1. Nancy E Fay MD FACOG Division of Reproductive Medicine

2. Definition-AUB Any bleeding that is not regular cyclic menstrual flow Intermenstrual spotting Post coital bleeding Excessively heavy bleeding Unpredictable bleeding

3. PALM-COIEN Classification PALM-Structural causes Polyp (AUB-P) Adenomyosis (AUB-A) Leiomyoma (AUB-L) Sub mucosal Intramural Malignancy/hyperplasia(AUB-M)

4. PALM-COEIN Classification COEIN: Nonstructural causes Coagulopathy (AUB-C) Ovulatory dysfunction (AUB-O) Endometrial (AUB-E) Iatrogenic (AUB-I) Not yet classified (AUB-N)

5. Physiology of the menstrual cycle Proliferative or follicular phase Endometrium Height starts <5 mm to <15 mm Mitotic growth of tubular glands response to rising estrogen

6. Follicular phase *Primordial follicles develop INDEPENDENT of FSH Estradiol promotes FSH receptors Ends with LH surgeand meiosis of dominant follicle

7. Secretory or luteal phase Endometrium Stromal height fixed, becomes edematous Glands tortuous, sub nuclear vacuoles Arteries spiral Endometrium stratified into basalis 25%, spongiosa 50% and outer compacta 25% Endometrial biopsy to date endometrium; luteal insufficiency. Timed progesterone alternative

8. Secretory or luteal phase Ovary LH surge causes reduction division of oocyte Growth of granulosa cells in size, #’s and metabolic activity Day 8 capillary growth and progesterone peak If no HCG to stimulate, follicular atresia begins *Progesterone suppresses new follicular growth

9. Luteal or secretory phase

10. Menstrual phase Steroid withdrawal causes lysosomal instability releasing prostaglandin synthetase, proteases and collagenases High thromboxane A2 results in vasospasm and ischemic necrosis of the endometrium at the level of basalis layer Endometrial healing by rising estrogen from new follicles with estradiol mediated growth

11. Adolescent development Average development Breast bud 9.8 yrs Pubic hair 10.5 yrs Maximal growth velocity 11.4 yrs Menarche at 12.8 yrs Adult pubic hair by 13.4 yrs Adult breast by 14.6 yrs

12. Adolescent development 55% of cycles first year are anovulatory Usually at least 15 months from menarche to achieve 10 cycles Normal fertile adults have 1-2 anovulatory and 10-12 cycles per year Adolescent menstrual pattern ends 2-3 yrs after menarche

13. Tanner Stages

14. Adolescent AUB, persistent 10% with menorrhagia will have coagulopathy Most common are ITP, Von Willebrand’s, Glanzmann's, Thalassemia major and Fanconi’s anemia Tests: INR, PTT, bleeding time, platelet count and VonWillebrand’s screen

15. Other terms Polymenorrhea; frequent cycles <18 days Metrorrhagia; intermittent intermenstrual bleeding Menorrhagia; regular but excessively heavy flow Menometrorrhagia; irregular, frequent, heavy and light bleeding Hypomenorrhea; light flow at regular intervals Oligomenorrhea; irregular, infrequent cycles >45 days apart, ovulatory or anovulatory

16. Average menses Estrogen + progesterone withdrawal 5 day flow (2-8 normal) Volume loss 30 cc (>80 cc abnormal) Average cycle range 21-35 days

17. Menstrual cycle Mature follicle 2-2.5 cm size Corpus luteum complex cyst 1-3 cm size Endometrial height range 3-14 mm

18. Causes of anovulation (AUB-O) Physiologic: adolescence, perimenopause, lactation and pregnancy Pathologic Hyperandrogenic Hypothalamic Thyroid disease Primary pituitary Premature ovarian failure Medications/herbal supplements

19. History the most important Qualify and quantify bleeding: type of protection, frequency of change saturation, clotting Establish current complaint and find out what ‘normal’ menses usually are like OFF any hormonal contraceptives (many women don’t think of hormonal contraceptives as a medication) Other symptoms such as cramping, dyspareunia Evaluate use of medications prescriptive as well as OTC and herbal supplements

20. Pregnancy ALWAYS check HCG

21. Polycystic ovary syndrome Affects 1 in 9 women Most common cause of anovulation Diagnosis, Oligo or anovulation with one of: Evidence of androgen excess Polycystic ovary Begins in teen years or early twenties Multifactorial inheritance associated with insulin resistance and metabolic syndrome. Family history of type II DM

22. PCOS Need to treat proactively with OCP’s, cyclic progesterone to decrease their risk of endometrial cancer from unopposed estrogen For fertility purposes, use of insulin sensitizers (metformin) may decrease insulin resistance enough to allow ovulation along with low carb diet and exercise. Ideal body weight the goal. Otherwise ovulation induction needed to conceive. Milder cases of PCOS ovulatory, low progesterone, and have a higher risk of miscarriage

23. PCOS Associated with thyroid dysfunction. Hirsutism treated with spironolactone and OCP’s Endometrial biopsy? When needed ?

24. Hypothalamic dysfunction Hyper or hypothyroidism Age factor in screening >35 hypo Hyperprolactinemia Amenorrhea or hypomenorrhea 2/3 Galactorrhea present in 1/3 Infertility with normal menses Need repeat >48 hrs apart to confirm Level >50 need to consider MRI of sella

25. Hypothalamic dysfunction CNS suppression, low FSH and LH Stress most common cause Anorexia Athletic Lower suppression higher estradiol, more suppression hypoestrogenic Rare congenital absence of LH or mutation in gonadotropins or GnRH (the latter primary amenorrhea)

26. Coagulation disorder Most common causes are ITP, VonWillebrand’s, Glanzman’s, Thallasemia major or Fanconi’s anemia Test for bleeding time, INR, PTT, platelet count and VonWillebrand’s screen Remember if severely anemic testing skewed In adolescents 10% will have coagulopathy Usually ovulatory cycles with severe menorrhagia Tranexamic acid may be of benefit for some

27. Chromosome disorders Suspect if initial normal cycles then irregular or amenorrhea and evidence of diminished reserve <25 y/o Turner mosaic more likely Later 20’s to early mid 30’s diminished reserve associated with Fragile X pre-mutation or on the older end BRCA 1 mutation If mutation and some reserve left consider ART options: gamete freezing, IVF with PGD Otherwise fertility with donor eggs and use of HRT or OCP’s as replacement therapy till 50

28. Anatomic causes of AUB Endometrial polyp Sub mucus fibroid

29. Ovarian masses Endomctrioma Hormone secreting tumors PID

30. Malignancies Endometrial cancer What age should you biopsy to rule out? Endometrial hyperplasia Simple Complex adenomatous Atypical complex Ovarian

31. Treatment of AUB Anatomic causes treat and usually bleeding controlled. If not likely hormone issue Thyroid dysfunction treatment will resolve AUB once normal functions after 2 months Hyperprolactinemia treat with cabergoline or bromocriptine. When prolactin normal, normal menses in 2 cycles If unable to treat cause then cyclic progestins or hormonal contraceptives best treatment.

32. Treatment of hemorrhage Usually at extremes of menstrual ages Rule out pregnancy, trauma, coagulopathy; replace blood products as needed Endometrial biopsy depending on age and history High dose IV conjugated estrogen 25 mg Q4-6 hrs till bleeding slows then switch to oral estrogen and progestin. Give for 3 weeks then withdrawal. Antiemetics Oral high dose E+P an option if stable Cycle with hormonal contraceptives 2 months