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? Duration
4-6 days Menses
Volume
Approx 30 ml
Interval
24-35 days
Menometrorrhagia
<2 >7 days > 80 ml < 24 > 35 days
Menorrhagia
Polymenorrhea Oligomenorrhea
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
Bleeding disorder
• Thrombocytopenia • Platelet function abnormalities • von Willebrand’s disease
Inflammatory conditions
• Endometritis
Systemic illness
• • • • Thyroid dysfunction Hyperprolactinemia Renal failure Hepatic dysfunction
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 Endometrial Hyperplasia
Adenocarcinoma
Evaluation of Abnormal Menstruation Step 4: Imaging
Who needs imaging?
Abnormal bleeding, evidence of ovulation
Regular cycles volume duration
Regular cycles intermenstrual bleeding
Failed medical management
RULE OUT ANATOMIC LESION
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
Polyps
Hyperplasia
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
Progestin Estrogen
Rx Cyclic OCP
Progestin Estrogen
Endogenous estrogen
1 5 9 13 17 21 25 1 5 9 13 17 21 25
Pill Cycle Day
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
Regular Irregular, crowded Regular Irregular, crowded
Risk of neoplasia
1% 3% 8% 29%
Simple hyperplasia Complex hyperplasia Simple + atypia Complex + atypia
Kurman et al, Cancer, 1985
Treatment: Anovulation
Preventing Endometrial Neoplasia
ATYPIA
Present
Yes Fertility desired? No
Absent
Megace 40-80mg x 3-6 months Re-biopsy
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
3
Hysteroscopic Resection
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
Secondary Amenorrhea
Asherman’s syndrome Premature ovarian failure Pituitary lesion
• Most common = prolactinoma • Sheehan’s syndrome
Other causes
Hypothalamic hypogonadism Other causes
Abnormal Puberty
Precocious Puberty
<8 years old GnRH-dependent
• Idiopathic – most common • CNS abnormality
Delayed Puberty
See primary amenorrhea
GnRH-independent
• Ovarian cyst/tumor • McCune Albright syndrome
Treatment:
• Surgery when appropriate • GnRH agonist
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 Adenomyosis
Intramural myoma
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