Download Learning Objectives Epidemiology The Normal Menstrual Cycle The

Disclosure Statement
Abnormal Uterine Bleeding and
Amenorrhea
E.J. Mayeaux, Jr., M.D.
Professor and Chairman
Department of Family and Preventive Medicine
Professor of Obstetrics and Gynecology
University of South Carolina School of Medicine, Columbia
Learning Objectives
1. Implement current screening recommendations for endometrial
cancer in women who present with postmenopausal bleeding.
2. Identify a plan to communicate ways to increase quality of life and
functional activities for women with abnormal uterine bleeding.
3. Formulate a treatment plan for women with abnormal uterine
bleeding, including dysfunctional uterine bleeding, menorrhagia, and
amenorrhea.
4. Evaluate patients based on their treatment choice, tolerance, and
clinical risk profile when selecting a therapeutic intervention for the
management of heavy menstrual bleeding.
It is the policy of the AAFP that all individuals in a position to control content disclose
any relationships with commercial interests upon nomination/invitation of
participation. Disclosure documents are reviewed for potential conflicts of interest. If
conflicts are identified, they are resolved prior to confirmation of participation. Only
participants who have no conflict of interest or who agree to an identified resolution
process prior to their participation were involved in this CME activity. The following
individual(s) in a position to control content for this activity have disclosed the
following relevant financial relationships.
Edward J. Mayeaux, Jr., MD was a consultant/advisory board member for Merck &
Co. (HPV vaccination); Pharmaderm (Condyloma); and Roche Diagnostics (HPV
testing)
The course chair and all other staff in a position to control content for this activity
have indicated they have no relevant financial relationships to disclose.
Epidemiology
Abnormal uterine bleeding (AUB) 1
– Occurs in 9-14% of women between menarche and
menopause
– Significantly impacts quality of life
– Imposes notable financial burden
Average age of menarche in U.S. = 12.3 years 2
– Irregular and anovulatory cycles may persist for
1-5 years after onset of menstrual periods
1. Fraser IS. Expert Rev Obstet Gynecol. 2009;4(2):179-189. 2. Anderson SE. J Pediatr. Dec 2005;147(6):753-60.
The Normal Menstrual Cycle
The Normal Menstrual Cycle
Menstrual Phase – Day 1 to 5
– Involves the disintegration and
sloughing of the functionalis layer
– Prostaglandin F2-alpha causes
contractions and vasoconstriction
– Prostaglandin E2 causes
vasodilatation and muscle relaxation
Courtesy of Dr. E.J. Mayeaux, Jr.
Courtesy of Dr. E.J. Mayeaux, Jr.
Fraser IS, et al. Expert Rev Obstet Gynecol. 2009;4(2):179-189.
The Normal Menstrual Cycle
Follicular Phase – Day 5 to 14
– Estrogen produced by developing
follicles
• Stimulated by FSH
– Cellular proliferation and increase in
convolutedness of spiral arteries
– Estrogen + feedback causes
FSH and LH surge and ovulation
Courtesy of Dr. E.J. Mayeaux, Jr.
The Normal Menstrual Cycle
Luteal Phase – Day 15 to 28
– Corpus luteum produces
progesterone and less potent
estrogens
– The functionalis layer increases
in thickness
– Glands become tortuous
with dilated lumens and
stored glycogen
Courtesy of Dr. E.J. Mayeaux, Jr.
Fraser IS, et al. Expert Rev Obstet Gynecol. 2009;4(2):179-189.
Fraser IS, et al. Expert Rev Obstet Gynecol. 2009;4(2):179-189.
The Normal Menstrual Cycle
Menses
– Estrogen and progesterone cause positive feedback
– FSH and LH production falls
– The spiral arteries become coiled and have
decreased blood flow
– They alternately contract and relax, causing
sloughing of functionalis layer and menses
Abnormal Uterine Bleeding (AUB)
Menstrual flow outside of normal volume,
duration, regularity, or frequency
Diagnosis of abnormal uterine bleeding in reproductive-aged
women. Practice Bulletin No. 128. American College of
Obstetricians and Gynecologists. Obstet Gynecol
2012;120:197-206.
Fraser IS, et al. Expert Rev Obstet Gynecol. 2009;4(2):179-189.
Amenorrhea Evaluation
Abnormal Uterine Bleeding (AUB)
1. UPT/HCG
Evidence of
Androgen Excess
Amenorrhea “no
bleeding”
DUB
Anovulatory bleeding
“irregular bleeding”
DHEA
Testosterone
Serum 17-hydroxyprogesterone
Abnormal
Menorrhagia
Ovulatory bleeding
“heavy menstrual bleeding”
2. Physical
Examination
EMB
Normal
Adrenal Hyperplasia
(17-HP <800 & +ACTH stimulation test)
Androgen secreting tumor
(DHEA-S > 7000 ng/dL)
21-hydroxylase deficiency
(17-HP > 800 ng/dL)
HCA/PCOS
Evidence of
Estrogen Excess
(DHEA =3300-7000 ng/dL or increased free
testosterone <200 ng/dL)
Normal
3. TSH &
Prolactin
Abnormal
Endometrial Hyperplasia
or Precancerous State
Amenorrhea Evaluation (cont.)
Amenorrhea Evaluation (cont.)
3. TSH &
Prolactin
Abnormal
TSH
Hypothyroidism
Hyperthyroidism
Withdrawal
bleeding
Chronic Anovulation:
Physiologic
PCOS
Both
normal
High
prolactin
4. Progesterone
Challenge Test
No withdrawal
bleeding
5. Estrogen &
Progesterone
Challenge
No withdrawal
bleeding
MRI
Abnormal
Intracranial pathology:
Pituitary tumor
Pituitary destruction
Hypothalamic Disease
True statements about ovulatory AUB
characteristics include which of the
following?
A. Periods occur at irregular intervals
B. Periods are often scant and of shorter than normal
duration
C. <1% of women develop cancer or hyperplasia if they have
no more than one risk factor for endometrial cancer
D. It results from an estrogen-excess state
Tract Abnormality: Asherman’s
Syndrome
Mullerian Agenesis
Karyotype
Gonadal
Failure
Intracranial pathology:
Pituitary tumor
Pituitary destruction
Hypothalamic Disease
5. Estrogen &
Progesterone
Challenge
Withdrawal
bleeding
6. FSH, LH
Low
High
7. MRI
Normal
Abnormal
Hypothalamic
Amenorrhea:
Drug Use
Eating Disorder
Excessive Exercise
Psychosocial Stress
Marijuana Use
Consider reevaluation for
chronic disease.
Ovulatory AUB Characteristics
Regular intervals (every 24 to 35 days) with excessive
bleeding or duration greater than 7 days
<1% of women develop cancer or hyperplasia if they
have no more than 1 risk factor for endometrial cancer
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
True statements about ovulatory AUB (DUB)
characteristics include which of the following?
A.
B.
C.
D.
Periods are regular
It results from an estrogen-deficient state
Periods are usually excessive in volume and time
14% of women with recurrent anovulatory cycles develop
hyperplasia or cancer
DUB is caused by which of the following?
A.
B.
C.
D.
Pregnancy or pregnancy-related disorders
Thyroid disease
Coagulation disorders
None of the above
DUB – Anovulatory Cycles
Most common cause in adolescents and adults
High estrogen with no progesterone
– Continuous development of the functionalis layer
– Blood supply is outgrown and parts of the
endometrium slough
– Estrogen promotes healing
Anovulatory DUB Characteristics
Irregular, infrequent periods
Progesterone-deficient/estrogen-dominant state
Flow ranges from absent or minimal to excessive
14% of women with recurrent anovulatory cycles develop
cancer or hyperplasia
Extremes of reproductive life and PCOS
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
DUB – Anovulatory Cycles
Also from excessive estrogen from fatty tissue or
exogenous sources
Diminishing number and quality of ovarian follicles
– No FSH trigger
– Estrogen continues to be produced, which
usually results in late cycle estrogen
breakthrough bleeding
DUB – Luteal Phase Deficiency
Shortened luteal phase – insufficient progesterone
Coexistent with high, low, or normal estrogen
Similar to anovulatory cycles
May be especially prominent in amenorrheic athletes and
anorexia
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
DUB in Adolescence
AUB Diagnosis
Pregnancy related (inc. SAB, ectopic)
Obtain history and perform physical examination to rule
out systemic disease, medication effects, polycystic
ovary syndrome, and cervical or vaginal pathology
Laboratory tests for pregnancy, TSH and prolactin levels
Determine by pattern if
– Ovulatory – periods regular but heavy or >7 days
– Anovulatory (DUB) – irregular or infrequent periods
CDC. Youth risk behavior surveillance – U.S. MMWR
2008:57(No.SS-4)
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Management Principles
Dx & Tx of Anovulatory Bleeding
Excluded pregnancy (including ectopic pregnancy) and pelvic
infections
All adolescents treated for DUB should maintain a menstrual
calendar to monitor response, subsequent episodes of DUB 1
Monitor for iron deficiency anemia
Additional evaluation and consultation should be obtained if
bleeding not controlled with HRT 2
Obtain history and perform physical examination to rule out systemic
disease, medication effects, polycystic ovary syndrome, and cervical or
vaginal pathology
Laboratory tests for pregnancy, TSH and prolactin levels
1. Adams PJ. Pediatr Clin North Am 2005; 52:179.
2. Rimsza ME. Pediatr Rev 2002; 23:227.
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Dx & Tx of Anovulatory Bleeding
Females <35 years with no
risks of endometrial cancer
Treat with combination OCP (ethinyl estradiol, ≤35 mcg)
or medroxyprogesterone acetate 10 mg per day for 10 to 14 days per month
or norethindrone 2.5-10 mg daily for 5-10 days per month
continued irregular or excessive bleeding
Endometrial biopsy
normal
normal
Refer to
Gyn
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Office hysteroscopy
Treat with MPA 10
mg/day x
14 days/month or
Daily megesterol
40 mg or
Insert
levonorgestrelreleasing IUS
Females ≥35 years or <35 years with recurrent anovulation
and/or other risks of endometrial cancer
Hyperplasia (no atypia)
normal
Treat with combination OCP (ethinyl estradiol, ≤ 35 mcg) or
or MPA10 mg per day for 10 to 14 days per month
or Norethindrone 2.5-10mg daily for 5-10 days per month
Atypia or
Adenocarcinoma
Refer to
Gyn
normal
Endometrial biopsy
Continued irregular or
excessive bleeding
Endometrial biopsy
normal
Perform TUS or saline infusion sonohysterography to
rule out structural abnormality
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Comparison of Imaging/Tissue Sampling for
Endometrial Pathology
Endometrial biopsy
Dx & Tx of Anovulatory Bleeding
Adenocarcinoma
or atypia
Perform TUS or saline infusion sonohysterography to
rule out structural abnormality
Test
Females ≥35 years
or <35 years with recurrent
anovulation and/or other risks of
endometrial cancer
Females <35 years with no
risks of endometrial cancer
Endometrial Biopsy
Effectiveness
91% sensitive and 98% specific for detecting cancer
82.3% sensitive and 98% specific for detecting hyperplasia
with atypia
94% sensitive and 89% specific for detecting intracavitary
abnormality
Saline infusion
sonohysterography
88 to 99% sensitive and 72 to 95% specific for detecting
intracavitary abnormality in premenopausal women
Transvaginal
ultrasonography
Less sensitive and specific than saline infusion
sonohysterography 60-92% sensitive and 62-93% specific for
intracavitary abnormality in premenopausal women
ACOG PB 128. Obstet Gynecol 2012;120:197-206.
• Rarely required in adolescents
• Should be reserved for adolescents with
unresponsive uterine bleeding
• DUB histology = disordered proliferative
pattern without secretory activity (no
progesterone effect)
• EMB with hormonal therapy = hormonal
effects and may interfere with biopsy
interpretation
Courtesy of Dr. E.J. Mayeaux, Jr.
Dx & Tx of Ovulatory Bleeding
Obtain history and perform physical examination to rule out systemic
disease or enlarged uterus
Test for pregnancy, measure thyroid-stimulating hormone level
perform complete blood count
Dx & Tx of Ovulatory Bleeding
Imaging and endometrial biopsy
Submucosal
fibroid
Refer for possible
fibroidectomy or
Uterine artery
embolization
Endometrial
polyp
Refer for
polypectomy
Adolescent or adult with possible bleeding disorder
No
Yes
Evaluate for bleeding disorder
and treat as indicated if
bleeding diathesis present
Perform imaging test for structural abnormality with
transvaginal ultrasonography or saline infusion
sonohysterography (if high risk of endometrial cancer,
consider adding endometrial biopsy
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Risk factors for bleeding disorders in AUB patients
include all of the following EXCEPT which one?
A.
B.
C.
D.
Family history of bleeding disorder
A patient history of “using lots of pads”
History of treatment for anemia
History of excessive bleeding with tooth extraction,
delivery or miscarriage, or surgery
Consider endometrial
biopsy, hysteroscopy,
endometrial ablation, or
hysterectomy
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Unresponsive to
3-6-month trial of
therapy
Normal
imaging
Treat with 10 mg of MPA for
21 days/month for 3-6 mo
or
Norethindrone 2.5-10 mg
daily for 5-10 days
or
Insert levonorgestrelreleasing IUS
or
Trial of nonsteroidal antiinflammatory drug
or
Tranexamic acid 2 650-mg
3x/day days 1-5 of cycle
Ovulatory – Bleeding Disorder?
• Adolescents and women with 1 or more of the following risk
factors:
– family history of bleeding disorder
– menses lasting 7 days or more with flooding or impairment of
activities with most periods
– history of treatment for anemia
– history of excessive bleeding with tooth extraction, delivery or
miscarriage, or surgery
• von Willebrand disease (vWD), most common
– 13% of women with menorrhagia
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Observe vs Treat with HRT
• Decision for adolescents depends upon 1
– Severity and chronicity of the DUB
– Patient considerations
– Guardian considerations
• The primary purpose of hormonal treatment is to
stabilize endometrial proliferation and promote cyclic
shedding
• >90% of adolescents respond to hormonal treatment 2
1. Slap GB. Best Pract Res Clin Obstet Gynaecol 2003; 17:75.
2. Strickland JL,. Obstet Gynecol Clin North Am 2003; 30:321.
AUB: Emergency Management
• IV conjugated estrogen 25 mg q 4 hours until bleeding
slows or for 12 hours
– 75% will be controlled in 6 hours
• Oral conjugated estrogen 1.25 mg or estradiol
2 mg for 7-10 days
• Start OCPs or 10 days of monthly progestin after bleeding
stops to prevent recurrence
– Can be given without placebos for 3 months (patients
prefer)
Anovulatory Treatment
• Adolescent or <35 years with no Ca risks
– Mild DUB consists of observation and reassurance
– Combination OCP – ethinyl estradiol, 30-35 mcg
• Usually for 3-6 months
• Treatment of choice in women with known von Willebrand
disease who also desire contraception
– Progestin only treatment – MPA 10 mg/day for
10-14 days/mo or similar
– Consider Iron therapy
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Ovulatory AUB Treatment
• Medroxyprogesterone acetate 10 mg/day for 21 days
per month or norethindrone 2.5-10 mg daily for
5-10 days
– Does not provide contraception
– Effective short-term therapy
– Not tolerated long-term as well as levonorgestrelreleasing IUD
– Caution in patients with severe hepatic dysfunction
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Ovulatory AUB Treatment
• Tranexamic acid 650 mg; two tablets 3x/day,
5 days/month begin day 1 of menses
– FDA-approved for menorrhagia in 2009
• Antifibrinolytic – prevents plasminogen activation
– Caution in patients with history or risk of thromboembolic or renal
disease
– Contraindicated with active intravascular clotting or subarachnoid
hemorrhage
• Desire fertility or have contraindications to OCPs
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Endometrial Hyperplasia
(Without Atypia) Treatment
• Medroxyprogesterone acetate 10 mg per day for 14 days per
month
• Norethindrone 2.5-10 mg/day for 5-10 days
• Levonorgestrel-releasing intrauterine device – releases
20 mcg per 24 hours
• Micronized progesterone 200 mg/day for 12 days of each
calendar month
– NOT FDA indicated for this use or age group
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Ovulatory AUB Treatment
• NSAIDs, 5 days/ month begin day 1 of menses
– Ibuprofen 600-1,200 mg/day
– Naproxen sodium 550-1,100 mg/day
– Mefenamic acid 1,500 mg/day
– Treats dysmenorrhea
– Caution in patients with gastrointestinal risks
• Levonorgestrel-releasing IUD
– FDA-approved for menorrhagia in 2009
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Surgical Therapies
• Available evidence suggests that hysteroscopic
polypectomy reduces AUB 75 to 100%
• Menorrhagia with submucosal fibroids
– Surgical resection may allow childbearing and
normalize menses
– Uterine artery embolization
• ~20 percent of women subsequently undergo a
hysterectomy for recurrent AUB
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Surgical Therapies
• If unresponsive to medical intervention, endometrial ablation
(the surgical destruction of the endometrium) may be
considered
– Permanent - incompatible with continued fertility
• Hysterectomy is definitive treatment
– Women who no longer wish to conceive
– Increased number of adverse effects, longer recovery
time, and higher initial health care costs
– May be associated with earlier ovarian failure
Sweet MG, et al. Am Fam Physician. 2012 1;85(1):35-43.
Hysterectomy vs Medical Tx
• Women with excessive uterine bleeding for
4 years, unresponsive to medical therapy
• Randomized to hysterectomy or continued medical
therapy
• Hysterectomy group: greater improvements in mental
health, sexual desire, overall satisfaction
• 53% of medical group eventually received
hysterectomy
Learman LA, et al. Obstet Gynecol. 2004 May;103(5 Pt 1):824-33.
Quality of Life
Quality of Life
• Young patients with irregular bleeding often only need
reassurance and observation prior to instituting a drug
regimen
• Instruct patients to continue prescribed medications
although bleeding may still be occurring at first
• Tell patients that medications will probably not be
necessary once cycles become regular
• Discuss ways to maintain a normal BMI
• Health professionals can help support patients’ selfesteem by providing reassurance and information on
physiology, treatments, and hygiene
– Written educational materials are often helpful
– Low-literacy and culturally sensitive and inclusive
materials often best
• Communication with school or work may be necessary
Dunn NF. Haemophilia. Jul 2011;17 Suppl 1:38-41.