FAR EASTERN UNIVERSITY - NICANOR REYES MEDICAL FOUNDATION

Gynecology

What are the Role of Hormones?

Abnormal Uterine Bleeding Estrogen  Estradiol stimulates synthesis of PG from
Dr. Jennifer T. Co arachidonic acid by cyclic endoperoxides
 PGE2 are normal because estrogen is
Normal Menstrual Physiology normal.
HPO feedback system Progesterone  Progesterone necessary to increase levels
• Hypothalamus of arachidonic acid, the precursor of
- GnRH PGF2α.
• Anterior pituitary  With the absence of progesterone in
- FSH anovulatory cycles, PGF2α lower.
- LH  Decreased levels of PGF2α could cause
• Ovary heavier or more prolonged bleeding
- Estrogen
- Progesterone Menorrhagia in Ovulatory DUB
1. Reduced uterine synthesis of PGF2α
*Go back to the Reproductive 2. Increase in synthesis of PGE2 and prostacyclin
Endocrinology trans :)*
3. Increase in PGE receptor in the myometrium
4. Decreased thromboxane in the endometrium
5. Greater amount of phospholipase C in the endometrium
Normal Limits for Menstrual Parameters (Mid-reproductive Years)
Forms of Abnormal Uterine Bleeding
Clinical dimensions Descriptive Normal limits
of menstruation and terms (5th-95th percentiles) Intervals between
menstrual cycle Oligomenorrhea bleeding episodes vary
Infrequent
Frequency of Frequent < 24 from 35 days to 6 months
episodes
menses (days) Normal 24-38 No menses for at least 6
Amenorrhea
Infrequent > 38 months
Regularity of menses Absent - Bleeding at irregular but
(cycle to cycle Regular Variation of 2 to 20 days Metrorrhagia frequent intervals, the
variation over 12 Irregular Variation > 20 days Frequent amount being variable
months; in days) Intervals Bleeding occurring at
Duration of flow Prolonged > 8.0 Polymenorrhea regular intervals of less
(days) Normal 4.5-8.0 than 21 days
Shortened < 4.5 Prolonged (> 7 days) or
Volume of monthly Heavy > 80 Menorrhagia excessive (> 80 mL)
blood loss (ml) Excessive/
Normal 5-80 (hypermenorrhea) bleeding occurring at
Prolonged
Light <5 regular intervals
duration of
Prolonged uterine
menses
Factors that come into play for Hemostasis Menometrorrhagia bleeding occurring at
 Higher thromboxane level (PGF2) in relation to prostacyclin irregular intervals
(PGE2 ) Intermenstrual Bleeding of variable amounts occurring
 Platelet adhesion bleeding between regular menstrual periods
 Fibrin clot formation
 Stabilization of the hemostatic platelet plug 12-month cumulative incidence
The absence of any, or all of these factors, may result in heavier
menstruation. Metrorrhagia 29%
Menorrhagia 25%
Intermenstrual bleeding 17%
Oligomenorrhea 15%
Postcoital bleeding 6%

Paradigm shifts in terminologies

Heavy menstrual bleeding (HMB)
Hemostatic Mechanism in Menstruation  Should replace the term “menorrhagia” for the symptom of
Normal ovulatory Endometrial PGF2α/PGE2 ratio steadily excess menstrual bleeding
women increasing from midcycle to menses. Intermenstrual bleeding
Alterations in prostaglandin synthesis and  Now used in place of “metrorrhagia” to describe bleeding
release occur in women with both that occurs between clearly defined cyclic and
Women with DUB
anovulatory and ovulatory DUB. predictable menses
(Ovulatory and
Why these changes occur and their exact Dysfunctional uterine bleeding (DUB)
anovulatory)
causal relation with menorrhagia have not  Previously used as a diagnosis when there was no organic
yet been determined. cause for the AUB has been abandoned.
Women with 1. Low levels of PGF2α
ANOVULATORY 2. Decreased PGF2α/PGE2 ratio The FIGO 2009 Congress recommended that the term DUB should
DUB be excluded
The justifications for abolishing the term ‘DUB’ are as follows:
 A diagnosis of exclusion and admission of our ignorance
about local mechanisms

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 FAR EASTERN UNIVERSITY - NICANOR REYES MEDICAL FOUNDATION
Gynecology

 Terminology used varies in different countries (symptoms, psychotropic drugs

signs, diagnoses) Digitalis
 “Old DUB” includes the following – coagulopathies Dilantin
(congenital and acquired), ovulatory disorders and LNG-IUS
endometrial dysfunction (infection, disturbances of local
hemostasis, inflammation, vasoactive regulators) PALM-COEIN Classification
 Based on the recommendation of an international group of
Types of Abnormal Uterine Bleeding clinician-investigators from 6 continents and over 17
 Significant blood loss that results in countries that was ratified in a plenary session at the FIGO
hypovolemia (hypotension or tachycardia) or Convention in Capetown, Africa
shock.  FIGO approved a universal nomenclature and classification
Acute
 Warrants immediate intervention to prevent system for AUB: PALM-COEIN Classification
AUB
further blood loss  Nine (9) general source of bleeding according to this
 May occur in the presence of an existing classification:
chronic AUB P - polyp
 Bleeding from the uterine corpus that is A - adenomyosis
abnormal in duration, volume, regularity, L - leiomyoma (indicated whether submucosal or other)
Chronic
and/or frequency and has been present for M - malignancy and hyperplasia
AUB
the majority of the last six (6) months.
 Does not require immediate intervention C - coagulopathy
O - ovulatory dysfunction
AUB across the lifespan E - endometrial
Adolescents Reproductive age Postmenopausal I - iatrogenic
Von Willebrand Pregnancy Atrophy N - not yet classified
Anovulatory Anovulatory Polyps PALM Discrete or structural entities
bleeding bleeding Hyperplasia Can be measured visually with objective imaging
Pregnancy Fibroids Endometrial cancer techniques and histopathology
Polyps COEI Non-structural
Hyperplasia Related to pathologies that are not defined by imaging
Endometrial cancer or histopathology
N This is reserved for entities that are not yet classified
Organic causes of AUB
Von Willebrand’s Disease  Utilizes a notation that reflects the presence or absence of
Platelet deficiency each of the 9 causes of AUB in each patient
Prothrombin deficiency “0” if the entity is absent
Blood
Leukemia “1” if present
coagulation
ITP “?” if not yet assessed
Systemic Recognizes that one or more underlying entities could
Severe sepsis 
Disease cause or contribute to a woman’s bleeding.
Hypersplenism
Hypothyroidism Menorraghia
Oligomenorrhea,
Hyperthyroidism
amenorrhea
Cirrhosis
Abortion and ectopic
gestation
Complications of Retained products of
surgery conception P - polyp
Placental polyp  Are localized overgrowths of
Trophoblastic diseases endometrial tissue, containing glands,
Leiomyomata uteri and stroma, and blood vessels, covered with
polyps epithelium
Reproductiv  Most commonly found in reproductive-
Adenomyosis and
e Tract age women, and estrogen stimulation is
Benign Pelvic endometriosis
Disease thought to play a key role in their
lesions Endometritis, salpingitis,
cervicitis  development
Traumatic lesions  Most often asymptomatic
Foreign body  Categorized as being present or absent
Cervix, endometrium, tube, based on ultrasound and/or hysteroscopic imaging with or
Malignant Pelvic ovary, vagina, vulva without histopathology
lesions Precancer: endometrial  No distinction as to the size and number of polyps
hyperplasia  Polypoid endometrium should be excluded from this
Contraception category – a variant of normal endometrium
Oral and HRT
Iatrogenic Injectable Dysmenorrhea
causes steroids Hirsutism/acne
Endometriosis
Tranquilizers and

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Gynecology
A - adenomyosis
 Defined by the presence
of endometrial glands
and stroma in the uterine
myometrium. The
presence of ectopic
endometrial tissue leads
to hypertrophy of the
surrounding myometrium.
 Adenomyosis is a
histologic diagnosis, but findings of an enlarged,
asymmetric uterus on ultrasound and magnetic resonance
imaging (MRI) are indicative.
 Anechoic avascular cysts scattered throughout the
myometrium on sonography are considered
pathognomonic for adenomyosis on ultrasound.
 MRI, which is both more sensitive and specific than
ultrasound, will demon strate thickening of the junctional
zone, the area between the endo metrium and the
myometrium, equal to or greater than 12 mm
 Diagnosis is based on the finding of endometrial tissue
beneath the endometrial-myometrial interface seen
through histopathology of hysterectomy specimens
 Sonographic criteria for adenomyosis comprise the
minimum requirements for assigning the diagnosis of
adenomyosis in the PALM-COEIN calssification system
 Abnormal bleeding due to adenomyosis is thought to be a
result of altered uterine contractility and is commonly
associated with profound dysmenorrhea.
L - leiomyoma
 or fibroids, are
benign tumors of the
uterine myometrium
 The pathogenesis is
thought to initiate
from myometrial
injury leading to
cellular proliferation,
decreased
apoptosis, and
increased production
of extracellular matrix
 It increase the overall surface area of the endometrial
cavity or alter uterine contractility, these effects in turn lead
to abnormal and excessive uterine bleeding
 Primary system reflects only the presence or absence of
one or more leiomyomas
 Secondary system requires the clinician to distinguish
leiomyomas that are submucosal (SM) (which are more
likely to contribute to the genesis of AUB) from others (O)
 Tertiary system includes the categorization of intramural
and subserosal leiomyomas as well as parasitic leiomyomas
 When a leiomyoma abuts or distorts both the endometrium
and serosa, it is categorized first by the submucosal
classification, then by the subserosal classification – with the
2 values separated by a hyphen: P0 A0L1(SM-O)M0 –C0O0E0I0N0
 Considered but not yet included: uterine size, single longest
measurement, location, and the estimated number of
leiomyomas.
 Clinicians and investigators are encouraged to include
such data in their recording systems and
forms
NO-FACE
M - Malignancy/Hyperplasia
 AUB is the most common presenting symptom of
endometrial cancer
 Conditions that lead to increased circulating levels of
estrogen are risk factors. Obesity is associated with
increased estrone levels due to peripheral conversion by
aroma tase in adipose tissue; but the primary source of
estrogen in premenopausal women remains the ovary.
Impaired ovulation and the absence of progesterone
withdrawal can result in sustained exposure of the
endometrium to estrogen.
 Hyperestrogenic state can lead to the pathologic
progression from normal endometrium to hyperplasia and
ultimately to adenocarcinoma
 PALM-COEIN not designated to replace the WHO and FIGO
classifications of endometrial hperplasia and neoplasia
 When a premalignant hyperplastic or malignant process is
identified, it would be classified as AUB-M and then
subclassified using the appropriate WHO or FIGO system
C - coagulopathy
 Encompasses a spectrum of
systemic disorders of
hemostasis that may be
associated with AUB
 About 13% of women with HMB have biochemically
detectable systemic disorders of hemostasis, most often
von Willebrand disease
 Such women will be classified as having a coagulopathy.
 Reproductive-age women taking anticoagulants (heparin,
warfarin) - more appropriate to classify them under the
category of coagulopathy rather than under iatrogenic
O - ovulatory dysfunction
 The predominant cause of ovulatory dysfunction (AUB-O) in
postmenarchal and premenopausal women is secondary
to alterations in neuroendocrine function
 There is continuous estradiol production without corpus
luteum formation and progesterone production. The steady
state of estrogen stimulation leads to a continuously
proliferating endo metrium, which may outgrow its blood
supply or lose nutrients with varying degrees of necrosis.
Uniform slough to the basalis layer does not occur, which
produces excessive uterine bleeding.
 Generally manifest as a combination of unpredictable
timing of bleeding and variable amount of flow (AUB),
which in some cases result in HMB
 Encompassed by the discarded term “DUB”
E - endometrial
 Determined by exclusion of other identifiable abnormalities
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 FAR EASTERN UNIVERSITY - NICANOR REYES MEDICAL FOUNDATION
Gynecology

in women of reproductive age who seem to have normal Laboratory Tests

ovulatory function  Pregnancy test
 In the absence of other definable cause, the mechanism is  Complete blood count
probably a primary disorder of the endometrium  Coagulation parameters (early age, with personal and
(deficiency in local production of vasoconstrictors like family history)
endothelin-1 and PGF2, or acclerated lysis of endometrial  Female hormone - NOT routinely done (E, P, LH, FSH)
clot because of excessive production of plasminogen  TSH - if there are s/sx of thyroid disease
factor)
 The primary line of defense to excessive bleeding during Imaging procedure
normal menses is the formation of the platelet plug. This is  Ultrasound is the first-line diagnostic tool for identifying
followed by uterine contractility, largely mediated by structural
prostaglandin F2α(PGF2α). Thus prolonged and heavy abnormalities - IC
bleeding can occur with abnormalities of the platelet plug  Saline-infusion
or inadequate uterine levels of PGF2α. sonography should
 Deficiency of uterine PGF2α or excessive production of PGE NOT be used as first-
(another vasodilatory prostaglandin) may also explain line diagnostic tool,
ovulatory DUB. The ratio of PGF2α/PGE correlates inversely but may be useful in
with menstrual blood loss. providing a more
I - iatrogenic accurate
 Medical interventions or devices (IUD) evaluation of the
 Cyclic estrogen-progestin agents that cause unscheduled uterus with
bleeding (breakthrough bleeding) intracavitary lesions
 Cigarette-smoking, anticonvulsants, antibiotics like - IA
Rifampicin and Griseofulvin (may cause AUB by lowering  Hysteroscopy should
the levels of circulating estrogens and progestins) be used only when ultrasound results are inconclusive, e.g.
 TCA and phenothiazines (may interfere with dopamine to determine the exact location of a fibroid or the exact
metabolism by reducing serotonin uptake and may have nature of an abnormality - IA
the potential to cause AUB)
N - not yet classified Submucous myoma vs Endometrial polyp
 Thought to cause AUB but have been poorly defined and
have not been demonstrated conclusively
 May be caused by foreign bodies or trauma
 Chronic endometritis, AV malformations, and myometrial
hypertrophy
 Treatment is tailored to the specific cause.

Diagnosis
1. Thorough history.
2. Indirect assessment of MBL. Hemoglobin concentration, serum
iron levels, and serum ferritin levels.
3. Other laboratory tests if necessary:
a. hCG determination Biopsy
b. TSH and Prolactin  First-line in women with AUB who are older than 45 years old
c. Screening for coagulation defects  < 45 years old with risk factors
d. Document ovulation: Serum progesterone, endometrial  Chronic
biopsy anou\vulation
e. Pelvic sonography  PCOS
f. Investigate endometrial cavity: Hysteroscopy or SIS  Obesity
g. Dilatation and curettage  Ineffective medical
management
History  Persistent AUB
 Is she hemodynamically stable?  Postmenopausal women
 Asses the bleeding (frequency, amount and duration) with bleeding
 Pay special attention to: /premenopausal women
- Fertility desire with heavy and/ or
- Risk factors for uterine cancer (obesity, chronic irregular vaginal bleeding
anovulation, unopposed estrogen stimulation, PCOS  Postmenopausal women
- History of gynecologic pathology with endometrial cells
- Family history of gynecologic cancer or colon cancer seen on pap smear /
premenopausal women
Physical Examination with atypical glandular
 BMI cells on pap smear
 Abdominal exam  Breast cancer patients on
- Masses Tamoxifen with abnormal
 Pelvic exam vaginal bleeding; and
- Uterine size, shape, masses  Women who are still
- Cervical lesions “menstruating” after 52
- Rectal lesions years of age

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Gynecology

Two (2) types of DUB Androgenic Steroid (Danazol)

Anovulatory Ovulatory GnRH analogs
 Predominant cause of  Ovulatory DUB occurs most Necessitates immediate cessation of bleeding
DUB in the commonly after the If bleeding Requires the use of
postmenarcheal and adolescent years and is profuse pharmacologic doses of
premenopausal years before the perimenopausal estrogen or curettage
 90% of cases years Curettage to be used more
 10% of ovulatory women liberally in older women with risk
factors or in those who are
Pathogenesis hemodynamically
Premenarcheal  Estradiol rise not followed by LH surge compromised.
girls  Indicates absence of positive feedback Not dependent on whether the
Acute
due to HPO immaturity patient is anovulatory or
bleeding
Pre-menopausal  Lessened capacity to secrete estradiol ovulatory.
women leads to abnormal LH surge Estrogen will be temporarily
 Indicates defect in follicular maturation helpful, even if there are
(dysfolliculogenesis) abnormal anatomic findings,
Anovulation is key pathophysiologic mechanism such as fibroids, it is preferable
No corpus luteum to perform curettage if
No progesterone pathology is suspected.
Necrosis If bleeding High doses of progestogen
Continous estradiol production is not alone may be used
Continuous endometrial proliferation profuse
Endometrium outgrows its supply
Disorganized sloughing Acute Phase of Bleeding
Excessive uterine bleeding  High dose of conjugate equine estrogen (CEE)
 CEE 25 mg IV q4hrs x 24 hrs, OR
Goals of Management  CEE 10-20mg/24 hr p.o. till bleeding stops
Goals of treatment  Stop the acute bleeding  then CEE 1.25 mg/day x21 days
for anovulatory  Avert future episodes  Add progesterone on last 7 days of treatment
bleeding  Prevent long-term complications  OCP (35 ug/tab) 1 tab BID-QID x5-7 days, then OD x21 days
 OC 1 tab/d for 21 days, rest 7 days, for 3 cycles or longer
Management of AUB
 In some cases surgical intervention is indicated, but the Day Frequency
foundation of treatment has been a medical approach. 1-2 1 tab 4x a day
 If the patient fails to have resolution of the bleeding with Regimen for low 3-4 1 tab 3x a day
medical therapy, another cause of the bleeding must be dose of 5-9 One tab daily
suspected, and reevaluation is necessary monophasic COC 20-25 Expect menses
26 Start COC at
Organic cause Identify and treat standard dosage
Estrogens
NSAID’s Progestins
Progestogens *Adolescent anovulatory patient: ideal model for progestigen
Anti-fibrinolytic use
Medical Brand
COC’s Progestogens Dose
Endocrine or therapy name
Ergot
dysfunctional
LNG-IUS Dydrogesterone 10mg Duphaston 10 mg BID day 11 – 25
cause
Danazol Norethisterone 5mg Primolut 5-15 mg/d on day 16–
GnRH analog 25
Dilatation and curettage Medroxyprogesterone Provera 10 mg/d for first 10
Surgical
Endometrial ablation acetate days each month
therapy
Hysterectomy Clomiphene citrate
For women desirous of pregnancy
Treat Acute High dose estrogens / High dose progestogens Tranexamic acid
bleeding Combined Oral contraceptives 2007 National Institute for Clinical Excellence (NICE) Guidelines
episode for Heavy Menstrual Bleeding (HMB):
Anovulatory Adolescent: cyclic progestin Dose: 1 gram every 3-4x a day from the onset of bleeding up to 4
Reproductive age: COC’s or days
Clomiphene
Citrate 2004 Cochrane Database of Systemic Reviews on Antifibrinolytic
Prevent
Perimenopausal: Low dose for HMB by Lethaby, Farquhar, & Cooke:
Recurrence
COCs Dose used: 1 gram 4x a day from days 1-5 of the menstrual cycle
(Long-term
Ovulatory Progestins
Management)
LNG-IUS 54% reduction on MBL
NSAIDs
Antifibrinolytic agents Non steroidal anti inflammatory drugs
Ergot  Mode of Action NOT CLEAR

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Gynecology

 Prostaglandin synthase inhibitors Endometrial Ablation

 Inhibit the biosynthesis of cyclic endoperoxides  An initial treatment for HMB in women who have a normal
 These endoperoxides convert arachidonic acid to uterus and also those with small uterine fibroids (<3cm).
prostaglandins  In women with HMB alone, with uterus no bigger than a 10-
 Block the action of prostaglandins by interfering directly at week pregnancy,it should be considered preferable to
their receptor sites hysterectomy.
 DOSE: For 3 days ONLY  Second-generation ablation techniques should be used
Mefenamic acid 500mg TID where no structural or histological abnormality is present
Ibuprufen 400mg TID
Meclofenamate sodium 100mg TID Hysterectomy
Naproxen sodium Loading dose: 550mg then 275mg  Should NOT be used as first-line treatment for heavy
q 6 hours menstrual bleeding.
Ergot and Androgenic Steroids
Danazol
 Doses of 200-400 mg/d given for 12 weeks
 Reduced menstrual blood loss from >200 ml to <25 ml over
12 weeks
 More effective than mefenamic acid
 Adverse androgenic effects, weight gain, acne
Gonadotropin Releasing Hormone
 Rationale: Induce medical menopause
 MOA: inhibit ovarian steroid production
 Dosage: Depot preparations (Zoladex, Lupron)IM every 28
days for 3-6 months
- Use limited by expense and side effects
- Reserved for heavy bleeders unresponsive to other
medical therapy and desirous of future fertility
- Add-back hormone replacement therapy to prevent
bone loss with prolonged therapy
 Effects: Menstrual blood loss reduced from 100-200 ml to 0-
30 ml per cycle

Acute Heavy Menstrual Bleeding: Medical Management

High dose CEE IA
Combined OCs IB
Tranexamic acid IA
Progestins (limited evidence) IIB
Chronic Heavy Menstrual Bleeding: Medical Management
LNG-IUS IA
Tranexamic acid IA
NSAIDs IA
COC IB
Danazol IA
Cyclic progestins IA

First line LNG-IUS (levonorgestrel- A

releasing intrauterine system)
Second line Tranexamic acid A
NSAIDs A
COC A
Third line Oral progestogen A
Injected progestogen A
Others GnRH analogue

Chronic Heavy Menstrual Bleeding (HMB)

Surgical Management
1. Dilatation and curettage - IIIC
2. Endometrial ablation - IA
3. Hysterectomy Sources:
Moodle PPT 2022 and Live lecture by Dr. Ivy-Lim
Dilatation and Curettage Comprehensive Gynecology 7th Edition Chapter 26
 Shoud NOT be used as a
therapeutictreatment.
 May be performed for acute HMB
unresponsive to initial medical
management

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