Disorders of MenstruationPathophysiology, 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

MensesMenses

22 44 66 88 1010 28281212 1414 1616 1818 24242020 2222 2626

Estrogen

Progesterone

NORMAL MENSTRUAL BLEEDING IS SELF-LIMITED

Menstrual CycleWhat is normal?

Menses

Normal

Abnormal

Duration Volume Interval

4-6 days Approx

30 ml

24-35 days

< 2

> 7

days

> 80 ml < 24

> 35

days

PolymenorrheaOligomenorrhea

Menorrhagia

Metrorrhagia

Menometrorrhagia

Menstrual Cycle CharacteristicsAge 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 MenstruationDifferential 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 syndromeTeenagers or peri-menopausal women

• Rarely short follicular or luteal phase

Evaluation of Abnormal MenstruationStep 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 MenstruationStep 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?

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

Weight Thyroid exam Signs of other illnesses Signs of hyperandrogenism

• Hirsutism• Acne

Pelvic exam• Cervical and vaginal lesions• Size, shape of uterus

Evaluation of Abnormal MenstruationStep 2: Exam

EndocervicalPolyps

Squamous CellCarcinoma of Cervix

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 MenstruationStep 3: Laboratory Tests

Risk of endometrial carcinoma:• Age 30-34: 2.3/10,000• Age 35-39: 6.1/10,000• Age 40-49: 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

Evaluation of Abnormal MenstruationEndometrial Biopsy

Ash, J Reprod Med, 1996.; ACOG Practice Bulletin 14, 2000.

Endometrial Biopsy

Chronic endometritis

Endometrial Hyperplasia

Adenocarcinoma

Who needs imaging?

Evaluation of Abnormal MenstruationStep 4: Imaging

Regular cyclesvolumeduration

Regular cyclesintermenstrual

bleeding

Abnormal bleeding,

evidence of ovulation

Failedmedical

management

RULE OUT ANATOMIC LESION

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

Evaluation of Abnormal MenstruationStep 4: Imaging

Becker, 2002.

Normal endometrium

Late proliferative or luteal phase

Thin endometrium

Early proliferative phase or atrophy

Uterine ImagingUltrasound

Submucous myomaEndometrial

polyp

Uterine Imaging

Routine Ultrasound

Saline Sonogram

Polyps

Myoma

Atrophy

Adenocarcinoma

Hyperplasia

Uterine ImagingHysteroscopy

Treatment of Abnormal Menstruation

DUB Restore growth,

development and shedding of a stable endometrium

Prevent development of hyperplasia or neoplasia

Bleeding from Specific Cause

What is the diagnosis?

Cycle Physiology

22 44 66 88 1010 28281212 1414 1616 1818 24242020 2222 2626

Menses

Estrogen

Progesterone

Ovulatory CycleDUB/Anovulation

Estrogen

Endogenous estrogen

Rx Progestin Rx Progestin

1 5 9 13 17 21 25 1 5 9 13 17 21 25

Calendar DayCalendar Day

Treatment: DUBTreatment: DUB

Progestins: 1. Medroxyprogesterone (MPA) 10mg qd

2. Norethindrone acetate 5 mg qd

Option 1: Cyclic Progestins

Treatment: DUBTreatment: DUB

Option 2: Oral Contraceptives

Endogenous estrogen

1 5 9 13 17 21 25 1 5 9 13 17 21 25

Pill Cycle DayPill Cycle Day

Rx Cyclic OCP

Progestin

Estrogen

Progestin

Estrogen

Rx Cyclic OCP

Treatment of Anovulation with Acute, Heavy Bleeding

Hemodynamically stable??• IVF, CBC, transfusion• D&C

Strongly consider biopsy Ultrasound Treatment – High dose OCP taper

• Goal: Restore regular menstrual bleeding patterns• Prevent endometrial cancer!!

• Failed management = further workup

Treatment of AnovulationMaintenance Therapy

Kurman et al, Cancer, 1985

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%

Treatment: Anovulatory BleedingPreventing Endometrial Hyperplasia & Neoplasia

ATYPIA

Present Absent

Cyclic progestins or OCPS

Rebiopsy if abnormal bleeding occurs

Fertility desired?

Yes No

Megace 40-80mg x 3-6 months

Re-biopsy

Hysterectomy

Treatment: AnovulationPreventing Endometrial Neoplasia

Treatment of Abnormal Menstruation

DUB Bleeding from Specific Cause

Treat underlying cause Decrease volume and

duration of menses

What is the diagnosis?

Ectopic pregnancy• Salpingostomy• Salpingectomy• Methotrexate

Threatened abortion• Observation

Incomplete/inevitable abortion• Curettage

TreatmentComplications of Pregnancy

TreatmentComplications of Pregnancy

Ectopic

Empty Sac

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

TreatmentChronic endometritis

TreatmentChronic endometritis

Medical treatment• OCPs: decrease volume/duration of

menses• NSAIDS• GnRH agonists

Surgical treatment• Myomectomy• Hysterectomy

TreatmentLeiomyomas

TreatmentLeiomyomas

TreatmentSmall Submucous Myomas,

Polyps

TreatmentSmall Submucous Myomas,

Polyps

11 22 33

Hysteroscopic Resection

TreatmentProlapsing, Large Myomas

TreatmentProlapsing, Large Myomas

VaginalMyomectomy

Abdominal or LaparscopicMyomectomy

Abdominal Hysterectomy

TreatmentMultiple Myomas

Completed Childbearing

TreatmentMultiple Myomas

Completed Childbearing

Treatment: Ovulatory Patient with Unexplained Menorrhagia Medical Options

• NSAIDS: 20-40% decrease• OCPs: 40% decrease• Levonorgestrel IUD: 75-95% decrease

Excellent option with chronic illnessesWomen 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

Outflow obstruction, Mullerian abnormalities

Androgen insensitivity syndrome – 46 XY

Ovarian failure• Turners syndrome, 45

XO• Autoimmune• Cancer treatments

Other causes

Asherman’s syndrome Premature ovarian

failure Pituitary lesion

• Most common = prolactinoma

• Sheehan’s syndrome

Hypothalamic hypogonadism

Other causes

Primary Amenorrhea Secondary Amenorrhea

Abnormal 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

See primary amenorrhea

Precocious Puberty Delayed Puberty

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?

14 28Follicular Phase Luteal Phase

Endogenous Progesterone

Provera C

Provera B

Provera A

Ovulation

Examples of Effects of Exogenous Progestin in Ovulatory Cycles

Simple Hyperplasia Complex Hyperplasia

Treatment: Anovulatory Bleeding

Preventing Endometrial Hyperplasia & Neoplasia

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

Submucous myoma

Adenomyosis

Intramural myoma

Uterine ImagingUltrasound

ADD: (4/7)• Info about PCOS vs. hypo-hypo.• Look up DUB (is it almost always PCOS??)• More about HIV?

MensesMenses

Endogenous Estrogen

Estrogen

Rx OCP (monophasic) bid X 7d, qd X 7-14d

Progestin

Treatment: Acute bleedingHigh dose OCP ‘Taper’

MensesMenses

Endogenous Estrogen

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)

RxProgestin

Treatment: Atrophic EndometriumSequential Estrogen and Progestin