1. 8th Edition APGO Objectives for Medical Students
Normal and Abnormal Bleeding

2. Rationale
The occurrence of bleeding at times other than expected menses is a common event. Accurate diagnosis of abnormal uterine bleeding is necessary for appropriate management.

3. Objectives The student will be able to:
Describe endocrinology and physiology of the normal menstrual cycle
Distinguish abnormal uterine bleeding from dysfunctional uterine bleeding
List causes of abnormal uterine bleeding
Evaluate and diagnose abnormal uterine bleeding
Describe therapeutic options

4. Normal Menstrual Cycle
Basic functional components
Hypothalamic-pituitary unit
Ovaries
Uterus-endometrium

5. Normal Menstrual Cycle
Normal parameters
Cycle interval 28 days + 7 days
Duration of menstrual flow days
Average blood loss mL
Ovulatory bleeding is cyclic and predictable

6. Normal Menstrual Cycle
Follicular phase (days 1-13)
Rapid endometrial growth due to stimulation by ovarian estrogen
Regeneration in region of glandular stumps
Maximum thickness in late follicular phase

7. Normal Menstrual Cycle
Luteal phase (days 14-28)
Dependent upon ovulation (day 14) and development of corpus luteum, progesterone production
Progesterone inhibits further endometrial thickness
Microvasculature becomes well-differentiated (spiral arterioles)

8. Normal Menstrual Cycle
Menstrual phase
Fall in progesterone as corpus luteum involutes
Vasoconstriction → ischemia and hemorrhage
Release of PGF2α
Hemostasis
Platelet plugs
Vasoconstriction
Regeneration of functional layer (estrogen stimulation)

9. Normal Menstrual Cycle
Hormonal changes
LH peaks day 14
FSH is slightly increased day 14 and day 27-28
Estradiol peaks day 12-13
Progesterone peaks day 18-22, then falls
Inhibin increased in luteal phase

10. Normal Menstrual Cycle
Pathways of ovarian steroidogenesis
∆ 4 → Estradiol, testosterone androstenedione
∆ 5 → Dehydroepiandrosterone; Dihydrotestosterone

11. Abnormal uterine bleeding
Definition
Excessive flow or prolonged bleeding
Frequent bleeding episodes
Prolonged intervals between bleeds
Organic cause (structural or systemic) vs. hormonal dysfunction

12. Abnormal uterine bleeding
Terminology
Hypermenorrhea/menorrhagia
Regular bleeding
Prolonged bleeding >7 days
Excessive bleeding >80 mL
Metrorrhagia - irregular bleeding at frequent intervals
Polymenorrhea - regular uterine bleeding at intervals <21 days
Intermenstrual - bleeding between regular and identifiable periods
Oligomenorrhea - bleeding at intervals >40 days

13. Menorrhagia Affects approximately 15% of adult women
Etiology - pathologic conditions
Bleeding disorders
Leiomyomas
Adenomyosis
Thyroid dysfunction
Chronic endometritis
Endometrial polyps or hyperplasia
Estrogen-producing tumors Cervical or endometrial cancer Intrauterine device Anovulation (dysfunctional uterine bleeding)

14. Menorrhagia Laboratory evaluation Urine pregnancy test
CBC with platelets
EMB (endometrial biopsy)
Thyroid functions (TSH)
Coagulation studies
Pelvic sonography

15. Menorrhagia Medical management Prostaglandin synthetase inhibitors
Combination hormonal contraceptives
Progestins
Correct medical conditions

16. Menorrhagia Surgical management D&C - if clinically indicated
Myomectomy - if leiomyomata are cause and fertility desired
Hysteroscopy with lesion resection
Endometrial ablation
Hysterectomy

17. Intermenstrual bleeding
Unpredictable
Generally associated with structural abnormalities
Differential diagnosis
Ovulatory (Mittelschmerz)
Inflammatory - endometritis
Structural
Malignancy
Leiomyomas
Polyps
Iatrogenic
Oral contraceptives
Hormone Replacement Therapy (HRT)

18. Anovulatory (dysfunctional) uterine bleeding
Etiology
Obesity
Adrenal hyperplasia
Polycystic ovary syndrome (PCO) - increased ovarian production of androgens, insulin resistance, chronic anovulation
Increased circulating androgens aromatized to E1 (estrone) providing negative feedback to pituitary
Low FSH (due to chronic elevation of estrogens) and high LH - static levels do not trigger ovulation

19. Anovulatory (dysfunctional) uterine bleeding
Etiology
Obesity
Adrenal hyperplasia
Polycystic ovary syndrome (PCO) - increased ovarian production of androgens, insulin resistance, chronic anovulation
Increased circulating androgens aromatized to E1 (estrone) providing negative feedback to pituitary
Low FSH (due to chronic elevation of estrogens) and high LH - static levels do not trigger ovulation

20. Anovulatory (dysfunctional) uterine bleeding
Laboratory evaluation
Urine pregnancy test
CBC with platelets
DHEAS and testosterone, if symptoms of hirsutism
Endometrial biopsy (R/O neoplasia)
Thyroid stimulating hormone (TSH)

21. Anovulatory (dysfunctional) uterine bleeding
Medical management
Combination hormonal contraceptives
Progestins (cyclic or continuous)
Weight reduction/exercises
Metformin

22. References
Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 36: , 1981.
American College of Obstetricians and Gynecologists Practice Bulletin #16, Surgical Alternatives to Hysterectomy in the Management of Leiomyomas, ACOG: Washington, DC, May 2000.
Adapted from Association of Professors of Gynecology and Obstetrics Medical Student Educational Objectives, 7th edition, copyright 1997

23. Normal and Abnormal Uterine Bleeding
Clinical Case
Normal and Abnormal Uterine Bleeding

24. Patient Presentation
41-year-old G2P0020 LMP=10 days ago presents with persistent heavy vaginal bleeding. She denies dizziness, but complains of feeling weak and fatigued. Her cycles have been heavy for a long time, but seem to be worsening over the last several months. Her cycles come every days and she bleeds for 7-10 days. She describes bad cramps, passing clots and using 2 boxes of maxi pads each cycle. She is worried about losing her job if the bleeding is not better controlled. She only gets designated break times from the assembly line to use the bathroom. She takes Ibuprofen every 4-6 hours for cramps. She denies any bleeding disorders in the family. She uses condoms for contraception. She also complains of a pressure sensation and increased urinary frequency.
Allergies: None; Medications: Ibuprofen as needed

25. Patient Presentation
Ob-Gyn history Menarche 13/cycles days/ 7-10 days. Normal pap smears. History of Gonorrhea once and treated 1 elective termination at 16-years-old and 1 miscarriage at 10 weeks, about 2 years ago
Past medical history None
Past surgical history D & C for miscarriage; tonsils and adenoids as a child
Social history Nonsmoker. Occasional alcohol. No drugs. Works at a factory for machine parts assembly.
Family history Hypertension in mother and father. Mother had 1 miscarriage and 3 sons. Her brothers are healthy and one has sickle trait. Her paternal grandfather died of lung cancer.

26. Patient presentation ROS Negative, except as noted above.
Physical exam VS: BP=130/88; Pulse= 110; Respirations= 18; Ht=5’6’; Wt=150 pounds African-American women who appears pale and with bags under her eyes
HEENT: NC and AT
Lungs: clear to auscultation and percussion
CV: rapid rate, no murmurs
Breasts: Non-tender, no masses, no dimpling, retraction or discharge
Abdomen: Non-tender, No hepatomegaly, firm palpable mass in the lower abdomen
Extremities: Non-tender, no edema, 2+/= DTRs bilaterally
Pelvic exam: Normal external genitalia; moist and pink vagina with rugae and dark blood in the vault; cervix is non-tender, no lesions, and nullipara; uterus is 16 weeks size, firm, mobile, non-tender; adnexae: non-tender, no palpable masses

27. Patient presentation Laboratory/studies Hbg: 9.0, HCT: 27%
HCG: negative
TSH: 3.5 uIU/mL (Normal range: )
Prolactin: 19 ng/dl (Normal range <20)
PT/PTT: normal
Urinalysis: negative for infection
Endometrial biopsy: Proliferative endometrium
Pelvic Ultrasound: Multiple myomas (intramural and submucosal in location), Normal ovaries

28. Diagnoses Menorrhagia Anemia Leiomyomatous uterus
Possible anovulation (when her cycles are greater than or equal to 35 days)

29. Treatment
This patient was treated with GnRH analog for three months. Her hemoglobin increased to 12. She had some minor spotting during therapy. She complained of hot flushes and irritability. Her follow-up examination at 2.5 months of therapy showed a decrease in uterine size to weeks size. Her repeat ultrasound confirmed these findings. She was counseled regarding medical management with oral contraceptives, progestins or continued GnRH analog with hormonal add-back. Given the presence of submucosal myomas, it is likely that this treatment may not be effective in the long run. However, she has had an optimal response thus far.

30. Treatment
She was also counseled regarding surgical management. If she is interested in maintaining her fertility, her options include: hysteroscopic resection of submucosal myomas only or abdominal myomectomy. If fertility is not desired and she wants a definitive therapy, then a hysterectomy is indicated. Risks and benefits for these medications and surgeries were discussed. This patient is at increased risk for requiring a blood transfusion if the bleeding recurs and is heavy, or if the bleeding is significant during surgery. She will think about her options and decide over the next week.

31. Teaching points
Leiomyomas occur with a high prevalence of 25-50% of women (Buttram and Reiter). They are more common in the African-American population.
If this patient did not respond to the gonadotropin agonist therapy and the bleeding worsened, she would have been a candidate for high dose oral contraceptives, high-dose Premarin intravenously or a D&C to control her bleeding. If none of these options were effective, a uterine artery embolization or hypogastric artery ligation could be options prior to hysterectomy. In the near future, other medical therapies may become standard. Currently, gonadotropin-releasing hormone antagonists and progesterone antagonist mifepristone (RU 486) are under investigation. Gene therapies may be developed as we learn more about leiomyoma formation and growth.

32. Teaching points
After a myomectomy, the recurrence rate of leiomyomas ranges from 27-51%. Approximately, 15% require another operative procedure. The incidence of re-operation is increased with multiple myomas (26%) as opposed to a single myoma (11%).
It is important to rule out the other differential diagnoses in women with leiomyomas, i.e. pregnancy with possible incomplete abortion or ectopic, thyroid disease, endometrial cancer, etc). These disorders are also present in these women and we cannot assume we have the correct diagnosis unless tested.