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Clinical Screening for an Underlying Disorder of Hemostasis in the Patient With Excessive

Menstrual Bleeding
Initial screening for an underlying disorder of hemostasis in patients with excessive menstrual
bleeding should be structured by the medical history. A positive screening result* comprises the
following circumstances:

 Heavy menstrual bleeding since menarche


 One of the following conditions:
—Postpartum hemorrhage
—Surgery-related bleeding
—Bleeding associated with dental work
 Two or more of the following conditions:
—Bruising, one to two times per month
—Epistaxis, one to two times per month
—Frequent gum bleeding
—Family history of bleeding symptoms
*Patients with a positive screening result should be considered for further evaluation, including consultation with a
hematologist and testing for von Willebrand factor and ristocetin cofactor

Laboratory Testing for the Evaluation of Patients


With Acute Abnormal Uterine Bleeding

Laboratory Evaluation Specific Laboratory Tests

Initial laboratory testing Complete blood count


Blood type and cross match
Pregnancy test

Initial laboratory evaluation for Partial thromboplastin time


disorders of hemostasis Prothrombin time
Activated partial
thromboplastin time
Fibrinogen

Initial testing for von Willebrand von Willebrand factor


disease* antigen†
Ristocetin cofactor assay†
Factor VIII†

Other laboratory tests to Thyroid-stimulating


consider hormone
Serum iron, total iron
binding capacity, and ferritin
Liver function tests
Chlamydia trachomatis

Disorders of the Menstrual Cycle


• Amenorrhea
• Dysmenorrhea
• Premenstrual Syndrome

Definitions
• Menorrhagia: heavy or prolonged uterine bleeding that occurs at regular intervals. Some sources
define further as the loss of ≥ 80 mL blood per cycle or bleeding > 7 days.
• Hypomenorrhea: periods with unusually light flow, often associated with hypogonadotropic
hypogonadism (athletes, anorexia). Also may be associated with Asherman’s syndrome
• Metrorrhagia: irregular menstrual bleeding or bleeding between periods
• Menometrorrhagia: metrorrhagia associated with > 80 mL
• Polymenorrhea: frequent menstrual bleeding. Strictly, menses occur q 21 d or less
• Oligomenorrhea: Menses are > 35 d apart. Most commonly caused by PCOS, pregnancy, and
anovulation

Differential Diagnosis
• Structural
– Cervical or vaginal laceration
– Uterine or cervical polyp
– Uterine leiomyoma
– Adenomyosis
– Cervical stenosis/Asherman’s (hypomenorrhea)
• Hormonal
– Anovulatory bleeding
– Hypogonadotropic hypogonadism
– Pregnancy
– Hormonal Contraception (i.e. OCPs, Depo-Provera)
• Malignancy
– Uterine or Cervical cancer
– Endometrial hyperplasia (potentially pre-malignant)
• Bleeding disorders
– von Willebrand’s Disease, Hemophilia/Factor deficiencies, platelet disorders

Workup

• History
– Timing of bleeding, quantity of bleeding, menstrual hx including menarche and recent periods,
associated sxs, family hx of bleeding disorders

• Physical
– R/o vaginal or cervical source of bleeding. Bimanual may reveal bulky uterus/discrete fibroids
– Assess for obesity, hirsutism, stigmata of thyroid disease (hypothyroidism associated with
anovulation), signs of hyperprolactinemia (visual field testing, galactorrhea)
– Pap smear
– Endometrial biopsy, if appropriate

• Pregnancy Test

• Imaging
– Pelvic ultrasound
– Sonohystogram or hysterosalpingogram

• Surgical
– Hysteroscopy
–D&C

Normal Ovulatory Cycle


• Follicular development à ovulation (d14) à corpus luteal function à luteolysis
• Endometrium is exposed to:
– ovarian production of estrogen à
(proliferation)
– Combination of estrogen and progesterone à
(secretory phase)
– Estrogen and progesterone withdrawal
(desquamation and repair)
Anovulatory Bleeding
• Corpus luteum is not produced
– Ovary fails to secrete progesterone, although estrogen production continues
– Result is continuous, unopposed E stimulation of endometrium:
• endometrial proliferation without P-induced differentiation / stabilization
– Endometrium becomes excessively vascular without stromal support à fragility and irregular
endometrial bleeding

Etiologies
• Hyperandrogenic anovulation (PCOS, CAH, androgen-producing tumors)
• Hypothalamic dysfunction (stress, anorexia, exercise)
• Hyperprolactinemia
• Hypothyroidism
• Primary pituitary disease
• Premature ovarian failure
• Iatrogenic (secondary to radiation or chemo)

Anovulatory Bleeding: Adolescents (13-18 years)


• Anovulatory bleeding may be normal physiologic process, with ovulatory cycles not established
until 1-2 yrs after menarche (immature HPG axis)
• Screen for coagulation disorders (PT/PTT, plts)
• May be caused by leukemia, ITP, hypersplenism
• Consider endometrial bx in adolescents with 2-3 year history of untreated anovulatory bleeding,
especially if obese

Anovulatory Bleeding: Management in Adolescents


• High dose estrogen therapy for acute bleeding episodes (promotes rapid endometrial growth to
cover denuded endometrial surfaces): conjugated equine estrogens PO up to 10 mg/d in 4 divided
doses or IV 25 mg q 4 hrs for 24 hrs
• Treat pts with blood dyscrasias for their specific diseases, r/o leukemia
• Prevent recurrent anovulatory bleeding with:
• cyclic progestogen (i.e. Provera)
or
• low dose (≤ 35 μg ethinyl estradiol) oral contraceptive
– suppresses ovarian and adrenal androgen production and increases SHBG à decreasing
bioavailable androgens

Anovulatory Bleeding: Reproductive Age (19-39 years)


• Anovulatory bleeding not considered physiologic, evaluation required
• 6-10% of women have hyperandrogenic chronic anovulation (i.e. PCOS), characterized by
noncyclic bleeding, hirsutism, obesity (BMI ≥ 25)
– Underlying biochemical abnormalities: noncyclic estrogen production, elevated serum
testosterone, hypersecretion of LH, hyperinsulinemia.
– h/o rapidly progressing hirsutism with virilizationà suggests tumor
• Lab testing: HCG, TSH, fasting serum prolactin
– If androgen-producing tumor is suspected, serum DHEAS and testosterone levels
– If POF suspected, serum FSH
• Chronic anovulation resulting from hypothalamic dysfunction (dx’d by low FSH level) may be due
to excessive psychologic stress, exercise, or weight loss

Anovulatory Bleeding:
Reproductive Age (19-39 yrs)
When is endometrial evaluation indicated?
• Sharp increase in incidence of endometrial CA from 2.3/100,000 ages 30-34 yrs à 6.1/100,000
ages 35-39 yrs
• Therefore, endometrial bx to exclude CA is indicated in any woman > 35 yrs old with suspected
anovulatory bleeding
• Pts 19-35 who don’t respond to medical therapy or have prolonged periods of unopposed estrogen
2/2 anovulation merit endometrial bx

Anovulatory Bleeding: Reproductive Age (19-39 yrs)


Medical therapies
• Can be treated safely with either cyclic progestogen or OCPs, similar to adolescents.
• Estrogen-containing OCPs
– relatively contraindicated in women with HTN or DM
– contraindicated for women > 35 who smoke or have h/o thromboembolic dz
• If pregnancy is desired, ovulation induction with clomid is initial tx of choice
– Can induce withdrawal bleed with progestogen (i.e. provera), followed by initiation of therapy with
Clomid, 50 mg/d for 5 days, starting b/t days 3 and 5 of menstrual cycle
Anovulatory Bleeding:
Later Reproductive Age (40-Menopause)
• Incidence of anovulatory bleeding increases toward end of reproductive years
• In perimenopausal women, onset of anovulatory cycles is due to declining ovarian function.
• Can initiate hormone therapy for cycle control
When is endometrial evaluation indicated?
• Incidence of endometrial CA in women 40-49 years: 36.2/100,000
• All women > 40 yrs who present with suspected anovulatory bleeding merit endometrial bx after
excluding pregnancy

Medical therapy
• Cyclic progestogen, low-dose OCPs, or cyclic HRT are all options
• Women with hot flashes secondary to decreased estrogen production can have symptomatic relief
with ERT in combination with continuous or cyclic progestogen

Surgical therapy
• Surgical options include: hysterectomy and endometrial ablation
• Surgical tx only indicated when medical mgmt has failed and childbearing complete
• Some studies suggest hysterectomy may have higher long-term satisfaction than ablation
• Endometrial ablation: NovaSure, thermal balloon
– YAG laser and rollerball less widely-used currently
– 45% of women achieve amenorrhea after YAG laser or resectoscope. 12 month post-op
satisfaction is 90%. Only 15% of women achieve amenorrhea after thermal balloon ablation, and 1
yr satisfaction rate still 90%
– Long-term satisfaction with ablation may be lower:
• in 3-year f/u study, 8.5% of women who had undergone ablation were re-ablated, an additional
8.5% had hyst
• In a 5-year follow up study, 34% of women who underwent ablation later had a hyst.

Frequency of menses (or length of menstrual cycle)


 Mean is 28 days (95% CI 24–38 days); frequent <24 days, infrequent >38 days.

As age increases, the menstrual cycle tends to shorten; age 13 –19 years, mean cycle length 35 days (90th
centile range: 28–44 days), age 35–52 years, mean cycle length 28 days (90th centile range: 25 –32 days).

As age increases, the frequency of irregular periods reduces. The frequency of irregular periods is around 21%
between the ages 15 and 19 years and reduces 11% between ages 40 and 44 years.

Duration of menstruation

–8.0 days; prolonged >8 days, shortened <4.5 days.
–8 days).






Components used to describe type of Normal limits (5th–95th


AUB centile)
Frequency of menses (days) Frequent <24 Normal 24–38 Infrequent >38
Duration of flow (days) Prolonged >8.0 Normal 4.5–8.0 Shortened <4.5
Volume of monthly blood loss (ml) Heavy >80 Normal 5–80 Median 40 Light <5
Regularity of menses (cycle to cycle Regular variation: ± 2 to 20 variation over 12 months; in days) days
Irregular variation: >20 days or absent

Menstruation is controlled by the cyclical hormonal change in the menstrual cycle.

Normal frequency is between 24–38 days.

Normal duration is 4.5–8 days.

Normal volume is between 5–80 ml.

Regular cycle-to-cycle variation is between 2–20 days

Heavy menstrual bleeding is a subjective diagnosis as it is defined by the woman based on how it interferes with her quality
of life. HMB affects 3% of premenopausal women. Pathological causes of HMB include uterine fibroids (20–30%), uterine
polyps (5–10%), adenomyosis (5%); endometriosis rarely presents as AUB, but is identified in <5% of cases of
AUB. DUB should not be used to describe HMB.

FIGO have approved this new classification system and have called it PALM-COEIN:
• structural causes for AUB: polyp; adenomyosis; leiomyoma; malignancy and hyperplasia
• non-structural causes for AUB: coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet
classified.
Causes of AUB should be classified as per the PALM-COEIN model. PALM causes (Polyps, Adenomyosis, Leiomyomas
[subserosal and other], Malignancy and hyperplasia) are structural. COEIN causes (Coagulopathy, Ovulatory dysfunction,
Endometrial, Iatogenic, Not otherwise specified) are nonstructural
Causes of vaginal bleeding in postmenopausal women

Polyps 30%

Submucosal fibroids 20%

Endometrial atrophy 30%

Hyperplasia 8–15%
Endometrial carcinoma 8–10%

Ovarian, tubal, cervical malignancy 2%

Second-generation ablation techniques are less costly than


hysterectomy but hysterectomy provides greater gain in quality
of life over the long term

Hysteroscopy should be undertaken post-dilation of the cervix


and prior to insertion of the ablation device in the uterus to
confirm uterine integrity

Endometrial thinning pre-ablation is required for most


ablative techniques