Disorders of
Menstruation
Pathophysiology, Evaluation and Management
Jennifer Mersereau, MD
Division of Reproductive Endocrinology & Infertility
Department of Obstetrics & Gynecology
University of North Carolina
March, 2009
Objectives
 What defines abnormal menstruation?
 Burden of disease
 Differential diagnosis of abnormal
menstruation patterns
 Classification of abnormal menstruation
 Evaluation
 Treatment
Physiology of Menstruation
•Exact hormone levels  not crucial
•Exact cycle day  not crucial
•General sequence  crucial
Ovulatory Cycles
 Orderly proliferation
 Synchronous, stable
endometrial development
 Lysosomal digestion,
vasoconstriction & ischemia
 desquamation,
coagulation, hemostasis
Progesterone
Estrogen
2
4
6
8 10 12 14 16 18 20 22 24 26 28
Menses
NORMAL MENSTRUAL BLEEDING IS
SELF-LIMITED
Menstrual Cycle
What is normal?
Menses
Duration
Volume
Interval
4-6 days
Approx
30 ml
24-35
days
Menometrorrhagia
<2
>7
days
> 80 ml
Menorrhagia
Polymenorrhea
Oligomenorrhea
< 24
> 35
days
Metrorrhagia
Menstrual Cycle Characteristics
Age Variations
 Highest variation in early adolescent and
perimenopausal years
 Adolescent: long intervals for 5-7 years
after menarche
 Reproductive years:
• Majority of cycles 25-28 days
• Cycle length can change around age 40-42
until menopause
Health, 1986; Belsey, 1997; Volman, 1977; Treolar, 1967; O’Connor, 2001; Taffe, 2002.
Abnormal Menstruation:
Burden of Disease
 Most common reason for GYN visits
 600,000 hysterectomies each year
• ¼ US women will have a hysterectomy by age 60
• 2nd most frequent surgery among reproductive-aged
women
• Annual cost of $5 billion
 Most common conditions for hysterectomy:
• Fibroids, endometriosis, prolapse
• If < 30 years old, menstrual disturbances and
dysplasia
Surveillance for Reproductive Health, Hysterectomy Surveillance—United States, 1994-1999.
Evaluation of Abnormal
Menstruation





Consider differential diagnosis
Target history to narrow differential
Exam
Labs
Imaging
Evaluation of Abnormal Menstruation
Differential Diagnosis
 Pregnancy complication!
•
•
•
•
Threatened or incomplete abortion
Ectopic pregnancy
Gestational trophoblastic disease
Retained products of conception
 Benign anatomical lesion
• Cervical or endometrial polyp
• Leiomyoma
• Adenomyosis
 Malignancy
• Cervical or uterine cancer (esp HIV +
women)
Evaluation of Abnormal
Menstruation
Differential Diagnosis
 Trauma/foreign body
• Children
 Inflammatory conditions
• Endometritis
 Systemic illness
•
•
•
•
Thyroid dysfunction
Hyperprolactinemia
Renal failure
Hepatic dysfunction
 Bleeding disorder
• Thrombocytopenia
• Platelet function
abnormalities
• von Willebrand’s disease
 Medications
• Steroidal
• Psychiatric
 Or…..
Dysfunctional Uterine Bleeding
 DUB is a diagnosis of exclusion!
 DUB is:
• Abnormal bleeding pattern, AND
• NO ATTRIBUTABLE UNDERLYING ILLNESS OR
PATHOLOGY
 Causes:
• Anovulation (90%)
Polycystic ovarian syndrome
Teenagers or peri-menopausal women
• Rarely short follicular or luteal phase
Evaluation of Abnormal Menstruation
Step 1: History
 Detailed menstrual history
• Inter-menstrual intervals
Consistent, normal (q 24-35 days)
Variable
• Character, volume
• Duration
Normal (3-7 days)
Prolonged
• Initial onset of symptoms
Evaluation of Abnormal Menstruation
Step 1: History
 Other associated symptoms
•
•
•
•
•
Dysmenorrhea
Post-coital bleeding
Galactorrhea
Hirsutism
Fatigue, weight gain, constipation (thyroid)
 Temporal associations w/ other events
• Weight changes
• Medication changes
 Medical history & medications
 GOAL OF HISTORY:
• Does she ovulate? If not, DUB LIKELY!
• What labs do you need to confirm you initial diagnosis?
Evaluation of Abnormal Menstruation
 Ovulation - does she or doesn’t she?
•
•
•
•
•
Menstrual history
Basal body temperature (BBT) monitoring (biphasic)
Ovulation predictor kits
Timed serum progesterone (> 3 ng/ml)
Ultrasound
 Implications: if ovulatory…
• Search for an anatomical/pathological cause
Evaluation of Abnormal Menstruation
Step 2: Exam




Weight
Thyroid exam
Signs of other illnesses
Signs of hyperandrogenism
• Hirsutism
• Acne
Endocervical
Polyps
Squamous Cell
Carcinoma of Cervix
 Pelvic exam
• Cervical and vaginal lesions
• Size, shape of uterus
Evaluation of Abnormal Menstruation
Step 3: Laboratory Tests
 All patients: screen for
• Pregnancy (history or urine hcg)
• Thyroid disorder (TSH)
• Anemia, thrombocytopenia (CBC)
 Select patients:
•
•
•
•
Hyperprolactinemia (PRL)
Bleeding disorders (coagulation panel, vWF)
Chemistry (AST, ALT, Creatinine)
Endometrial biopsy????
Evaluation of Abnormal Menstruation
Endometrial Biopsy
 Risk of endometrial carcinoma:
• Age 30-34:
• Age 35-39:
• Age 40-49:
2.3/10,000
6.1/10,000
36.2/10,000
 Duration of time exposed to unopposed estrogen
is more important than age
 Possible results: proliferative, secretory,
hyperplasia, atypia, carcinoma, acute or chronic
endometritis
Ash, J Reprod Med, 1996.; ACOG Practice Bulletin 14, 2000.
Endometrial Biopsy
Chronic
endometritis
Adenocarcinoma
Endometrial
Hyperplasia
Evaluation of Abnormal Menstruation
Step 4: Imaging
Who needs imaging?
Regular cycles
volume
duration
Regular cycles
intermenstrual
bleeding
Abnormal
bleeding,
evidence of
ovulation
RULE OUT
ANATOMIC LESION
Failed
medical
management
Evaluation of Abnormal Menstruation
Step 4: Imaging
 Ultrasound can help diagnosis:
•
•
•
•
Fibroids
Polyps
Adenomyosis
Endometrial stripe
 < 5 mm, denuded, atrophic
 5-12 mm, normal
 > 12 mm, thick, biopsy!
 Hydrosonogram: increases sensitivity to detect
endometrial lesions, 70%  90%
 Hysteroscopy
Becker, 2002.
Uterine Imaging
Ultrasound
Normal
endometrium
Late proliferative or
luteal phase
Thin endometrium
Early proliferative
phase or atrophy
Uterine Imaging
Routine Ultrasound
Saline Sonogram
Submucous myoma
Endometrial
polyp
Uterine Imaging
Hysteroscopy
Hyperplasia
Polyps
Atrophy
Myoma
Adenocarcinoma
Treatment of Abnormal Menstruation
What is the diagnosis?
DUB
 Restore growth,
development and
shedding of a stable
endometrium
 Prevent development
of hyperplasia or
neoplasia
Bleeding from
Specific Cause
Cycle Physiology
Progesterone
Estrogen
Estrogen
2 4 6 8 10 12 14 16 18 20 22 24 26 28
Menses
DUB/Anovulation
Ovulatory Cycle
Treatment: DUB
Option 1: Cyclic Progestins
Rx Progestin
Rx Progestin
Endogenous estrogen
1
5
9
13
17
21
25
1
5
9
13
17
21
25
Calendar Day
Progestins:
1. Medroxyprogesterone (MPA) 10mg qd
2. Norethindrone acetate 5 mg qd
Treatment: DUB
Option 2: Oral Contraceptives
Rx Cyclic OCP
Rx Cyclic OCP
Progestin
Progestin
Estrogen
Estrogen
Endogenous estrogen
1
5
9
13
17
21
25
1
5
Pill Cycle Day
9
13
17
21
25
Treatment of Anovulation with
Acute, Heavy Bleeding
 Hemodynamically stable??
• IVF, CBC, transfusion
• D&C
 Strongly consider biopsy
 Ultrasound
 Treatment – High dose OCP taper
Treatment of Anovulation
Maintenance Therapy
• Goal: Restore regular menstrual
bleeding patterns
• Prevent endometrial cancer!!
• Failed management = further
workup
Treatment: Anovulatory Bleeding
Preventing Endometrial Hyperplasia & Neoplasia
Histology
Cytologic
Atypia
Architectural
Pattern
Risk of
neoplasia
Simple
hyperplasia
--
Regular
1%
Complex
hyperplasia
--
Irregular,
crowded
3%
Simple +
atypia
+
Regular
8%
Complex +
atypia
+
Irregular,
crowded
29%
Kurman et al, Cancer, 1985
Treatment: Anovulation
Preventing Endometrial Neoplasia
ATYPIA
Present
Yes
Fertility
desired?
Megace 40-80mg x
3-6 months
Re-biopsy
Absent
No
Hysterectomy
Cyclic progestins or OCPS
Rebiopsy if abnormal
bleeding occurs
Treatment of Abnormal Menstruation
What is the diagnosis?
DUB
Bleeding from
Specific Cause
 Treat underlying cause
 Decrease volume and
duration of menses
Treatment
Complications of Pregnancy
 Ectopic pregnancy
• Salpingostomy
• Salpingectomy
• Methotrexate
 Threatened abortion
• Observation
 Incomplete/inevitable abortion
• Curettage
Empty Sac
Ectopic
Treatment
Chronic endometritis
 Indirect cause of bleeding
 Twice as common in HIV+ patients
 Doxycycline 100mg bid x 10 days
Kerr-Layton et al, Infect Dis Obstet Gynecol, 1998
Treatment
Leiomyomas
 Medical treatment
• OCPs: decrease volume/duration of
menses
• NSAIDS
• GnRH agonists
 Surgical treatment
• Myomectomy
• Hysterectomy
Treatment
Small Submucous Myomas,
Polyps
1
2
Hysteroscopic Resection
3
Treatment
Prolapsing, Large Myomas
Abdominal or
Laparscopic
Myomectomy
Vaginal
Myomectomy
Treatment
Multiple Myomas
Completed Childbearing
Abdominal Hysterectomy
Treatment: Ovulatory Patient
with Unexplained Menorrhagia
 Medical Options
• NSAIDS: 20-40% decrease
• OCPs: 40% decrease
• Levonorgestrel IUD: 75-95% decrease
Excellent option with chronic illnesses
Women highly satisfied
• GnRH agonists
 Surgical Options
• Endometrial ablation
• Hysterectomy
Hall, Br J Obstet Gynecol, 1987; Fraser, Aust NZ J Obstet Gynecol, 1995; Cochrane Database Syst Rev, 2002.
Absence of Menstruation
Primary Amenorrhea
 Outflow obstruction,
Mullerian abnormalities
 Androgen insensitivity
syndrome – 46 XY
 Ovarian failure
• Turners syndrome, 45
XO
• Autoimmune
• Cancer treatments
 Other causes
Secondary Amenorrhea
 Asherman’s syndrome
 Premature ovarian
failure
 Pituitary lesion
• Most common =
prolactinoma
• Sheehan’s syndrome
 Hypothalamic
hypogonadism
 Other causes
Abnormal Puberty
Precocious Puberty
 <8 years old
 GnRH-dependent
• Idiopathic – most
common
• CNS abnormality
 GnRH-independent
• Ovarian cyst/tumor
• McCune Albright
syndrome
 Treatment:
• Surgery when
appropriate
• GnRH agonist
Delayed Puberty
 See primary
amenorrhea
Conclusions
 Abnormal menstruation is extremely common
 Most common cause of a sudden change in
bleeding patterns is a complication of pregnancy!
 Careful menstrual history
 Use labs and imaging to support your clinical
suspicions
 Anovulatory bleeding: goal is to restore normal
menstrual patterns
 Bleeding from other causes: correct underlying
pathology and decrease volume/duration of
menses
Questions?
Examples of Effects of Exogenous
Progestin in Ovulatory Cycles
Ovulation
Provera C
Provera B
Provera A
Endogenous Progesterone
Follicular Phase
14
Luteal Phase
28
Treatment: Anovulatory
Bleeding
Preventing Endometrial Hyperplasia & Neoplasia
Simple Hyperplasia
Complex Hyperplasia
Complex Atypical Hyperplasia
Menstrual Cycle
Definitions of Abnormalities
 Irregular intervals
• Oligomenorrhea, > 35 days
• Polymenorrhea, < 24 days
 Excess amount and/or duration
• Menorrhagia
 Irregular interval
• Metrorrhagia
 Irregular interval and amount/duration
• Menometrorrhagia
Uterine Imaging
Ultrasound
Submucous
myoma
Intramural
myoma
Adenomyosis
 ADD: (4/7)
• Info about PCOS vs. hypo-hypo.
• Look up DUB (is it almost always PCOS??)
• More about HIV?
Treatment: Acute bleeding
High dose OCP ‘Taper’
Progestin
Rx OCP (monophasic)
bid X 7d, qd X 7-14d
Estrogen
Endogenous Estrogen
Menses
Treatment: Atrophic Endometrium
Sequential Estrogen and Progestin
Rx
Progestin
Rx Estrogen (CEE 1.25-2.5 mg/d
or micronized estradiol 2.0 mg/d, q4h prn;
CEE 25 mg i.v. q4h prn)
Endogenous Estrogen
Menses