1. 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

2. Objectives What defines abnormal menstruation? Burden of disease
Differential diagnosis of abnormal menstruation patterns
Classification of abnormal menstruation
Evaluation
Treatment

3. Physiology of Menstruation
Exact hormone levels  not crucial
Exact cycle day  not crucial
General sequence  crucial
Review of ovarian and endometrial cycles
Cycle day 1 = menses begin
Ovarian Follicular phase = Endometrial proliferative phase
Really begins w/ end of last cycle as the E&P drop and release negative feedback on FSH
-FSH recruiting new follicles
-estrogen levels , first slowly
-dominant follicle emerges, estrogen   
-Promotes endometrial growth
Estrogen peak  LH surge  ovulation
Ovarian luteal phase = endometrial secretory phase
-corpus luteum  progesterone, smaller amount estrogen
-E & P levels  together
-Endometrium stops growing and starts organizing as it prepares for conceptus
Pregnancy occurs =  hcg = continued support for endometrium
OR Corpus luteum regresses
E&P fall = no support for endometrium = menses
KEY = Sequence (rather than quantity)
E, then E&P, then removal of both
= stable endometrium, reproducible menstrual characteristics
Minimal deviation in pattern = menstrual changes

4. NORMAL MENSTRUAL BLEEDING IS SELF-LIMITED
Ovulatory Cycles
Orderly proliferation
Synchronous, stable endometrial development
Lysosomal digestion, vasoconstriction & ischemia  desquamation, coagulation, hemostasis
Menses 2 4 6 8 10 28 12 14 16 18 24 20 22 26
Estrogen
Progesterone
NORMAL MENSTRUAL BLEEDING IS SELF-LIMITED

5. Menstrual Cycle What is normal?
Duration
Volume
Interval
4-6 days
Approx
30 ml
24-35 days
< 2
> 7
days
> 80 ml
< 24
> 35
Normal
Menses
Menometrorrhagia
Duration:
3% of women, menses , 2 or > 7
Volume:
This is average
-difficult to objectively quantify - # pads/tampons per day, or how often to change?
-Not really necessary b/c IF menstrual abnormalities are disturbing to the patient/interfering w/ QOL, need w/u
Abnormal
Menorrhagia
Polymenorrhea
Oligomenorrhea
Metrorrhagia

6. 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 days
Cycle length can change around age until menopause
Cycle Variations reflect follicular phase differences
Luteal phase consistent, days
Reproductive:
Reason for increase in cycle length = depleted supply of ovarian follicles = decreased ovulations
Once 25, 40-60% cycles days
END WITH:
So now that we understand the physiology and characteristics of a NORMAL menstrual cycle, and the definitions of what constitutes an abnormal cycle, now lets move on and consider what can cause abnormalities and how to evaluate them.
Health, 1986; Belsey, 1997; Volman, 1977; Treolar, 1967; O’Connor, 2001; Taffe, 2002.

7. 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,

8. Evaluation of Abnormal Menstruation
Consider differential diagnosis
Target history to narrow differential
Exam
Labs
Imaging

9. 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)
Pregnancy complication most common; puerperium complications included in this
Anatomic: fibroid, polyp, adenomyosis
Inflammatory; acute or chronic endometritis
Systemic illness; renal/hepatic failure
Coagulation defects:
1/3 adolescents w/ menorrhagia; but most common abnormality in adolescents is anovulation
10-20% women w/ unexplained menorrhagia
Meds: glucocorticoids, tamoxifen, anticoagulants, herbs
Of note: in the past post-tubal ligation syndrome was considered to be a cause of menstrual abnormalities; BUT Most recent analysis of data from the US Collaborative Review of Sterilization (multicenter prospective cohort study) followed 10,000 women, showed decreased menstrual duration, volume and pain, only increased irregularity
Suggests they are no more likely to have menstrual problems

10. 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…..
Pregnancy complication most common; puerperium complications included in this
Anatomic: fibroid, polyp, adenomyosis
Inflammatory; acute or chronic endometritis
Systemic illness; renal/hepatic failure
Coagulation defects:
1/3 adolescents w/ menorrhagia; but most common abnormality in adolescents is anovulation
10-20% women w/ unexplained menorrhagia
Meds: glucocorticoids, tamoxifen, anticoagulants, herbs
Of note: in the past post-tubal ligation syndrome was considered to be a cause of menstrual abnormalities; BUT Most recent analysis of data from the US Collaborative Review of Sterilization (multicenter prospective cohort study) followed 10,000 women, showed decreased menstrual duration, volume and pain, only increased irregularity
Suggests they are no more likely to have menstrual problems

11. 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

12. Evaluation of Abnormal Menstruation Step 1: History
Detailed menstrual history
Inter-menstrual intervals
Consistent, normal (q days)
Variable
Character, volume
Duration
Normal (3-7 days)
Prolonged
Initial onset of symptoms
INTERVALS ARE KEY;
Various patterns predict diagnosis
Exp:
Irregular menses, skipped cycles, followed by either menorrhagia or persistent irregular bleeding = anovulatory, estrogen BTB
Reg intervals, heavy bleeding, prolonged =
Anatomical lesion
PMP bleeding =
Think of cancer
Postcoital bleeding = cervical or endometrial polyp, cervical cancer
INITIAL ONSET:
-since menarche – PCO, coagulation d/o
-acute onset 2 months ago, anatomical lesion -
TEMPORAL: wt gain/loss, postpartum, d/c hormonal meds?
PMH: had other illnesses develop and then start having abnormalities?
(renal, hepatic, thyroid, blood)
MEDS: anticoags, hormones, breast cancer meds
IF BASED ON HX, DX CLEARLY ANOVULATION:
Proceed straight to treatment, don’t necessarily need US, labs.
Otherwise, continue w/ w/u.

13. 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?
INTERVALS ARE KEY;
Various patterns predict diagnosis
Exp:
Irregular menses, skipped cycles, followed by either menorrhagia or persistent irregular bleeding = anovulatory, estrogen BTB
Reg intervals, heavy bleeding, prolonged =
Anatomical lesion
PMP bleeding =
Think of cancer
Postcoital bleeding = cervical or endometrial polyp, cervical cancer
INITIAL ONSET:
-since menarche – PCO, coagulation d/o
-acute onset 2 months ago, anatomical lesion -
TEMPORAL: wt gain/loss, postpartum, d/c hormonal meds?
PMH: had other illnesses develop and then start having abnormalities?
(renal, hepatic, thyroid, blood)
MEDS: anticoags, hormones, breast cancer meds
IF BASED ON HX, DX CLEARLY ANOVULATION:
Proceed straight to treatment, don’t necessarily need US, labs.
Otherwise, continue w/ w/u.

14. 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

15. Evaluation of Abnormal Menstruation Step 2: Exam
Endocervical
Polyps
Weight
Thyroid exam
Signs of other illnesses
Signs of hyperandrogenism
Hirsutism
Acne
Pelvic exam
Cervical and vaginal lesions
Size, shape of uterus
Squamous Cell
Carcinoma of Cervix
Other illnesses:
Liver disease (spider angiomata, varices
Coagulopathy (petechiae, bleeding)

16. 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????
B/c pregnancy complication is most common diagnosis; ALWAYS check hcg first
CBC to r/o anemia, thrombocytopenia
Timed prog: mid luteal, > 3 ng/ml
TSH: hyper and hypo can both cause menstrual abnormalities
Coags and LFTS; dependant on history and other comorbid illnesses
If unexplained menorrhagia, should check vWF
Biopsy, move to next slide

17. Evaluation of Abnormal Menstruation Endometrial Biopsy
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
WHEN SHOULD YOU PEFORM A BIOPSY?
Most people know the guideline that if a women is over 35, you should consider biopsy to r/o endometrial cancer
And that >40, you absolutely should biopsy,
Based on this data:
From 2 agegroups, increase 3fold your risk
BUT, an obese, anovulatory patient who has had years of irregular menses but is only 30 years old is still at high risk of hyperplasia, atypia, carcinoma.
In general:
Let the cutoff age of 35 guide you BUT always use clinical judgement so you don’t miss the younger women w/ risk factors who has an early endometrial lesion
IF you have SECRETORY, in absence of exog prog, you MUST have recent ovulation.
Ash, J Reprod Med, 1996.; ACOG Practice Bulletin 14, 2000.

18. Endometrial Hyperplasia
Endometrial Biopsy
Chronic endometritis
Adenocarcinoma
Endometrial Hyperplasia
Chronic endo: plasma cells

19. Evaluation of Abnormal Menstruation Step 4: Imaging
Who needs imaging?
Regular cycles
volume
duration
intermenstrual
bleeding
Abnormal
bleeding,
evidence of
ovulation
Failed
medical
management
RULE OUT
ANATOMIC LESION
When you have one of these 4 clinical conditions, again
-Review history; have you missed a systemic illness/medicine/coagulopathy?
If not, image

20. 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
Goal is to see: is there a lesion which is distorting the cavity; fibroids that are subserosal or intramural but well away from the cavity shouldn’t really be causing the bleeding
STRIPE: tremendously helpful in pointing to your diagnosis:
< 5mm; atrophic, denuded endometrium which needs some estrogen to stop bleeding before any further exposure to prog
-in peri/postmenopausal pts, risk of cancer < 1%, no need for bx
If normal: let clinical hx direct need for biopsy
HYDROSONOGRAM; use HSG catheter, intill 3-10 cc NS
As sensitive as hysteroscopy, cheaper, less invasive
HYSTEROSCOPY: reserved for people w/ diagnosed lesions, more invasive, more complications, some people perform office hysteroscopy BUT compared to the ease of sonohysterography, there is really no reason to jump straight to this.
Becker, 2002.

21. Uterine Imaging Ultrasound
Left:
Sagital view of uterus
Normal uterine appearance, trilaminar appearance of endometrial stripe
Right: sagital
Normal endometrium
Late proliferative or luteal phase
Thin endometrium
Early proliferative phase or atrophy

22. Uterine Imaging Routine Ultrasound Saline Sonogram Endometrial polyp
Submucous myoma

23. Uterine Imaging Hysteroscopy
Adenocarcinoma
Hyperplasia
Polyps
Myoma
Atrophy
Now that we have reviewed how to evaluate abnormal bleeding and how to look for underlying causes of abnormal bleeding, lets focus on DUB

24. 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

25. Cycle Physiology DUB/Anovulation Ovulatory Cycle Progesterone Estrogen2 4 6 8 10 28 12 14 16 18 24 20 22 26
Menses
Estrogen
Progesterone
Ovulatory Cycle

26. Option 1: Cyclic Progestins
Treatment: DUB
Option 1: Cyclic Progestins
Endogenous estrogen
Rx Progestin 1 5 9 13 17 21 25
Calendar Day
Progestins: 1. Medroxyprogesterone (MPA) 10mg qd
2. Norethindrone acetate 5 mg qd

27. Option 2: Oral Contraceptives
Treatment: DUB
Option 2: Oral Contraceptives
Endogenous estrogen 1 5 9 13 17 21 25
Pill Cycle Day
Rx Cyclic OCP
Progestin
Estrogen

28. Treatment of Anovulation with Acute, Heavy Bleeding
Hemodynamically stable??
IVF, CBC, transfusion
D&C
Strongly consider biopsy
Ultrasound
Treatment – High dose OCP taper
Clearly you first need to make sure they are stable; rarely a patient will come in and be symptomatic of anemia and need IVF, possible transfusion
Most patients will come in w/ heavy bleeding but not hemodynamically unstable
Start w/ H&P
Use US to guide your treatment
DENUDED: Rare to have heavy bleeding – usually just prolonged spotting. may need estrogen to aid re-epithelialization and proliferation to stop bleeding
THICKENED: need progesterone to stabilize the endometrium

29. Treatment of Anovulation Maintenance Therapy
Goal: Restore regular menstrual bleeding patterns
Prevent endometrial cancer!!
Failed management = further workup

30. Architectural Pattern
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 + 8%
Complex + atypia
29%
Simple: dilated glands, abundant stroma
Complex: crowded glands, little stroma, complex pattern w/ outpouching formations
Cytologic atypia: increase in nuclear/cytoplasm ratio, irregularly shaped nuclei
Severe = CIS
Most hyperplasias regress w/ therapy, progression to cancer takes years
Kurman et al, Cancer, 1985

31. Treatment: Anovulation Preventing Endometrial 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
Once you diagnose hyperplasia, it requires treatment, regimen based on presence/absence of atypia
Present:
Need high dose, potent progestin like megestrol acetate
75-90% will respond to meds
Resistant lesions:
Longer and higher doses of progestin
Recommend pregnancy ASAP
Close surveillance
So WE’VE NOW COVERED our 2 goals of treatment of anovulatory bleeding, restoring menses and preventing hyperplasia,
Lets move on to treatments of other underlying causes

32. Treatment of Abnormal Menstruation
What is the diagnosis?
DUB
Bleeding from Specific Cause
Treat underlying cause
Decrease volume and duration of menses

33. Complications of Pregnancy
Treatment
Complications of Pregnancy
Ectopic
Empty Sac
Ectopic pregnancy
Salpingostomy
Salpingectomy
Methotrexate
Threatened abortion
Observation
Incomplete/inevitable abortion
Curettage

34. Treatment Chronic endometritis Indirect cause of bleeding
Twice as common in HIV+ patients
Doxycycline 100mg bid x 10 days
Endometritis usually not main culprit but propagates abnl bleeding b/c of increased inflammatory cells, release of proteolytic enzymes, damage to epithelium and capillaries = bleeding
Copper IUD = inflammatory environment, same mechanism of abnl bleeding as above
Kerr-Layton et al, Infect Dis Obstet Gynecol, 1998

35. Treatment Leiomyomas Medical treatment Surgical treatment
OCPs: decrease volume/duration of menses
NSAIDS
GnRH agonists
Surgical treatment
Myomectomy
Hysterectomy
OCPS not as helpful w/ submucous myomas

36. Small Submucous Myomas, Polyps Hysteroscopic Resection
Treatment
Small Submucous Myomas, Polyps 1 2 3
Hysteroscopic Resection

37. Prolapsing, Large Myomas
Treatment
Prolapsing, Large Myomas
Abdominal or
Laparscopic
Myomectomy
Vaginal
Myomectomy

38. Completed Childbearing
Treatment
Multiple Myomas
Completed Childbearing
Abdominal Hysterectomy

39. Treatment: Ovulatory Patient with Unexplained Menorrhagia
Medical Options
NSAIDS: 20-40% decrease
OCPs: 40% decrease
Levonorgestrel IUD: % decrease
Excellent option with chronic illnesses
Women highly satisfied
GnRH agonists
Surgical Options
Endometrial ablation
Hysterectomy
In some OVULATORY women, despite thorough evaluation and w/u, no underlying cause of menorrhagia can be found
NSAIDS: inhibit PG synthesis, decrease menstrual loss
Any NSAID is acceptable
OCPs: works well in women w/ unexplained menorrhagia OR menorrhagia secondary to fibroids, adenomyosis, etc
Mirena: 52 mg LNG
20 micrograms/day
More effective than cyclic aygestin
GnRH: often used preoperatively to stop blood loss, shrink fibroids
Helpful before endometrial ablation to thin the endometrium
Re myomectomy: use if trying to shrink the size to perform vaginal hyst, but NOT helpful if performing myomectomy, makes fibroids more difficult to identify
Costly, side effects
Hall, Br J Obstet Gynecol, 1987; Fraser, Aust NZ J Obstet Gynecol, 1995; Cochrane Database Syst Rev, 2002.

40. Absence of Menstruation
Primary Amenorrhea
Secondary Amenorrhea
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:
Mullerian – outflow obstructions, mull-agenesis (no uterus)
AIS – abnl androgen receptor
Turner’s – short stature
POF:
Autoimmune – unknown cause, can be assoc most commonly with auto-immune thyroiditis. Rare Autoimmune polyglandular syndrome
Fragile X

41. Abnormal Puberty Precocious Puberty Delayed 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:
CNS lesion: hamartomas, craniophyargiomas, meningitis
GnRH independent – ovarian tumor – granulosa cells, theca cell tumors
Mccune albright – café au lait, cystic bone lesions, precocious puberty
Exam: Ht, tanner, abdominal exam, neuro exam.
Labs: bone age, MRI head, US abdomen
FSH, LH, E2
TFT’s, steroids

42. 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

43. Questions?

44. Examples of Effects of Exogenous Progestin in Ovulatory Cycles
Ovulation
Provera C
This is a picture illustrating various points in the cycle where exogenous progestin may be administrated and how it will impact bleeding
In someone who still occasionally ovulates
Provera is just an example of one progestin, holds true for all progestin therapy
Example Provera A; administering provera in synchrony with her endogenous progesterone production, RARELY HAPPENS,
No harm or effect
Example B: administer AFTER she ovulates and AFTER she has already started making her own progesteron
EFFECT: once ENDOGENOUS prog falls, she will bleed, then either stop bleeding and bleed again with end of provera regimen, OR continue bleeding throughout
Example C: administer BEFORE ovulation; now she won’t have a withdrawal bleed because she is making her own endogenous prog; cause of concern to not see any bleeding, bleed much later.
YOU CAN SEE HOW THIS WILL MAKE A PATIENT CRAZY AND IS OFTEN INTERPRETED AS FAILED MEDICAL MANAGEMENT
A better option is a low dose OCP
If cannot take OCPs, continuous progestin is a better choice because at least then you would suppress HPO axis
Provera B
Provera A
Endogenous Progesterone
Follicular Phase 14
Luteal Phase 28

45. Complex Atypical Hyperplasia
Treatment: Anovulatory Bleeding Preventing Endometrial Hyperplasia & Neoplasia
Simple Hyperplasia
Complex Hyperplasia
Simple:
See that there a normal number of glands, appear dilated, but not crowded
Complex: increased number of glands, crowded, back to back appearance
Complex Atypical Hyperplasia

46. 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
So now let me define these abnormalities we have discussed:

47. Uterine Imaging Ultrasound
Left: transverse view through fundus
ADENOMYOSIS:
myometrial cystic spaces uterine wall; an enlarged uterus with a widened posterior wall
Right; transverse view, distortion of post surface
Submucous myoma
Intramural myoma
Adenomyosis

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

49. Treatment: Acute bleeding High dose OCP ‘Taper’
Menses
Endogenous Estrogen
Estrogen
Rx OCP (monophasic)
bid X 7d, qd X 7-14d
Progestin

50. Treatment: Atrophic Endometrium Sequential Estrogen and Progestin
Menses
Endogenous Estrogen
Rx Estrogen (CEE mg/d
or micronized estradiol 2.0 mg/d, q4h prn;
CEE 25 mg i.v. q4h prn) Rx
Progestin