Download Perimenopausal Bleeding - Medical College of Wisconsin

2/3/2016
Perimenopausal
Bleeding
Anna Witt, MD
February 3, 2016
Disclosures/Affiliations
• Financial
• None
Objectives
• Review the clinical course of perimenopause
• Review the standardized terminology, definitions, and
classification of abnormal uterine bleeding
• Differentiate normal and abnormal bleeding during
perimenopause
• Learn current recommendations to evaluate abnormal uterine
bleeding that occurs during perimenopause
• Learn current recommendations to treat abnormal uterine
bleeding associated with perimenopause
Objective #1
• Review the clinical course of perimenopause
• Pharmaceutical
• None
Perimenopause
Perimenopause
• Perimenopause (a.k.a. menopausal transition)
• The period around the onset of menopause that is often marked by
various physical signs (as hot flashes and menstrual irregularity)
• Merriam-Webster Dictionary
• Time period during which a woman’s body makes its natural transition
toward permanent infertility
• Mayo Clinic
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Perimenopause
• Onset
• On average, 4 years before the final menstrual period (FMP)
• Median age is 47 years
• May occur as early as the mid-30’s and as late as the early-50’s
• Duration
• May last 2-10 years
• End
• 12 consecutive months without a menstrual period
• This retrospectively determines when menopause has occurred. The
median age of menopause is 51.4 years
< Age 40
Age 40-45
Primary ovarian insufficiency 5%
Age 45-55
> Age 55
90%
5%
Perimenopause Manifestations
• Progressive decline in
ovarian function
• Irregular menstrual
cycles
• Hormonal fluctuations
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Hot flashes
Sleep disturbances
Mood changes
Vaginal dryness
Bladder problems
Decreasing fertility
Sexual dysfunction
Joint pain
Breast pain
Menstrual Migraines
The Stages of Reproductive Aging Workshop (STRAW)
+10 Staging System for Reproductive Aging in Women
Perimenopause Manifestations
• Progressive decline in
ovarian function
• Irregular menstrual
cycles
• Hormonal fluctuations
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Hot flashes
Sleep disturbances
Mood changes
Vaginal dryness
Bladder problems
Decreasing fertility
Sexual dysfunction
Joint pain
Breast pain
Menstrual Migraines
Data
• Information about perimenopause comes from a number of
longitudinal, cohort studies of midlife women
• Study of Women’s Health Across the Nation (SWAN)
• Multiethnic, community-based, cohort of >3000 women ages 42-52
for 15 years
• A staging system was developed based on these cohort
studies to characterize reproductive aging
• Stage of Reproductive Aging Workshop (STRAW) staging system
Objective #2
• Review the standardized terminology, definitions, and
classification of abnormal uterine bleeding
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Normal Menses
• Normal menstrual flow is 3-7 days (average 5)
• Normal menstrual cycle length is 21-35 days (average 28)
A normal cycle starts when pituitary follicle stimulating hormone
induces ovarian follicles to produce estrogen
Estrogen stimulates proliferation of the endometrium
A leutinizing hormone surge prompts ovulation
the resultant corpus luteum produces
progesterone, inducing a secretory endometrium
in the absence of pregnancy, estrogen and
progesterone levels decline, and withdrawal
bleeding occurs 13-15 days post-ovulation
Abnormal Uterine Bleeding
• Menstrual flow outside the normal volume, duration,
regularity, or frequency is considered abnormal uterine
bleeding (AUB).
• It accounts for > 70% of all gynecologic consults in the
perimenopausal and postmenopausal years
AUB Terminology to Forget
• Menorrhagia/Hypermenorrhea
• Heavy menstrual bleeding
• Hypomenorrhea
• Light menstrual bleeding
• Metrorrhagia
• Bleeding between periods
• Menometrorrhagia
• Excessive or prolonged bleeding at and between menstrual periods
• Polymenorrhea/Polymenorrhagia/Epimenorrhea/Epimenorrhagia
• Bleeding that occurs more frequently than every 21 days
• Oligomenorrhea
• Bleeding that occurs less frequently than every 35 days
• Metropathia hemorrhagica
• Abnormal, excessive, often continuous uterine bleeding due to persistence and exaggeration
of the follicular phase of the menstrual cycle
• Dysfunctional uterine bleeding
• Irregular uterine bleeding in the absence of pathology or medical illness
• Functional uterine bleeding
• Bleeding in the absence of gross lesions, at unexpected times, or in abnormal amounts
AUB Terminology that is
Currently Acceptable
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Irregular menstrual bleeding (IrregMB)
Absent menstrual bleeding (Amenorrhea)
Infrequent menstrual bleeding
Frequent menstrual bleeding
Heavy menstrual bleeding (HMB)
Heavy and prolonged menstrual bleeding (HPMB)
Light menstrual bleeding
Prolonged menstrual bleeding
Shortened menstrual bleeding
Intermenstrual bleeding (IMB)
Irregular nonmenstrual bleeding
Postmenopausal bleeding (PMB)
Precocious menstruation
Acute AUB
Chronic AUB
AUB Classification System
• In 2011, the International Federation of Gynecology and
Obstetrics (FIGO) introduced a new classification system to
describe uterine bleeding abnormalities in reproductive-aged
women
• In 2012, the American College of Obstetricians and
Gynecologists (ACOG) said it supports adoption of this
nomenclature system to standardize the terminology used to
describe AUB
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PALM-COEIN
• Classifies abnormal uterine bleeding by pattern and etiology
• Pattern
• Menorrhagia  Heavy Menstrual Bleeding
• Metrorrhagia  Intermenstrual Bleeding
• Etiology
• Structural Causes (PALM)
• Polyp
• Adenomyosis
• Leiomyoma
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Submucosal
Other myoma
• Malignancy and hyperplasia
• Nonstructural Causes (COEIN)
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Coagulopathy
Ovulatory dysfunction
Endometrial
Iatrogenic
Not yet classified
(AUB/HMB)
(AUB/IMB)
(AUB-P)
(AUB-A)
(AUB-L)
Components of PALM-COEIN
• Polyp (AUB-P)
• Intracavitary and composed of endometrial tissue.
• Accounts for 39% of AUB in premenopausal women and 21-28% o f AUB in
postmenopausal women.
• Diagnosed by transvaginal ultrasound (TVUS), saline infusion sonohysterography
(SIS), and hysteroscopy
• Adenomyosis (AUB-A)
• Endometrial tissue that grows into the muscular tissue of the uterus
• 70% of women with adenomyosis have AUB
• Diagnosed by TVUS and magnetic resonance imaging (MRI)
(AUB-LS)
(AUB-LO)
• Leiomyoma (AUB-L)
(AUB-C)
(AUB-O)
(AUB-E)
(AUB-I)
(AUB-N)
• Malignancy and hyperplasia (AUB-M)
(AUB-M)
Components of PALM-COEIN
• Coagulopathy (AUB-C)
• 13% of women with HMB have a disorder of hemostasis, which is
often overlooked in the differential diagnosis
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Submucosal, Intramural, or Subserosal. Composed of muscle tissue.
Age is most common risk factor with lifetime risk of 60% in women > 45 years.
Submucosal lesions more likely to be associated with AUB
May be diagnosed by TVUS, SIS, MRI or hysteroscopy, but depends on location
• 15% of postmenopausal women with AUB will have endometrial carcinoma
• 15% of postmenopausal women with AUB will have endometrial hyperplasia
Objective #3
• Differentiate normal and abnormal bleeding during
perimenopause
• Ovulatory dysfunction (AUB-O)
• Unpredictable menses and variable flow that is usually associated
with endocrinopathies
• Endometrial (AUB-E)
• Usually present with HMB, which may be a disorder of
endometrial hemostasis, or IMB, which may be secondary to
inflammation or infection
• Iatrogenic (AUB-I)
• Causes include medications that affect blood coagulation or
ovulation, chemotherapy, or radiation.
Typical Menstrual Cycle Changes
during Perimenopause
• Overall, there is a general decrease in menstrual bleeding
• First, there is a lengthening of the intermenstrual interval.
• Persistent ≥ 7 day difference in length of consecutive cycles
• Then there are more dramatic changes with episodes of skipped
cycles and periods of amenorrhea.
• ≥ 60 days of amenorrhea
• And finally, there is persistent amenorrhea
• 365 consecutive days of amenorrhea
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Atypical Menstrual Cycle Changes
during Perimenopause
• An overall increase in menstrual bleeding is not normal
• Heavy menstrual bleeding
• Changing pad or tampon every 1-2 hours for 2 hours or more
Objective #4
• Learn current recommendations to evaluate abnormal uterine
bleeding that occurs during perimenopause
• Prolonged menstrual bleeding
• Bleeding lasts longer than 7 days
• Intermenstrual bleeding
• Bleeding in between cycles
• Frequent menstrual bleeding
• Menstrual cycles < 21 days apart
Clinical Case
• J.K. is a 45 yo female who presents to clinic with complaint of
irregular menses. Wonders if she is going through menopause.
Missed 2 cycles completely. Some months, menses have been
lighter and shorter than usual, followed by a few days of no
bleeding, but then bleeding returns for another few days.
Other months, menses heavier than what she considers
normal. She has also noticed breast tenderness in the middle
of her cycles rather than with bleeding. Thinks she is starting
to have hot flashes because she feels hotter than she is used
to when physically active and also occurs out of the blue at
rest. No idea about when other female relatives went through
menopause. Also complains of urinary frequency and urgency
for past week. Denies dysuria or vaginal discharge.
Evaluation
• Medical conditions
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Polyp
Adenomyosis
Leiomyoma
Malignancy or hyperplasia (endometrial)
Coagulopathy
Ovulatory dysfunction
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Pregnancy
Lactation
Hyperandrogenism
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Hypothalamic dysfunction
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Polycystic ovarian syndrome, congenital
adrenal hyperplasia, etc…
Anorexia nervosa
Pituitary disease
Premature Ovarian Failure
Hyperprolactinemia
Thyroid disorder
Diabetes
Endometrial
Iatrogenic
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Medications
Chemotherapy or radiation
• J.K.
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Bipolar 2 disorder, major depressive
Irritable bowel syndrome
Morbid obesity
Esophageal reflux
Hypertension
Anemia, iron deficiency
Osteoarthritis of right knee
Cholecystitis
Tibial plateau fracture
ASCUS and LSIL on pap smear
Sudden cardiac arrest
Takotsobu syndrome
Cardiomyopathy
ICD in place
G0P0
Evaluation
• Menstrual history
• Age of menarche and
menopause
• Menstrual bleeding patterns
• Severity of bleeding (clots or
flooding)
• Pain (severity and treatment)
• J.K.
• Onset of menses at age 13.
• Typical pattern
• Bleeding duration of 6 days
• Flow is heavy  light
• Cycle length is 24-29 days and
regular.
• Associated symptoms of breast
tenderness with bleeding.
• Severity is normally without
clots or flooding. Also denies
clots or flooding recently, just
heavier bleeding that usual and
recurrent bleeding several days
after she thinks her period has
ended
• Only pain is breast tenderness
and does not take medication
for it.
Evaluation
• Surgical history
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Brain
Endocrine
Pelvic
Complications
• J.K.
• Wisdom tooth
extraction
• Colposcopy with
biopsy/curettage
• Cholecystectomy
• ORIF proximal tibial
plateau fracture
• Endotracheal intubation
• Cardiac catheterization
• Cardiac defibrillator
placement
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Evaluation
• Use of medications
Antiplatelet
Anticoagulant
Antiepileptics
Antipsychotics
Hormonal
contraceptives
• Herbals
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Evaluation
• Physical examination
• General
• Pelvic
• J.K.
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clonazepam
duloxetine
ferrous sulfate
fluoxetine
lamotrigine
nadolol
Evaluation
• Symptoms and signs of
possible hemostatic
disorder
• Heavy menstrual bleeding
since menarche
• One of the following:
• Obese, otherwise
normal exam
• External genitalia
• Speculum
• Bimanual
• ? Heavy menstrual
bleeding
• Postpartum hemorrhage
• Surgery-related bleeding
• Bleeding associated with
dental work
• Two or more of the
following:
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• J.K.
• J.K.
Bruising 1-2 x per month
Epistaxis 1-2 x per month
Frequent gum bleeding
Family history of bleeding
symptoms
AUB Age Based Common
Differential Diagnosis
• 13 to 18 years
• 19 to 39 years
• 40 years to menopause
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Anovulatory bleeding
Endometrial hyperplasia or carcinoma
Endometrial atrophy
Leiomyoma
Pregnancy
Thyroid disease
Hyperprolactinemia
• Postmenopausal
Anovulatory Bleeding
In the absence of ovulation, the corpus luteum does not develop
and the ovary fails to produce progesterone
 Endometrial proliferation without progesteronewithdrawal induced shedding and bleeding
Endometrium that develops is fragile,
vascular, and lacking stromal support
As one area of bleeding begins to heal,
another area begins to slough.
Result is bleeding that is
noncyclic, unpredictable, and
inconsistent in volume
Hormonal Changes of Early
Perimenopause
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Endometrial Hyperplasia or
Malignancy
Cancer of the Corpus and Uterus, Age-Specific Rates, 2008-2012
SEER Cancer Statistics Review
Age at Diagnosis/Death
Incidence/100,000
Mortality/100,000
20-24
0.4
-
25-29
2.0
0.1
30-34
4.5
0.2
35-39
9.0
0.5
40-44
14.2
1.0
45-49
24.5
1.9
50-54
46.2
3.9
55-59
74.6
7.5
60-64
93.1
12.9
65-69
101.6
17.6
70-74
94.8
21.9
75-79
82.4
24.5
80-85
70.6
27.6
85+
56.3
33.7
Evaluation
• Tissue Sampling Methods
• Office endometrial biopsy (EMB)
• Hysteroscopy directed endometrial sampling (office or hospital)
• Dilation and curettage (D&C)
• Diagnostic or Imaging Tests
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Transvaginal ultrasound (TVUS)
Hysteroscopy
Saline infusion sonohysterography (SIS)
Magnetic resonance imaging (MRI)
Evaluation
Uterine Evaluation for Abnormal Uterine Bleeding, ACOG Practice Bulletin 128, Figure 2
Evaluation
• Laboratory Testing
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• J.K.
Pregnancy test
CBC
TSH
Prolactin
Cervical cancer screening
Cervicitis screening
• HCG Qualitative Urine
• Negative
• Hgb/Plt
• 11.7/395
• TSH
• 2.35
• Prolactin
• not obtained
• Cervical Cancer
• Cytology negative for
intraepithelial lesion or
malignancy
• HPV negative for high risk
types
• Cervicitis
• not obtained
Evaluation
Evaluation and Management of Abnormal Uterine Bleeding in Premenopausal Women. AFP. 2012; 85(1):35-43. Table 2
Test
Utility
Endometrial Biopsy
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Readily available
Low complication rate
Inexpensive
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Pregnancy
Clotting disorder
Acute PID or Cervicitis
Not able to diagnose AUBP,A,L
Endometrial carcinoma
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91% sen, 98% sp
Endometrial hyperplasia w/
atypia
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82.3% sen, 98% sp
Hysteroscopy
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Direct visualization of the
uterine cavity
Allows for directed biopsy
at time of procedure
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Pregnancy
Clotting disorder
Acute PID or Cervicitis
Does not evaluate
myometrium or ovaries
Intracavitary abnormality
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94% sen, 89% sp
Detects endometrial and
myometrial abnormalities
Assesses ovaries
Less sensitive and specific than
SIS
Intracavitary abnormality
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60-92% sen
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62-96% sp
Pregnancy
Clotting disorder
Acute PID or Cervicitis
More expensive than TVUS
Limited availability
Intracavitary abnormality
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88-99% sen
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72-95% sp
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Transvaginal
Ultrasound
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Saline Infusion
Sonohysterography
Has utility of TVUS with
improved capacity to diagnose
endometrial abnormalities
Limitations or
Contraindications
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Effectiveness
Evaluation
• J.K.
• Endometrial Biopsy
• DIAGNOSIS
• Benign endometrium with uneven hormone effect and features consistent with
exogenous hormone effect.
• GROSS DESCRIPTON
• Present are multiple fragments of clear mucoid material as well as pale to pinktan tissue measuring in aggregate 1.3 x 0.8 x 0.5 cm. The specimen is entirely
submitted in one cassette.
• MICROSCOPIC DESCRIPTION
• Sections from the endometrial biopsy show several fragments of endometrial
tissue. The endometrium has a variable appearance with some fragments
displaying small tubular-like inactive endometrial glands surrounded by
pseudodecidualized appearing endometrial stroma. Other fragments of
endometrium display irregularly contoured and coiled appearing endometrial
glands lined by vacuolated columnar epithelium. The glandular to stromal ratio
is not increased. Crush artifact is present. No definitive stromal breakdown is
identified. No atypical complex hyperplasia or malignancy is identified.
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Evaluation
• J.K.
• US Pelvic Transvaginal
• FINDINGS
• The uterus is retroverted. It measures 7.1 x 4.4 x 5 cm. Endometrial stripe
is of normal caliber measuring 3 mm. Within the uterine myometrium,
there is a solid right-sided myometrial mass measuring up to 4.7 cm in
diameter consistent with a uterine fibroid. The right and left adnexa are
identified. A 1 cm simple-appearing cyst is noted in the right adnexa.
Blood flow is noted to both adnexa. The right and left ovaries measure 2.5
x 2.2 x 2.1 and 2.1 x 1.7 x 1.9 cm. No complex adnexal masses or free
pelvic fluid is evident.
• IMPRESSION
• Retroverted uterus with evidence of right-sided uterine fibroid.
Tissue Sampling
Considerations
• Role of testing is to determine whether endometrial
hyperplasia or carcinoma is present
• Women 45+ and Women < 45 with history of unopposed
estrogen, failed medical treatment, and persistent AUB
• First line test
• Technique
• Office endometrial biopsy (EMB)
• Office or hospital hysteroscopy with endometrial sampling
• Dilation and curettage (D&C)
• If specimen insufficient, non-diagnostic, or cannot be performed,
try again with same or different technique.
• Only an endpoint if positive for hyperplasia or carcinoma
• Persistent bleeding necessitates further evaluation to rule out other
pathology
Imaging Considerations
• Literature is unclear about when evaluation with imaging is
indicated.
• Reasonable to perform if patient has an abnormal pelvic exam
• Polyps, Adenomyosis, Leiomyomas,
Imaging Considerations - Polyp
• Also if patient has a normal pelvic exam, but persistent AUB
symptoms despite medical treatment and benign endometrial tissue
sampling
• Imaging Choice
• Transvaginal Ultrasound (TVUS) is useful as a screening test
• Endometrial thickness
• Measurement is of limited value in the premenopausal women since thickness
varies throughout the cycle in response to hormonal changes
• Hysteroscopy
• Saline infusion sonohysterography (SIS)
• Magnetic resonance imaging (MRI)
• Routine use not recommended, but may be useful to guide treatment
such as myomectomy or uterine artery embolization
Imaging Considerations Adenomyosis
Imaging Considerations Leiomyoma
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Objective #5
• Learn current recommendations to treat abnormal uterine
bleeding associated with perimenopause
Treatment of AUB-O during
Perimenopause
• Initiate treatment after a complete diagnostic workup has
been completed
• Choice of treatment should be guided by goals of therapy
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Stop acute bleeding
Avoid future irregular or heavy bleeding
Provide contraception
Prevent complications such as anemia, unnecessary surgical
intervention, or diminished quality of life
• Because AUB-O is an endocrinologic abnormality, the
underlying disorder should primarily be treated medically
• Surgical therapy is rarely indicated unless medical treatment
fails, is contraindicated, is not tolerated by the patient, or the
patient has concomitant significant intracavitary lesions.
Treatment of AUB-O during
Perimenopause
• Medical Therapy
• Hormonal contraceptives are preferred to hormonal therapy unless
there is a contraindication
• Hormonal contraceptives have the benefit of menstrual control,
endometrial protection, contraception, and vasomotor symptom control
• Premenopausal use of hormone therapy will not provide contraception,
and is +/- on menstrual regularity and vasomotor symptom control
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Treatment of AUB-O during
Perimenopause
• Medical Therapy
• Nonhormonal options may relieve symptoms of heavy menstrual
bleeding, but do not offer benefit of menstrual control,
endometrial protection, or contraception
• NSAIDS
• Tranexamic acid
Combined hormonal contraceptives
• Oral pills, transdermal patches, vaginal rings
Progestin contraceptives
• Levonorgestrel intrauterine device
• Depot medroxyprogesterone acetate
Cyclical progestins
• Oral medroxyprogesterone acetate
• Norethindrone acetate
Continuous progestins
• Megestrol
Treatment of AUB-O during
Perimenopause
• Surgery
• Concomitant Intracavitary lesions
• Polypectomy
• Myomectomy
• Uterine artery embolization
• Hysterectomy
• For women who have completed childbearing and failed medical therapy
or have contraindications to medical therapy
• Risks of surgical complications, longer recovery time, increased cost
Treatment
• J.K.
• Elected no treatment
• 8 month follow-up
• Menses are still erratic. Not a regular interval between them.
Sometimes flow is very heavy, sometimes light. Sometimes has flow
for 2-3 days, nothing for 2-3 days, then flow for another 2-3 days.
Other times just has steady flow for 8-10 days. Gets crankier and
short tempered or emotional a few days before menses.
• Endometrial ablation
• Not first line
• Risks regarding future ability to detect and diagnose endometrial cancer
because methods of endometrial surveillance (EMB, hysteroscopy, TVUS,
SIS) may be compromised due to complications of procedure
(intrauterine synechiae or adhesions, cervical stenosis, and endometrial
contractures, strictures, or distortion)
• No contraceptive benefit
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Contraception
• Perimenopause vs. Menopause
• If using a hormonal method
• Discontinue when risk remote based on age: 50-55
• Switch to non-hormonal method until able to diagnose menopause
• If using a non-hormonal method
• Continue to use until able to diagnose menopause
Is there an indication for
testing serum FSH?
• In general, changes in menstrual bleeding patterns are a
better predictor of menopausal stage than serum FSH
concentrations (SWAN study) due to FSH variability
• Special situations
• Underlying menstrual cycle disorders
• Menstrual cycle changes may not occur and/or are not reliable. If
menopausal symptoms develop, measure FSH
• Estrogen-progestin contraceptives
• Women on these do not experience menstrual cycle changes or
menopausal symptoms. Stop the contraception at age 50-55 years
and measure FSH 2-4 weeks later
• Post-hysterectomy or endometrial ablation
• Women do not have bleeding. If menopausal symptoms develop,
measure FSH
The Stages of Reproductive Aging Workshop (STRAW)
+10 Staging System for Reproductive Aging in Women
• The STRAW staging system includes supportive criteria for
determining reproductive stage.
• Serum levels of FSH, inhibin B, AMH
• Pelvic ultrasound for antral follicle count (AFC)
• These are NOT diagnostic criteria for perimenopause or
menopause and have NOT been validated for such use. These
have been used to assess ovarian reserve in the setting of
assisted reproductive technologies.
Questions
References
• http://www.mayoclinic.org/diseasesconditions/perimenopause/basics/definition/con-20029473
• Harlow SD, Gass M, Hall JE, et al. Executive Summary of the Stages of
Reproductive Aging Workshop + 10: Addressing the Unfinished Agenda of
Staging Reproductive Aging. J Clin Endocrinol Metab 2012.
• Welt CK, McNicholl DJ, Taylor AE, Hall JE. Female reproductive aging is marked by
decreased secretion of dimeric inhibin. J Clin Endocrinol Metab 1999; 84:105.
• http://www.nature.com/articles/nrdp20154
• ACOG. Practice Bulletin #128. Diagnosis of Abnormal Uterine Bleeding in Reproductive Aged
Women. July 2012.
• ACOG. Practice Bulletin #136. Management of Abnormal Uterine Bleeding Associated with
Ovulatory Dysfunction. July 2013.
• ACOG. District 8. Abnormal Uterine Bleeding (AUB) New Standardized Terminology, Definitions,
Classification
• Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J,
Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics
Review, 1975-2012, National Cancer Institute. Bethesda, MD,
http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted
to the SEER web site, April 2015.
• http://www.advancedwomensimaging.com.au/saline-sono-hysterogram
• Sweet MG, Schmidt-Dalton TA, Weiss PM. Evaluation and Management of Abnormal Uterine
Bleeding in Premenopausal Women. American Family Physician. 2012; 85(1):35-43.
• http://www.drugs.com/dict/metropathia-hemorrhagica.html
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