (5 mg 3 times daily) for 21 days of the
cycle is highly effective in reducing MBL.
▶ This regimen led to a significant reduction in symptoms of intermenstrual
bleeding
Norethisterone given in high enough doses (15 mg) from early in the
cycle, leads to effective reduction in MBL
British Journal of Obstetrics and Gynaecology June 1998, Vol. 105, pp. 592-598
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
73
Norethisterone 15 mg in Menorrhagia
▶ In study conducted by Bonduelle et.al. Norethisterone 15 mg
was used from day 19 to 26 of the cycle for the treatment of
menorrhagia.
❑ The patient were included with following characteristics:
✓ Menstrual loss requiring more than 5 pads/tampons per day for
longer than 6 days cycle,
✓ Presence of flooding or clots on any day of the cycle,
✓ Presence of secondary anemia,
✓ Excessive menstrual loss proving socially and domestically disruptive
American Medical Journal 1 (1): 23-26, 201028-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
74
Study Results
▶ In this study, it was observed that NETA 15 mg (5 mg 3 times daily):
▶ Should be given from day 19 to 26 for anovulatory bleeding
▶ And for acute bleeding: it should be given from day 5 to day 26
▶ This dosage regimen of NETA is generally found to be more
effective.
American Medical Journal 1 (1): 23-26, 2010
▶ ↓mean MBL was observed
▶ ↓ associated symptoms - backache and abdominal pain
▶ Dysmenorrhoea improved to a significant degree with
norethisterone
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
75
▶ Generally well tolerated, with minimal side effects
▶ At clinical doses, it has hardly any androgenic
effect
NETA: Safety
1.Fertility and Sterility 2016; 105(3): 734 - 743.e3
2.Journal of Endometriosis (2010; 2 :4) 169-181
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
76
NETA: Guideline Recommendations
NETA 15mg should be used (which should stop
bleeding within 48 hours). In severe cases, 30 mg can
be used, tapering to 15mg for a further week
NICE
Guidelines
2007
For the control of acute bleeding, NETA 5 mg should
be administered 3 times daily for 1 week
ACOG
Guidelines
2013
NETA 5 mg–10 mg should be given every 4 hours until
bleeding stops (with a re-evaluation at 48 hours)
European
Consensus
group
2011
http://www.contemporaryobgyn.net/modern-medicine-cases/managing-acute-heavy-menstrual-bleeding/page/0/2
Pharmaceutical journal 2011; 286:71-7428-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
77
Summary of Medical Treatments For
Abnormal Uterine Bleeding
28-Aug-18
Dr Shashwat Jani.
+91 99099 44160.
78
Treatment Drugs & regimen Efficacy Contraception
Combined hormonal
contraceptives
1. cOCP for 21 days each month
2. Continous or extended regimen
3. Contraceptive ring or patch cyclic or
continuous
Menstrual regularity,
20% to 50% reduction in MBL,
reduction in dysmenorrhea and
PMS
Yes
LNG-IUS
20mcg/24hrs local LNG one IUS for up to
5 years
70% to 97% reduction in MBL,
amenorrhea in up to 80% at 1
year, reduced dysmenorrhea
Yes
Cyclic oral
progesterone
MPA 5-10mg po for 10-14d ( luteal,
anovulatory)
NETA 5mg tid day 5-26 (long phase,
ovulatory)
Bleeding reduced by up to 87%
with long phase regimen
No
Injected progesterone
DMPA 150 mg IM q90days 60% amenorrhea at 12 months,
68% at 24 months
Yes
Danazol
100-400mg po daily 80% reduction MBL,
20% amenorrhea,
70% oligomenorrhea
No
GnRH agonists
Leuoprolide acetate. IM Monthly, 3 to 6
months
Bleeding stopped in 89% by 3 to
4 weeks
No
NSAIDS
– Naprosyn 500mg od-bid
– ibuprofen 600-1200mg
– Mefenamic acid 500mg od starting day
or day before menses for 3 to 5 days
until ceases
20% to 50% reduction MBL,
reduction in dysmenorrhea in
70%
No
Anti-fibrinolytics TXA 40% to 59% reduction in MBL No
J Obstet Gynaecol Can. 2018 May;40(5):e391-e413
28-Aug-18 Dr Shashwat Jani.
+91 99099 44160.
79
AUB Guide Progesterone

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AUB Guide Progesterone

  • 1. F.I.G.O. Guideline & Medical Mx Of A. U. B. ( FOCUS ON PROGESTERONE ) Dr. Shashwat Jani M. S. ( Obs – Gyn ), F.I.A.O.G. Diploma in Advance Laparoscopy. Consultant Assistant Professor, Smt. N.H.L. Municipal Medical College. Sheth V. S. General Hospital , Ahmedabad. Mobile : 99099 44160. E-mail : drshashwatjani@gmail.com
  • 2. Abnormal Uterine Bleeding… Most common complaint in Gynecological and Family practice. It accounts for 70% of all Gynaecologic Consults. Affects 1/3 of women at some stage in their life. Key to management include: • establishing cause • instituting appropriate therapy 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 2
  • 3. Epidemiology ▶ The estimated worldwide prevalence of subjective, self-defined AUB varies greatly, from 4 to 52% ▶ Abnormal uterine bleeding is a common condition affecting women of reproductive age that has significant social and economic impact. ▶ India - Prevalence is about 17.9% F1000Prime Rep. 2015; 7: 33. https://www.nhp.gov.in/disease/gynaecology-and-obstetrics/abnormal-uterine-bleeding 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 3
  • 4. 4 Many terms Menorrhagia Hypermenorrhea Metrorrhagia Menometorrhagia Amenorrhea Polymenorrhea Oligomenorrhea 28-Aug-18 Dr Shashwat Jani. +91 99099 44160.
  • 5. Back To Basics… • Polymenorrhoea: frequent (<21 d) menstruation, at regular intervals • Oligomenorrhea: infrequent menstruation (>35 d) • Menorrhagia: Excessive (>80 ml) & / or prolonged menstruation, at regular intervals • Metrorrhagia: Excessive (>80 ml) & / or prolonged menstruation at irregular intervals. • Menometrorrhagia: both. • Intermenstual bleeding: episodes of uterine bleeding between regular menstruations • Hypomenorrhoea: scanty menstruation. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 5
  • 6. Etiology Of AUB Neonatal period Prepubertal period Adolescence Reproductive years Peri- menopause Post- menopause Estrogen withdrawal Foreign body Infection Blood dyscrasia Hypothalamic Anovulation (central, intermed, gonadal) Carcinoma (uterus, cervix) Atrophic vaginitis Sarcoma immaturity Functional (blood dyscrasia, hypothyroid, Climacteric Carcinoma (uterus, botryoides Ovarian tumor Inadequate luteal function luteal dysfunction) Iatrogenic (contraception, Polyps ovarian) Estrogen Trauma Psychogenic (including anorexia, bulemia) anticoagulation, hemodialysis) Pregnancy (abortion, ectopic, RPOC, GTD) replacement Uterine 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 6
  • 7. 7 We need a mnemonic..!!! • HELPERR • CHADSVASc • SIGECAPS • O BATMAN! • I GET SMASHED • ABCDEFGH • PPPPPPP Etiology 28-Aug-18 Dr Shashwat Jani. +91 99099 44160.
  • 8. WAVES OF CHANGE…!!!  In 2006, FIGO identified as the appropriate body to provide supervision & international credibility to the ongoing evaluation of new terminology  In 2009, FIGO Menstrual Disorders Group was formed. FIGO World Congress of Gynecology and Obstetrics , accepted the new terminology.  In 2011, the PALM-COEIN Classification System created.  In 2012, PALM-COEIN system was endorsed by ACOG. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 8
  • 9. If I Had A Coin In My Palm For Every Women With AUB… 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 9
  • 11. FIGO Classification System for Causes of Abnormal Uterine Bleeding in the Reproductive Years Structural abnormality No structural abnormality Polyp Adenomyosis Leiomyoma Malignancy & Hyperplasia Coagulopathy Ovulatory Dysfunction Endometrial Iatrogenic Not Yet Classified 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 11
  • 12. Terminology abandoned by FIGO Munro et al. Int J Gynecol Obstet 2011; 113: 3-13 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 12
  • 13. What’s Normal ? ( FIGO 2011 ) Character Descriptive term Normal limits Frequency of menses, days Frequent Normal Infrequent <21 21-38 >38 Regularity of menses: cycle- to-cycle variation over 12 months, days Absent Regular Irregular No Bleeding Variation ± 2-20 Variation >20 Duration of flow, days Prolonged Normal Shortened >8 3-8 <3 Volume of monthly blood loss, mL Heavy Normal Light >80 5-80 <5 1 normally soaked “regular” product is approximately 5mL of blood, a “super” or “maxi” size holds 10mL 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 13
  • 15. Structural Abnormalities • P – Polyps – scored as Present or Absent • A – Adenomyosis - scored as Present or Absent • L – Leiomyoma Primary level – Present or Absent Secondary level – Distinguish between submucosal (SM) & others (O) Tertiary level – Detail location/size of uterine fibroids • M – Malignancy & hyperplasia 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 15
  • 16. AUB – P ; POLYPS ( 8 – 35 %) • Diagnosis: US, SIS, hysteroscopy • Further sub-classification: Dimensions, location & number Pre-menopausal polyps: 64 – 88% have symptoms Present with HMB, AUB, IMB, or post-coital bleeding Symptoms do NOT correlate with number, diameter & site Post-menopausal polyps: Most are symptom free Cause for 21-28% of PMP bleeding Associated with cervical polyps in 24-27% Incidence of carcinoma varies between 0–4.8% 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 16
  • 18. AUB – A ; ADENOMYOSIS • Ectopic endometrial glands & stroma within the myometrium. • Hypertrophy & hyperplasia of surrounding myometrium. • Usual presentation: HMB, uterine enlargement, & dysmenorrhea. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 18
  • 19. AUB – L ; Leiomyoma • 1ry level: AUB-L • 2ry level: Submucosal – AUB- L SM Other – AUB – L O • 3ry level: Types 0 - 8 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 19
  • 21. The 3 stage Classification 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 21
  • 22. AUB – M ; Malignancy & Hyperplasia • Detected based upon results of office biopsy or curettage • FIGO AUB Staged only as present or absent • Use existing WHO and FIGO categorization • Up to 40% of patients with a biopsy diagnosis of complex hyperplasia with atypia will have a concomitant endometrial adenocarcinoma present. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 22
  • 24. Non - structural Abnormalities • C – Coagulopathy • O – Ovulatory Dysfunction • E – Endometrial • I – Iatrogenic • N – Not yet classified 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 24
  • 25. AUB – C ; COAGULOPATHY • Prevalence: 3% of women presenting with HMB • Etiologies: Von Willebrand’s disease (10%) Platelet Dysfunction Factor XI deficiency Factor X deficiency Category includes patient’s taking anticoagulants 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 25
  • 26. AUB – O ; OVULATORY DYSFUNCTION Etiology:  Polycystic Ovarian Syndrome (PCOS)  Hypothyroidism  Hyper- prolactinemia  Mental stress  Obesity  Anorexia  Weight loss  Extreme exercise  Adolescence  Menopausal transition 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 26
  • 27. AUB – E , ENDOMETRIAL It is diagnosed by exclusion Etiology: • Deficiencies of local production of vasoconstrictors Endothelin-1 Prostaglandin F2a • Excessive production of plasminogen activators • Increased local production of vasodilators Prostaglandin E2 Prostacyclin I2 • Disorders of endometrial repair (inflammation) • Chlamydia 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 27
  • 28. AUB – I ; IATROGENIC Etiology: Breakthrough bleeding (BTB) using gonadal steroids is the major component of AUB-I : • Oral contraceptives • Continuous or cyclic progesterone • IUD or implant related bleeding Cigarette smoking : reduces the level of steroids because of enhanced hepatic metabolism Systemic agents that interfere with dopamine metabolism : • Serotonin uptake inhibitors 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 28
  • 29. AUB – N ; NOT YET CLASSIFIED Disorders that would be identified or defined only by biochemical or molecular biology assays… • Arterio-venous malformations • Myometrial hypertrophy • Category for new etiologies • Pathological conditions of lower genital tract ?? 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 29
  • 30. Acc. To FIGO Classification… • Abnormal Uterine Bleeding (AUB): quantity, regularity and/or timing. • Acute AUB: episode of heavy bleeding that is of sufficient amount to require immediate intervention to prevent further blood loss. • Chronic AUB: AUB present for most of previous 6 months. Acute AUB can be spontaneous or in context of chronic AUB. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 30
  • 31. • Intermenstrual bleeding (IMB): bleeding between clearly defined cycles. • Heavy menstrual bleeding (HMB): excessive menstrual blood loss affecting quality of life – physical, emotional, social. Objective HMB: blood loss > 80ml/ cycle. 60% of these women will have evidence of iron deficiency anaemia. Subjective HMB: 50% of women presenting with heavy menses will have measured blood loss within normal limits , but must still be considered abnormal, and investigated accordingly. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 31
  • 32. AUB Patterns ▶ Ovulatory AUB ▶ Ovulatory bleeding may be heavy and can be associated with typical premenstrual symptoms and painful periods. ▶ Anovulatory AUB ▶ Found more frequently during the perimenopause, is often linked to prolonged periods, heavier flow and an irregular cycle. ▶ If prolonged (e.g. in PCOS or associated with obesity), anovulatory bleeding has a stronger link to endometrial cancer and endometrial hyperplasia . Am Fam Physician. 2012 Jan 1;85(1):35-4328-Aug-18 Dr Shashwat Jani. +91 99099 44160. 32
  • 33. NOTATION FOR AUB • A patient may be found to have more than one potential entity contributing to symptoms of AUB. • A notation approach has been designed to enable categorization. For example, if a patient is found to have endometrial hyperplasia and ovulation dysfunction with no other abnormalities, she would be Categorized as follows: • AUB P0 A0 L0 M1 - C0 O1 E0 I0 N0 • May be abbreviated as : AUB – M,0 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 33
  • 34. Notation: Each Case Has 1 Identified Abnormality 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 34
  • 35. Notation: >1 Positive Category 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 35
  • 36. Hormonal imbalance and AUB 28-Aug-18Dr Shashwat Jani. +91 99099 44160. 36
  • 37. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 37 Algorithm for evaluation of women with HMB
  • 39. Uterine Evaluation 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 39
  • 41. 41 Diagnosis: H&P • History 1. Acute vs Chronic 2. Characterize bleeding pattern 3. Menstrual bleeding hx (incl. severity and assoc pain) 4. FamHx: AUB/ bleeding disorders 5. Meds: warfarin, heparin, NSAID, OCP, ginkgo, ginseng, motherwort • Physical 1. PCOS: obesity, hirsutism, acne 2. Thyroid dysfunction: cold/heat intolerance, dry skin, lethargy, proptosis 3. DM: acanthosis nigricans 4. Bleeding disorder: petechiae, pallor, signs of hypovolemia 5. Pelvic exam ◦ Is it from the uterus?! 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 41
  • 42. 42 Diagnosis: Labs and Imaging • Labs 1. Pregnancy test (Strong recommendation) 2. CBC (Strong recommendation) 3. Targeted screening for bleeding disorder (when indicated) 4. TSH 5. Gonorrhea/Chlamydia in high risk patients • Imaging: 1. TVUS 2. Sonohysterography 3. Hysteroscopy 4. MRI • Endometrial biopsy 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 42
  • 43. Common Differential by Age 13-18 19-39 40-Menopause • Anovulation • OCP • Pelvic infection • Coagulopathy • Tumor • Pregnancy • Structural Lesions (leiomyoma, polyp) • Anovulatory cycles (PCOS) • OCP • Endometrial hyperplasia • Endometrial cancer (less common) • Anovulatory bleeding • Endometrial hyperplasia/ carcinoma • Endometrial atrophy • Leiomyoma 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 43
  • 44. Management Medical management should be initial treatment for most patients. Need for surgery is based on various factors (stability of patient, severity of bleed, contraindications to med management, underlying cause)  Type of surgery dependent on above + desire for future fertility .  Long term maintenance therapy after acute bleed is controlled. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 44
  • 45. Continue… • Determine acute vs. chronic • If acute, signs of hypovolemia/hemodynamic instability? – If yes, IV access with 1 to 2 large bore IV; prepare for transfusion and clotting factor replacement • Once stable, evaluate etiology (PALM-COEIN) • Determine Treatment 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 45
  • 46. Before selecting the best treatment consider following ▶ Treat patients with dignity and respect ▶ The need for current or future fertility ▶ Facilitate informed decision making of the women seeking treatment ▶ Allowing the woman to choose the treatment most appropriate for her 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 46
  • 47. Medical treatment ⦿ HORMONES › Es+Pr (COCP) › Progestogens › LNG IUS › GnRHa › Estrogen ⦿ PRM › Ulipristal acetate ⦿ SERMS › Ormeloxifene ⦿ ANTIFIBRINOLYTICS › TRANEXAMIC ACID (TA) ⦿ NSAIDs › Mefenamic acid (MA) › Naproxen, Ibuprofen, Aspirin ⦿ Radiotherapy ?? BMJ. 2007 May 26; 334(7603): 1110–1111. RCOG. National evidence-based clinical guidelines. The initial management of menorrhagia London: RCOG, 1998. BMJ. 2007 May 26; 334(7603): 1110–1111. RCOG. National evidence-based clinical guidelines. The initial management of menorrhagia London: RCOG, 1998 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 47
  • 48. Non-steroidal Inflammatory drugs ▪ Ideal NSAID would be a selective inhibitor of vasodilating PGs, permitting the vasoconstrictor PGs to inhibit the excessive menstrual blood loss ▪ Such a selective inhibitor is not yet available ▪ NSAIDs reduce blood loss by 25–30%, but not all women respond similarly ▪ Commonly used are mefenamic acid and naproxen but are less effective than tranexamic acid ▪ NSAIDS have shown only minimal effect in anovulatory menorrhagia ▪ Side-effects include minor gastrointestinal disturbance and headaches 1. Non-Invasive Management of Gynecologic Disorders. pp: 65-66 2. Medscape General Medicine. 1996;1(1).28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 48
  • 49. Tranexamic acid • Reduces blood loss by 50% ▶ However, many women remain menorrhagic and many are non- compliant due to daily dosing ▶ Large doses of tranexamic acid are required ▶ Incidence of GI side-effects, intermenstrual bleeding are relatively high ▶ Risk of thrombogenic disorders is a concern 1. Clinical Gynecologic Endocrinology and Infertility. pp: 564–565. 2. J. Obstet. Gynaecol. Res. Vol. 35, No. 4: 746–752, August 2009.28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 49
  • 50. 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 . 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 50
  • 51. LNG-IUS ▶ A progestogen releasing intrauterine device is an effective treatment for menorrhagia ▶ Its main advantages are relief of dysmenorrhoea, effective contraception, and long-term control of menorrhagia following insertion ▶ The main disadvantages are intermenstrual bleeding and breast tenderness in the first few months following insertion. ▶ Contraindicated in pregnancy, unexplained vaginal bleeding and uterine sepsis 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 51
  • 52. GnRH Agonists ▶ Utility should really be for short-term use ▶ Particularly useful in the treatment of leiomyoma, which can reduce considerably in size when ovarian hormone levels are suppressed ▶ May be used prior to surgical intervention in women with fibroids, or for those in whom surgery is not suitable or desirable ▶ Studies have demonstrated excellent efficacy, with an amenorrhea rate of up to 90% with GnRH agonist use ▶ Danazol is not frequently used because of its androgenic and long-term lipid profile side-effects 1. Friedman et al. 1991 2. Takeuchi H et al. 200028-Aug-18 Dr Shashwat Jani. +91 99099 44160. 52
  • 53. Oral Contraceptives ▪ Action is probably mediated through endometrial atrophy. OCPs suppress pituitary gonadotropin release, thus inhibiting ovulation ▪ High doses of estrogen are associated with an increased risk of thromboembolism ▪ These should be avoided in women with thrombosis or a family history of idiopathic venous thromboembolism ▪ The most common side-effects include weight gain, abdominal discomfort, and mid-cycle breakthrough bleeding ▪ Not suitable in patients desiring pregnancy 1. Medscape General Medicine. 1996;1(1). 2. Clinical Gynecologic Endocrinology and Infertility. pp: 560–561. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 53
  • 54. Injectable progestogens ▶ Depot medroxyprogesterone acetate [DMPA] can induce amenorrhea in up to 50% of users after 1 year and 80% after 5 years ▶ Injections are usually given every 12 weeks to maintain progestogen exposure and ensure contraceptive efficacy ▶ Side effects can limit compliance and include weight gain, greasy skin and hair, acne and bloating 1. Best Practice & Research Clinical Obstetrics & Gynaecology. 2014; 28(6): 795-806 2. Obstet Gynecol. 2013; 28(6): 795-806 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 54
  • 55. Progestin therapy ▪ Most commonly used hormonal therapy given during luteal phase. ▪ Norethisterone is the most commonly used oral progestogen in the treatment of HMB. ▪ Older women with hypertension or diabetes or who smoke are not good candidates ▪ “ Progestins modulate the effect of estrogen on target cells and metabolism of estrogen, the endometrium is maintained in a state of antimitosis and antigrowth. “ 1. Clinical gynecologic endocrinology and infertility. pp: 564–565. 2. J Midwifery Womens Health. 2003;48. 3. 3. Clinical gynecologic endocrinology and infertility. pp: 560–561. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 55
  • 56. Hormonal therapy vs Non hormonal treatment (When hormonal therapy??) ▶ Non-hormonal treatment is effective mainly in the setting of heavy menstrual bleeding when the timing of bleeding is predictable. ▶ Irregular or prolonged bleeding is most effectively treated with hormonal options that regulate cycles, decreasing the likelihood of unscheduled and potentially heavy bleeding episodes J Obstet Gynaecol Can. 2018 May;40(5):e391-e413 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 56
  • 57. Surgical Management Options D&C Endometrial Ablation Uterine Artery Embolization Hysterectomy 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 57
  • 58. Endometrial Ablation or Resection ▪ An alternative to hysterectomy; cost is a limiting factor ▪ About 20–30% have no improvement and up to 10% need hysterectomy ▪ These procedures are less effective in women aged under 35 years, where pain is a significant associated symptom or when the uterus is enlarged ▪ Contraindicated if future fertility is desired ▪ Younger women who use tobacco products, and have menometrorrhagia are more likely to fail hydrothermal ablation 1. J. Obstet. Gynaecol. Res. Vol. 35, No. 4: 746–752, August 2009. 2. . Oxford American Handbook of Obstetrics and Gynecology. pp 468–469. 3. 3. Am J Obstet Gynecol. 2010 Jun;202(6):622.e1–e6. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 58
  • 59. Medical Therapy or Hysterectomy?? ▪ Success with first-generation ablative procedures varies from 80 to 97%, but they require skill for hysteroscopy ▪ Second-generation procedures take less time to perform and are technically easier to conduct, but are expensive ▪ In low-resource settings, hot Foley catheters have been developed with no reported complications to reduce the cost of second-generation balloon devices, but the use of boiling saline has its own risks J. Obstet. Gynaecol. Res. Vol. 35, No. 4: 746–752, August 2009. Thus, drug therapy should be the first-line treatment before recourse to surgery 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 59
  • 60. Consideration of Medication Therapy ▶ A recent study showed 38% of women less than 40 years of age have unsupported pathology at the time of hysterectomy performed for AUB, uterine fibroids, endometriosis, or pelvic pain ▶ In addition, overall up to 38 % of the women who underwent a hysterectomy were never offered an alternative treatment option. ▶ Therefore, it is crucial to review the medical options available and to reduce the reliance on major surgical interventions, when possible J Obstet Gynaecol Can. 2018 May;40(5):e391-e413 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 60
  • 61. • 17-a-hydroxy-progesterone derivatives have substitutions at C17 that slow hepatic metabolism : medroxyprogesterone (MPA) • 19-nor testosterone derivatives display primarily progestational rather than androgenic activity : norethindrone • Replacement of the 13-methyl group of norethindrone with a 13-ethyl substituent are more potent progestins and less androgenic: norgestrel, nomegestrol 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 61
  • 62. Related to Progesterone Related to Testosterone Related to Spironolactone ✓ 17alpha- hydroxyprogesterone derivatives Cyproterone acetate, Chlormadinone acetate, Medroxyprogesterone acetate, Megestrol acetate ✓ 19-norprogesterone derivatives Nomegestrol, Promegestone, Trimegestone, Nesterone ✓ 19-nortestosterone derivatives Norethisterone, Levonorgestrel, Lynestrenol, Desogestrel, Gestodene, Norgestimate, Dienogest Drospirenone CLASSIFICATION OF PROGESTINS (Synthetic Derivatives Of Progesterone) 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 62
  • 63. Norethisterone Norethisterone (or norethindrone) is a molecule used in some combined oral contraceptive pills, progestogen only pills and is also available as a stand-alone drug. Used to treat PMS, painful periods, AUB, irregular periods, menopausal syndrome (in combination with oestrogen), or to postpone a period. It is also commonly used to help prevent uterine hemorrhage in complicated non-surgical or pre-surgical gynecologic cases 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 63
  • 64. Norethindrone Acetate (NETA): ▶ Norethisterone acetate (NA) is the acetic acid ester of norethisterone and is about twice as potent as norethisterone ▶ Therapeutic uses of Norethindrone acetate (NETA) have been longstanding and widely accepted ▶ It requires less frequent dosing ▶ Dose: 2.5 to 10 mg (may be given daily for 5 to 10 days) for the treatment of AUB The Obstetrician & Gynaecologist 2006;8:229– 234 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 64
  • 65. Mechanism of actions of NETA • Mitotic activity • Decreased growth of endometrium. • Prevents or reversal of the hyperplastic process Progesterone account for the diminished 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 65
  • 66. Side Effects ( Rare ) • Edema, • Nausea , • breast tenderness, • irregular menstrual cycle, • breakthrough bleeding, • spotting, • weight change, and • Headache . 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 66
  • 68. International Journal of Basic & Clinical Pharmacology 2012 ;1 (3) :191-195 Norethisterone acetate was more effective and better tolerated compared to COC N= 60 young girls from age of menarche to 19 years with menorrhagia Norethisterone Acetate Vs. COC Pills In puberty menorrhagia. 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 68
  • 69. NETA vs Drospirenone/ Ethinyl Estradiol ▶ N= 38 patients with dysmenorrhea ▶ Study type: Prospective, open-label study ▶ Treatment: Continuous NETA 5 mg daily or cyclical COC for 6 months ▶ Results: ❑ Both drugs were effective in suppressing dysmenorrhea ❑ Participants in the NETA group were less likely to use pain killers A continuous NETA regimen is well tolerated, effective, and inexpensive option for dysmenorrhea treatment and was as good as COC J Pediatr Adolesc Gynecol 29 (2016) 143e147 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 69
  • 70. Efficacy of NETA as compared to MPA in the treatment of peri-menopausal DUB N=60 women with perimenopausal DUB Group 1 : NETA Group 2: MPA Duration: Treatment was given for 20 days each cycle ( 3 treatment cycles) Group Cured Markedly effective Effective Total effective rate (%) NETA (30 cases) 14 11 3 93.33% MPA (30 cases) 5 9 10 80% Study results • Norethisterone was more effective than MPA in controlling irregular vaginal bleeding • Treatment with NETA significantly improved the quality of life of patients Open Access Library Journal 2017, Volume 4, e4136 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 70
  • 71. Progestin Estrogenic activity Glucocorticoid activity NETA slight No MPA No Yes Biological activities of NETA & MPA Progestogenic effectivity on level of endometrium Progestin Dose (mg per cycle) for secretory transformation of endometrium NETA 30–60 MPA 80 A.E. Schindler et al. / Maturitas 46S1 (2003) S7–S16 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 71
  • 72. Norethisterone 15 mg vs LNG-IUS in idiopathic menorrhagia Objective: To compare the efficacy of norethisterone vs LNG-IUS for the treatment of idiopathic menorrhagia Study Type: Randomized comparative parallel group study *LNG-IUS: Levonorgestrel intrauterine system *MBL: Menstrual blood loss Patient profile: Women with heavy regular periods and a measured MBL exceeding 80 ml Method: N= 44 women ▶ Group 1: N=22 women treated with LNG-IUS, inserted within the first 7 days of menses ▶ Group 2: N= 22 women received norethisterone 15 mg (5 mg 3 times daily) from day 5 to day 26 of the cycle for three cycles. British Journal of Obstetrics and Gynaecology June 1998, Vol. 105, pp. 592-598 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 72
  • 73. Study Results ▶ Both regimen were effective in reducing menstrual blood loss ▶ Oral norethisterone reduced mean MBL by 87% ▶ Norethisterone at a dose of 15 mg (5 mg 3 times daily) for 21 days of the cycle is highly effective in reducing MBL. ▶ This regimen led to a significant reduction in symptoms of intermenstrual bleeding Norethisterone given in high enough doses (15 mg) from early in the cycle, leads to effective reduction in MBL British Journal of Obstetrics and Gynaecology June 1998, Vol. 105, pp. 592-598 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 73
  • 74. Norethisterone 15 mg in Menorrhagia ▶ In study conducted by Bonduelle et.al. Norethisterone 15 mg was used from day 19 to 26 of the cycle for the treatment of menorrhagia. ❑ The patient were included with following characteristics: ✓ Menstrual loss requiring more than 5 pads/tampons per day for longer than 6 days cycle, ✓ Presence of flooding or clots on any day of the cycle, ✓ Presence of secondary anemia, ✓ Excessive menstrual loss proving socially and domestically disruptive American Medical Journal 1 (1): 23-26, 201028-Aug-18 Dr Shashwat Jani. +91 99099 44160. 74
  • 75. Study Results ▶ In this study, it was observed that NETA 15 mg (5 mg 3 times daily): ▶ Should be given from day 19 to 26 for anovulatory bleeding ▶ And for acute bleeding: it should be given from day 5 to day 26 ▶ This dosage regimen of NETA is generally found to be more effective. American Medical Journal 1 (1): 23-26, 2010 ▶ ↓mean MBL was observed ▶ ↓ associated symptoms - backache and abdominal pain ▶ Dysmenorrhoea improved to a significant degree with norethisterone 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 75
  • 76. ▶ Generally well tolerated, with minimal side effects ▶ At clinical doses, it has hardly any androgenic effect NETA: Safety 1.Fertility and Sterility 2016; 105(3): 734 - 743.e3 2.Journal of Endometriosis (2010; 2 :4) 169-181 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 76
  • 77. NETA: Guideline Recommendations NETA 15mg should be used (which should stop bleeding within 48 hours). In severe cases, 30 mg can be used, tapering to 15mg for a further week NICE Guidelines 2007 For the control of acute bleeding, NETA 5 mg should be administered 3 times daily for 1 week ACOG Guidelines 2013 NETA 5 mg–10 mg should be given every 4 hours until bleeding stops (with a re-evaluation at 48 hours) European Consensus group 2011 http://www.contemporaryobgyn.net/modern-medicine-cases/managing-acute-heavy-menstrual-bleeding/page/0/2 Pharmaceutical journal 2011; 286:71-7428-Aug-18 Dr Shashwat Jani. +91 99099 44160. 77
  • 78. Summary of Medical Treatments For Abnormal Uterine Bleeding 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 78
  • 79. Treatment Drugs & regimen Efficacy Contraception Combined hormonal contraceptives 1. cOCP for 21 days each month 2. Continous or extended regimen 3. Contraceptive ring or patch cyclic or continuous Menstrual regularity, 20% to 50% reduction in MBL, reduction in dysmenorrhea and PMS Yes LNG-IUS 20mcg/24hrs local LNG one IUS for up to 5 years 70% to 97% reduction in MBL, amenorrhea in up to 80% at 1 year, reduced dysmenorrhea Yes Cyclic oral progesterone MPA 5-10mg po for 10-14d ( luteal, anovulatory) NETA 5mg tid day 5-26 (long phase, ovulatory) Bleeding reduced by up to 87% with long phase regimen No Injected progesterone DMPA 150 mg IM q90days 60% amenorrhea at 12 months, 68% at 24 months Yes Danazol 100-400mg po daily 80% reduction MBL, 20% amenorrhea, 70% oligomenorrhea No GnRH agonists Leuoprolide acetate. IM Monthly, 3 to 6 months Bleeding stopped in 89% by 3 to 4 weeks No NSAIDS – Naprosyn 500mg od-bid – ibuprofen 600-1200mg – Mefenamic acid 500mg od starting day or day before menses for 3 to 5 days until ceases 20% to 50% reduction MBL, reduction in dysmenorrhea in 70% No Anti-fibrinolytics TXA 40% to 59% reduction in MBL No J Obstet Gynaecol Can. 2018 May;40(5):e391-e413 28-Aug-18 Dr Shashwat Jani. +91 99099 44160. 79