MEDICAL MANAGEMENT OF ABNORMAL UTERINE BLEEDING BY DR SHASHWAT JANI

1. 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
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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
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4. What’s Normal ?
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
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5. 5
Many terms
Menorrhagia
Hypermenorrhea Metrorrhagia
Menometorrhagia
Amenorrhea
Polymenorrhea Oligomenorrhea
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6. Clinical Types
• Polymenorrhoea: frequent (<21 d) menstruation,
at regular intervals
• 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.
• Oligomenorrhea: infrequent menstruation (>35 d)
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7. 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
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8. 8
We need a mneumonic!
• HELPERR
• CHADSVASc
• SIGECAPS
• O BATMAN!
• I GET SMASHED
• ABCDEFGH
• PPPPPPP
Etiology
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9. If I had a coin in my palm for every
women with AUB…
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10. 09-Jul-18
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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
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12. Best Pract Res Clin Obstet Gynaecol. 2016 Jul; 34: 54–65.
FIGO Classification
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13. 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.
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14. • 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.
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15. 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):35-4309-Jul-18
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16. Hormonal imbalance and AUB
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17. 09-Jul-18
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Algorithm for evaluation of
women with HMB

18. 09-Jul-18
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19. Uterine Evaluation
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20. 09-Jul-18
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21. 21
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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22. 22
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
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23. 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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24. 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.
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25. 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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26. 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
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27. 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
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28. 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).09-Jul-18
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29. 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 2009.09-Jul-18
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30. Etamsylate:
• 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
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31. 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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32. 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. 200009-Jul-18
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33. 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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34. 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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35. 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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36. 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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37. Surgical Management Options
D&C
Endometrial Ablation
Uterine Artery Embolization
Hysterectomy
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38. 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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39. 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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40. 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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41. • 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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42. 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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43. 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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44. 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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45. 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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46. Side Effects ( Rare )
• Edema,
• Nausea ,
• breast tenderness,
• irregular menstrual cycle,
• breakthrough bleeding,
• spotting,
• weight change, and
• Headache .
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47. Clinical
Evidences:
NETA
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48. 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.
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49. 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
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50. 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
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51. 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
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52. 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
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53. 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
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54. 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, 201009-Jul-18
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55. 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
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56. ▶ 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
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57. 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; 286:71-7409-Jul-18
Dr Shashwat Jani.
+91 99099 44160.
57

58. Summary of Medical Treatments For
Abnormal Uterine Bleeding
09-Jul-18
Dr Shashwat Jani.
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58

59. 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
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+91 99099 44160.
59

60. 09-Jul-18 60
Dr. Shashwat Jani
+91 99099 44160.