DYSFUNCTIONAL UTERINE BLEEDING

This article is based on a lecture given by Dr. Glenn Gill during the February Therapeutics Refresher Course at Dalhousie University. Because of its' length it has been divided into two sections, the first dealing with DUB in the adolescent and reproductive aged woman and the second dealing with the peri and post menopausal woman.

 

Definition of DUB

  • Any abnormal uterine bleeding for which no specific organic cause can be found
  • Most of the time the bleeding is anovulatory
  • Is common at the extremes of reproductive life (i.e. post menarchal and perimenopausally)
  • Is a diagnosis of exclusion, therefore term is often more confusing than useful

 

I. ADOLESCENCE

The normal ovulatory adult menstrual cycle is characterized by:

  • regular cycle length (between 21-35 days)
  • accompanied by moliminal symptoms (i.e. premenstrual mood changes, bloating, breast tenderness, dysmenorrhea of some degree)
  • mean duration of menses is 4.7 days (90% ~ 7 days)
  • average blood loss is 35 ml (recurrent bleeds of > 80 ml result in anemia)

During the first two years alter menarche most cycles are, however, anovulatory. The anovulatory cycle is characterized by:

  • irregular cycle length 21-40 days but can be as long as 3-4 months
  • absence of moliminal symptoms
  • periods are not painful, i.e. no dysmenorrhea
  • bleeds can be long and heavy and are due to "estrogen breakthrough" bleeding

 

Traditional Menstrual Definitions:

  • Oligomenorrhea -intervals greater than 35 days
  • Polymenorrhea -intervals less than 21 days
  • Menorrhagia -regular normal intervals but excessive flow and duration
  • Metrorrhagia -irregular intervals with excessive flow and duration

 

Figure 1

Graph illustrating hormone levels

Figure 1. The hormone levels during a normal menstrual cycle. From Wathen PI, Henderson MC, Witz CA: Abnormal Uterine Bleeding. In Medical Clinics of North America March 1995, p 344).

 

Pathophysiology of Anovulatory Cycle (refer to Figure 1)

Cause--> hypothalamic-pituitary-ovarian axis has not fully matured

  • pulsatile GnRH from hypothalamus stimulates pulsatile FSH from pituitary which causes follicles in ovary to produce estrogen but no positive estrogen feedback to stimulate FSH and LH midcycle surge and therefore no ovulation
  • if no ovulation then the corpus luteum does not form and there is no progesterone production to convert the endometrium from proliferative to secretory status and stabilize it.
  • Estrogen production continues (unopposed by progesterone) and causes further proliferation and thickening of the endometrium

So with anovulatory cycle you get:

  1. thick endometrium
  2. very vascular endometrium
  3. glands crowd together with very little stromal support
  4. endometrial tissue is very fragile
  5. the fragile, thick endometrium spontaneously bleeds at various sites and bleeding is random (not universal)

In absence of a controlled progesterone withdrawal there is:

  • No vasoconstriction
  • No tight coiling of spiral vessels
  • No orderly collapse to induce stasis. Therefore the anovulatory bleed is long and heavy!

 

Differential Diagnosis for Adolescent Abnormal Bleeding:

  1. DUB secondary to anovulatory cycles (estrogen breakthrough)
  2. Pregnancy related, eg. ectopic, spontaneous abortion
  3. Hematologic abnormality - ITP, Von Willebrand's disease, leukemia
  4. Exogenous hormones, eg. BCP, Norplant, Depoprovera
  5. Infections, eg. chlamydial cervicitis, chronic PID)
  6. Medical conditions, e.g. thyroid disease, DM, PCO, renal disease
  7. Anatomic abnormalities, eg. Mullerian abnormalities
  8. Genital tract neoplasia

 

Most Common Causes of Abnormal Adolescent Bleeding:

  1. DUB
  2. Pregnancy problems
  3. Hematologic abnormalities
  4. Idiopathic Thrombocytopenic Purpura (ITP)
    Von Willebrand's Disease
    (NB: 20% of adolescents with abnormal bleeding have an underlying hematologic abnormality!)
  5. Thyroid disorders

 

Investigations:

  • CBC (Hgb, Platelets)
  • ßHCG pregnancy test
  • PT, PTT, Bleeding time.
  • TSH
  • GC and chlamydia tests
  • + Pelvic ultrasound

 

Management of DUB

  1. after ruling out "organic" causes of bleeding the first line treatment for DUB is hormonal
  2. the objective of hormones is to promote universal, synchronous endometrial bleeding, structural stability and vasomotor rhythmicity. This can be accomplished with either progestin or oral contraceptive therapy
  3. progestins work by excreting a powerful anti-estrogen effect (i.e. antimitotic and antigrowth effect on endometrium)

    a) Anovulation with mild bleeding and normal Hgb:

      - explain pathophysiology
      - reassure patient
      - close follow up
      - iron supplementation

    b) Anovulation with relatively mild bleeding but mildly anemic (patient not bleeding heavily at present):

      - cyclic low dose monophasic BCP
      - re-evaluate in 3-6 cycles then:
        (a) if required birth control continue with BCP,

        (b) if no birth control required give medroxyprogesterone acetate (Provera) 10 mg po OD x 10 days each month,

        or (c) just watch and follow up

    c) Anovulation with moderate acute bleeding (i.e. acute bleeding but stable, admission not required):

      - monophasic low dose BCP one tablet po q6h until bleeding abates (24 hours) then one tablet po bid to complete 7 days then withdraw BCP for 5 days

      - after withdrawal bleed (warn patient that it will be heavy but controlled and will stop) on fifth day start BCP one tablet po OD cyclically for 3-6 months then reassess.

      NB: BCP reduces menstrual flow by at least 60% in normal uteri.

     

    d) Acute bleeding - Emergency:

    1. Stabilize.
      1. - IV fluids +/- transfusion
        - appropriate exam and investigations
    2. Conjugated estrogens (e.g. Premarin) 25 mg IVq4h until bleeding stops or for 12-24 hours.
      Coincidentally start low dose monophasic BCP (e.g. Minovral) one tablet po qid x 2 days, then one. tablet po tid x 2 days, then one tablet po bid x 2 days, then one tablet po OD x 2 weeks, then allow withdrawal bleeding. On day 5 of withdrawal bleeding start low dose monophasic BCP cyclically for 3-6 months
    3. If no response to high dose estrogen in 24 hours then do D&C + hysteroscopy
    4. Warn patient on above regimen about nausea/vomiting and give antinauseant along with estrogen.

      NB: Mechanism of Action of High Dose Estrogen is Debatable.

        - stimulates clotting at capillary level
        - promotes vaso constriction of spiral vessels?

 

II. ADULT WITH INTERMENSTRUAL BLEEDING ON BCP

Points to Remember:

  1. Normally 30% of women starting a BCP will have intermenstrual bleeding during first three cycles
  2. Ask about antibiotics or other medications that patient may be taking that could be interfering with efficacy of BCP
  3. Ask about missed pills
  4. Always rule out pregnancy, i.e. do ßHCG
  5. Always examine. patient and rule out genital tract neoplasia, i.e. do PV, PAP, etc.
  6. Rule out infection, e.g. cervicitis with chlamydia

 

Pathophysiology:

In the absence of sufficient estrogen the progestational effect of the BCP on the endometrium will predominate, such that the endometrium shrinks - "pseudo atrophy". This type of endometrium paradoxically leads to a fragile endometrium, typical of that caused by prolonged unopposed estrogen seen with prolonged BCP use, or with progestin- only medications such as levonorgestrel implants (Norplant) or Depo-medroxyprogesterone acetate (DepoProvera)

 

Management:

  • continue the BCP but add estrogen to slightly thicken and stabilize endometrium, i.e. conjugated estrogens 1.25 mg or estradiol 2.0 mg po OD x 7 days for one or two cycles

- Glenn Gill

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