Abnormal Uterine Bleeding…The Way Out

Amr Nadim, MSc, DUE,MDProfessor of Obstetrics, Gynecology

and Reproductive HealthAin Shams Faculty of Medicine

It’s about two ladies

Patient Profile: Mrs. AishaPresenting patient

• Mrs. Aisha, 48 year old school teacher, presenting with heavy bleeding during menstruation• Her general health is otherwise good

Medical ChartMedical History Regular Menstrual cycle et it is now

coming at 40-45 days intervalsBleeding is becoming heavy and prolonged

Social History Fatigue with impact on her work and QOL

Current Medication None

Adapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Patient Profile: HebaPresenting patient

• Miss Heba is 16. She is G11 school girl, presenting with heavy bleeding on a background of sparse menstruation•She a bit overweight with a BMI of 31•She complains of acne a generalized increase of her body hair

Medical ChartMedical History • Menarche was at the age of 14

• Cycles were regular for about 6 months than they started to be there for only 3 times a year.• Bleeding is becoming heavy and prolonged

Social History Annoyed because of acne, increased body hair and failing to loose weight.

Current Medication None

Making the point about definitionsMenorrhagia The symptom of heavy menstrual bleeding;

a term specifically used to describe ovulatory bleeding (that is, a normal, regular, and predictable cycle ranging from 21 to 35 days, most often 28 days).

Metrorrhagia The symptom of bleeding betweenmenstrual periods; theunpredictable timing of the flowgenerally reflects anovulation.

Menometrorrhagia The symptom of heavy bleedingbetween menstrual periods.

Heavy Menstrual Bleeding

Menstrual bleeding that may beBleeding either Ovulatory (menorrhagia) or Anovulatory

Breakthrough Bleeding

Bleeding that occurs despite the use of drugs such as oral contraceptives that are given to control uterinebleeding.

Chronic Acute IntermenstrualAbnormal bleeding in volume, regularity and/or timing which has been there for up to 6 month

An episode of HMB that is judged severe enough to require IMMEDIATE intervention to prevent further loss

Bleeding occurring between predictable menses whether predictable or randomly occurring

YOU Will Have To Decide…

Amount

Duration

Timing

A menstrual Calendar is Mandatory

What is the prevalence of heavy menstrual bleeding in women of reproductive age?

A. 1 in 3B. 1 in 5C. 1 in 10D. 1 in 20

Adapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Time’s UP51015

Prevalence 20% of women in the reproductive age

Burden• 20-30% of all Gynecologic

visits• 25% of all gynecologic

surgeries

Adapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

“The key to optimummanagement of a patient

withHMB, is to understand

the mechanism, thepathogenesis, and all the

factorsinvolved in the problem.

This will help defining which appropriate

Investigations are needed and will allow one to tailortherapy to individuals, and

with afairly successful

outcome.”

Absence of progestational effects in anovulatory cycles

UNPREDICTABLE BLEEDING

Progesterone Effects Secretory transformation

Stabilizing the extracellular matrix by inhibiting proteases

Enhancing hemostasis

Jabbour et al. Endocrine regulation of menstruation. Endocrine Reviews 2005

A Woman Presenting with Heavy Menstrual

BleedingTake Full History and Perform Examination and Order CBC

No structural or histological anomalies suspected

There is a possible structure or histological anomaly

Abnormal Bleeding..Making the Diagnosis

No abnormalities or a fibroid <3 cm.

Consider Endometrial

Biopsy

Uterus is enlargedAbdominal/Pelvic .

Consider Imaging / Hysteroscopy

No abnormalities or a fibroid <3 cm.

Consider Medical Treatment

Provide Information and Discuss Treatment Options

Adapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Abnormal Uterine Bleeding Diagnostic Tools

Reproduced from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Patient Profile: Mrs. AishaPresenting patient• Age of Menarche 14

•Menstrual pattern Bleeding 10/45 , heavy loss

•Medications or related medical illness None

•Evidence of bleeding disorder None

•Is it a bothersome condition Yes

Test Results

Pregnancy test Negative

CBC - Thyroid Function Normal

TVS No structural anomalies

Endometrial Thickness 8mm

Pipelle Biopsy Irregular shedding, No malignancy

Adapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Patient Profile: HebaPatient HistoryAge of Menarche 14Menstrual Cycle pattern 10-15 days / 60-90 daysMedications or related medical condition NoneSigns / Symptoms of any bleeding dyscrasias NoneAffecting her quality of life Yes, school and social life

Test Results

Pregnancy test NegativeCBC - Thyroid Function-PL NormalFSH 5 mIU/mlLH 13 mIU/mlTeststerone and DHEAS Within average limits for gender

TAS No structural anomalies of the uterus. Both ovaries PCO like

Endometrial Thickness 18mm

What is the most likely cause for Mrs. Aisha bleeding based on her history and investigations?

A. Bleeding disorderB. AnovulationC. Submucous myomaD. Atypical complex Hyperplasia

Adapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Time’s UP51015

What is the most likely cause for Heba bleeding pattern based on her history and investigations?

A. Bleeding disorderB. AnovulationC. Submucous myomaD. Atypical complex Hyperplasia

Time’s UP51015

Etiologies

Organic•Systemic•Reproductive Tract•Iatrogenic

Dysfunctional

•Ovulatory•Anovulatory

Updates from FIGO, 2011

Munro MG, et al, FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age, Int J Gynecol Obstet (2011)

Structural Non-StructuralFIGO System for AUB, 2011

FrequencyRegularityDurationVolume

Endometrial disorders (AUB-E) • Cyclic menstrual bleeding, typical of ovulatory cycles• Heavy menstrual bleeding by deficient local hemostasis• Prolonged bleeding by deficient endometrial repair

Ovulatory dysfunction (AUB-O) • Highly variable bleeding pattern, unpredictable timing, oligomenorrhea

or menorrhagia

Hormonal imbalance causes dysfunctional bleeding (DUB)• Absence of cyclic progesterone production from corpus luteum• “Luteal out-of-phase” events

Diagnosis often determined by exclusion

FIGO - AUB Absence of Structural Abnormalities

Munro MG, et al. Int J Gynecol Obstet 2011; 113(1): 3-13.

COEIN: Ovulatory

Anovulation

Hypothyroidism

Luteal Phase Defect

The majority of dysfunctional AUB in the premenopausal

woman is a result of anovulation.

COEIN: Ovulatory

Anovulatory Bleeding Anovulatory bleedingAge-related: peri-menarche, perimenopauseEstrogenic: unopposed endogenous estrogenAndrogenic: PCOS; CAH, acute stressSystemic: Renal disease, liver disease

Is a Diagnosis of exclusionMenometrorrhagia not caused by anatomic lesion, medications, pregnancy

COEIN: Ovulatory

Low T4 high TRH high TSH normal T4

high PRL amenorrhea + galactorrhea

Hypothyroidism Bleeding can be excessive, light, or irregular Only severe, uncorrected thyroid disease

causes abnormal bleeding patterns Normal pattern when corrected to euthyroidPrimary hypothyroidism is associated with

Secondary amenorrhea

COEIN: OvulatoryLuteal Phase Defect (LPD)

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

DiagnosisPolymenorrhea (periods every 2 weeks)Mid-luteal phase P level between 4-8 ng/mlEndometrial biopsy >2 days out of phase

ManagementUnexplained infertility: clomiphene, P supplementPregnancy not desired: observation or COCs

How should Mrs. Aisha be treated ?

A. Hysteroscopy/Dilatation and curettageB. Endometrial AblationC. ProgestagensD. Hysterectomy

Adapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Time’s UP51015

First : Pharmacologic Therapy

Should be offered before surgical therapyHormonal causes are amenable to hormonal manipulationTherapy choice depends onDegree of bleedingWomen’s ageNeed for contraceptionDrug adverse effect profile

Pharmacologic treatment proposedProgestagens high dose for 10 daysTranexamic acid / Epsilon Amino Caproic Acid

Second : Consider Surgical InterventionIf Pharmacologic therapy fails consider emergency surgical options:Uterine Foley Baloon 30 ml salineUterine irrigation by aminocaproic acidCurettageEndometrial ablationHysterectomy

Adapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Pharmacologic Therapy: Choices

Progestagen, High Dose

10 days

Progestagen, Low Dose(10 -14 days/cycle)

Combined Oral Contraceptive Pills

DydrogesteroneMPALynestrenolNorethindroneMedrogestone

LevonorgestrelDrosperinoneDesogestrel

Adapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

How should Heba be treated?

A. Combined Oral Contraceptive PillsB. Endometrial AblationC. ProgestagensD. Curettage

Time’s UP51015

Pharmacologic Therapy: Patient Factors Influencing the Choices

Reproduced from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

The Choice of a ProgestagenProgesterone Retroprogesterone

Progesterone Dydrogesterone

Progesterone Derivatives Testosterone Derivatives

17-OH-progesterone Derivates

19-progesterone Derivatives

19-nortestosterone Derivatives

Pregnane• Hydroxyprogesterone

Caproate• Hydroxyprogesterone

Heptanoate• Gestonorone Caproate• Chlormadinone Acetate• Medrogestone• Medroxyprogesterone

Acetate• Cyproterone Acetate

Nor-Pregnane• Nomegestrole

Acetate• Demegestone• Promegestone• Nestorone• Trimegestone

Estranes• Lynestrenol• Levonorgestrel• Norethisterone• Norethisterone

Acetate• Ethinodiol Diacetate• Norgestrienone• Dienogest

Gonanes• Norgestrel• Desogestrel• Gestodene• Norgestimate

SpirolactoneDerivative

Drospirenone

Adapted from: Druckmann R. Journal Für Menopause. 2002:1-5.

• Dydrogesterone is a retroprogesterone, a steroisomer of progesterone, with an additional double-bond between carbon 6 and 71

• Dydrogesterone, shaped by light, enhances the progestogenic effects• No estrogenic, androgenic, or glucocorticoid effects2

• Does not inhibit ovulation, at normal dosage2

• Anti-androgenic potential of dydrogesterone is less pronounced compared to progesterone3

Dydrogesterone – a Unique Retrosteroid

1. Kuhl H. Climacteric 2005; 8 (Suppl 1): 3–63. 2. Schindler AE. Maturitas 2009; 65S: S3–S11. 3. Rižner TL et al. Steroids. 2011;76(6):607–15.

Progesterone Dydrogesterone

Receptor Binding of Progestogens1

1. Adapted from: Schindler AE, et al. Maturitas 2009; 65(Suppl 1): S3-S11.2. Rižner TL, et al. Steroids. 2011; 76(6): 607-615.

• Anti-androgenic potential of dydrogesterone and DHD is less pronounced compared to progesterone2

Lockwood CJ. Menopause 2011; 18(4): 408-411.

Progestagens Simply Improve The Endometrial Characteristics

Stops estrogen-induced growth of the endometrium

Stabilizes endometrial vasculature and blocks unrestricted

vessel growth

Initiates the clotting cascade

Hemostatic and anti-fibrinolytic action (PAI-1 pathway)

Inhibits matrix metallo-proteinase activity

Regulating withdrawal Bleeding

Reproduced from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Acute Heavy Blood Loss

High dose Progestagens ( Norethisteron 5 mg 2-3 times X 10

days)

or 4 tabs OC during 5 days

± tranexamic acid 1-1.5 g tds

or ( curettage )

Adapted from Peter van de Weijer, Dysfunctional Uterine Bleeding, 2010

Surgical Therapy For Abnormal Uterine Bleeding Caused By Structural Abnormalities

Transvaginal Ultrasound or

Any imaging Modality

Uterine Myoma Or

Adenomyosis

No Intrauterine Pathology

Surgical Management

Myomectomy

Embolization

Hysterectomy

Endometrial AblationAdapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Patient Treatment and Follow-Up: Mrs. AishaTreatment since anovulation is the most likely cause, Mrs. Aisha was given a progestagen from day 5 to 25 of her menstrual cycle for three cycles.She agreed to try this medication for at least 3 months.

Follow-up Responded well to treatment.Withdrawal bleed lasted for 5 days after 3 monthsHeavy clots ceasedFeels full of energy againUnderstands that there is no need for surgical intervention

Adapted from Abnormal Uterine bleeding in a Healthy 48-year old : Knowing the right questions to ask. Peter HM Van De Weijer accessed at http://mp.peervoice.com/player/23145/51/1#3

Patient Treatment and Follow-Up: HebaTreatment since anovulation is the most likely cause, Mrs. Aisha was given a progestagen from day 5 to 25 of her menstrual cycle for three cycles.She agreed to try this medication for at least 3 months.

Follow-up Responded well to treatment.Withdrawal bleed lasted for 5 days after 3 monthsHeavy clots ceasedShe enrolled for group therapy to reduce weight and exerciseUnderstands that in 2 years she may start using COCs which will help her control acne and hirsutism

Coming to an end…

• Abnormal uterine bleeding is a rather common

presentation. It is met with among 1 out of 5

women in the reproductive age.

• FIGO updated classification of the causes of

bleeding helps to ask the right questions, chose

the proper investigations and tailor treatment

for a particular patient

• Progestagens act by stabilizing the endometrium

and promoting endometrial repair.

• Choosing the proper progestagen will help in

treating the condition while maintaining a high

level of compliance by minimizing the side effects.

• Treatment should be continued for at least 3

months to bring the endometrium back to its

normal pattern

It’s been about two ladies…