AUB

Physiology

• Estrogen: Causes proliferation of endometrial tissue (mitosis)
• Progesterone: Stabilizes endometrium causing it to stop proliferating and secrete glycogen to feed potential zygote.
• Menstrual flow: Withdrawal of progesterone/estrogen causes the bleed

• The menstrual cycle is regulated by a dynamic, complex relationship between pituitary 
  hormones (Follicle stimulating hormone (FSH) and Leutinizing hormone (LH)) and the 
  primary ovarian hormones: estradiol (E2) and progesterone (P).. 
  One way to understand it is in terms of its three phases: 
   Follicular phase (== proliferative) 
   Ovulation 
   Luteal phase (==secretory) 
• Follicular phase / Ovulation / Luteal Phase

   

   

  - Follicular phase: 

  - Orderly sequence of events resulting in release of one follicle per cycle (on 

  average) 

   - Takes 10-14 days (7 to 21 days is within normal) 

   - FSH rises and follicles are recruited by Day 5 

  - Follicles start to secrete E2 that acts on granulosa cells (GC) to increase GC# 

  - Rising FSH and E2 inhibits further FSH secretion from the pituitary. This inhibits 

  the development of all but the dominant follicle which secretes the greatest 

  amount of E2 because it has the largest # of GC’s and a high density of FSH 

  receptors. 

   - FSH induces LH receptors on the GC. 

  - The endometrium proliferates in this phase E2 increases mitotic activity of 

  endometrial cells and upregulates LH receptors. 

   

  II Ovulation

   Midcycle, LH and FSH surge 

  Ovulation occurs ~12 hrs after the LH surge: P begins to be secreted 

  which enhances production of proteolytic enzymes and prostaglandins in 

  the follicle leading to rupture 

   

  III Luteal Phase 

  Granulosa cells become vacuolated and accumulate lutein, a yellow pigment—

  forming the corpus luteum. FSH receptors are now suppressed. An increase in 

  LH receptors occurs and progesterone secretion increases. 

  Estrogen levels start to decline 

  This part of the cycle CONSISTANTLY lasts 14 days. 

  The corpus luteum declines unless fertilization occurs—progesterone drops and 

  the period occurs (signal is the decline of both E and P) 

  The endometrium stops dividing and secretes glycogen to feed a potential 

  zygote. It reaches a maximal single thickness of 7-8 mm.

AUB in Menarchy

• Dysfunctional uterine bleeding (DUB - i.e. unknown cause) is the primary cause of AUB, but is a diagnosis of exclusion
• Must rule out medical issues:  (Grouped in Hematologic and Endocrine)
  • Hematologic Causes:
    • Coagulopathy
      • Von Willebrands Disease (vWD) - bleeding, bruising, epistaxis, gum bleeding, post-surgical hemorrhage.
    • Platelet abnormalities
      • Thromabasthenia (Glanzman's Syndrome)  - Platelets >400,000 - malfunction
      • Immune Thrombocytopenia (ITP) - platelets <150,000
    • Leukemia
  • Endocrine Disorders
    • Inappropriate Testosterone/Estrogen/Progesterone secretion
      • Ovaries: Polycystic Ovarian Syndrome (PCO), tumors
      • Adrenals: Congenital adrenal hyperplasia (CAH), Cushings Syndrome
      • HPA stress: eating disorder, excessive exercise, stress, idiopathic
      • Thyroid disorders: Hypothyroidism
    • Pregnancy
      • Threatened/missed/incomplete abortion
      • Ectopic pregnancy
      • Molar pregnancy
    • (Incorrect OCP use?)
  • DUB
• Investigations:
  • Pelvic exam probably not informative (ovarian masses on abdo exam)
  • Blood work:
    • CBC (cross and type if unstable)
    • BhCG if applicable
    • TSH, Prolactin
    • Testosterone panel:
      • Free testosterone
      • 17-hydroxyprogesterone (CAH - adrenal source, high if enzymes defective)
      • DHEA/DHEAS (steroid hormone produced predominanty by adrenals.  Used to detect excess adrenal activity such as adrenal cancers and some forms of CAH)  DHEAS elevated in PCOS
    • Coag Profile:
      • APTT (vWD - but can be normal if mild vWD).  If suspect vWD do vVWF:AC (vWF activity assay)
• Management
  • ABCs
  • ESTROGEN!!! (all therapies involve estrogen, not clear why it works)
    • Premarin 25mg iv q4h x24h (premarin in this dose causes nausea+++ so add gravol)
    • OCP (monophasic prep) one tablets po tid for 3-4days then bid for 3-4 days then od for 21 more days.  Can maintain for several months to regular HPA until it matures.  (will not close epiphysis)

AUB in Perimenopausal Women

• In mature women two major problems
  • 1. anovulatory bleeding characterized by irregular menses
  • 2. ovulatory cycles characterized by short luteal phase which causes menorrhagia. (aka ovulatory DUB)
• Physiology: Estrogen causes proliferation, progesterone stops proliferation and causes glycogen secretion.  If no ovulation occurs, estrogen goes unopposed causing increase in thickness until endometrium becomes unstable --> bleed.
• Longstanding estrogen exposure can cause endometrial hyperplasia.
• Endometrial Hyperplasia can cause AUB, excessive blood loss, and precede or occur with endometrial carcinoma.
• An endometrial biopsy must be obtained to exclude hyperplasia or malignancy in all women over 40.
• DDx: (anatomical approach)
  • Cervix: Dysplasia (also post-coital bleeding)
  • Uterus: endometriosis, fibroids, PID, pregnancy
  • ---Endocrine---
  • Ovaries: PCOS, ovarian tumors
  • Adrenals: Cushings, CAH (adult onset)
  • Hypothyroidism
  • HPA: stress, prolactinoma, weight loss
  • ---Iatrogenic---
  • Forgotten IUD, OCP/HRT, Neuroleptics (dopamine-prolactin)
  • ---Hematologic ---
  • Coagulation disorders (vWB, ITP, Leukemia, Liver disease - estrogen not metabolized)
  • Dysfunctional Uterine Bleeding (absence of any organic cause, likely due to anovulation - common)
• Exam:
  • VSS, anemia signs?
  • Pelvic/Abdo exam + pap smear.
  • If >40 with AUB: Endometrial Hyperplasia or Endometrial Cancer until proven otherwise!!!
• Labs:
  • CBC, Ferritin, 
  • TSH, prolactin
  • BhCG, coag profile
• Other tests:
  • Sonohysterogram: (saline infusion hysterography) can see polyps, submucous fibroids
  • Ultrasound: good for screening for polyps/fibroids
    • Also see thickness (can be up to 14mm in reproductive years, 3-5mm in menopausal women), but unreliable cutoffs, and should use endometrial biopsy anyway.
• Medical Management:

  • Drug	Mechanism	%decr in flow	other
    NSAID	inhibits COX2	20-50	also decr. dysmenorrhea
    Cyclokapron	anti-fibrinolytic	40
    Danazol	inh steroidogenesis	up to 80	15% amenorrhea
    Progestin	decidualizes endometrium	~50	decr. dysmenorrhea
    OCP	inh. steroidogenesis	50%	decr. dysmenorrhea
    Mirena IUD	decidualizes endometrium	up to 80%	treats E.H.

  • +++ Ferrous gluconate 300mg po tid will raise Hb 10points/week.
  • Surgeries:
    • Hysteroscopic resection: removes submucous fibroids and polyps
    • Hysteroscopic endometrial ablation: 80% improvement over 5y.  Endometrium can grow back.  20% need retreatment in 5y.
    • Hysterectomy: last resort, definitive, highest morbidity