1. This stasis is initiated by constriction of the coiled arteries. 2. This is because there is usually a lack of orderly exposure to estrogen and progesterone.
1. Platelets first adhere to the subendothelium of the damaged vessel wall. Occlusion of the site of injury by aggregation Initiates release of proaggregatory compounds such as thromboxane which accelerates aggregation and initiates coagulation This is an important interaction because vWF serves as the bridge between platelets and the damaged endothelium. This is important when considering DUB in perimenarchal adolescents. 2. Vascular occlusion by both methods is never total so blood leakage occurs until endometrial regeneration is completed.
Normal menstrual bleeding due to postovulatory estrogen-progesterone withdrawal is stable and precisely regulated. It is generally agreed that the normal menstrual cycle will be between 24 and 35 days in length, measured from the first day of menstrual flow of once cycle to the first day of the next cycle. The usual duration of menstrual flow is 4-6 days, but many women may have a flow for as little as 2 days or as much as 7 days. Normal menstruation also tends to be consistent in the amount of blood that is lost. The usual volume of menstrual blood loss is 30 mL, and a menstrual flow greater than 80 mL is considered abnormal. In practice, however, it is virtually impossible for either the patient or her clinician to estimate menstrual volume of blood loss accurately.
1. Diagnosis arrived at after pregnancy, benign and malignant dz of the reproductive tract, systemic illness, and iatrogenic causes are ruled out.
1. This gives rise to continuously proliferating endometrium which may outgrow its blood supply or lose nutrients with varying degrees of necrosis. Asynchronous development of stroma, glands, and blood vessels as well as overdevelopment of Golgi-lysosomal complexes may occur. Uniform slough to the basalis layer does not occur, which leads to excessive and irregular uterine blood flow. Overactivity of the fibrinolytic system may be present as well, but this relationship is not well studied.
Medical management is the preferred initial treatment, especially if the woman desires future fertility and there is no associated pelvic pathology Selection of treatment depends primarily on whether it is used to stop acute heavy bleeding or to control recurrent episodes
Acute bleeding can be managed by estrogen which promotes rapid regrowth of the endometrium over denuded epithelial surfaces. It also causes proliferation of the endometrial ground substance and stabilizes lysosomal membranes. There are no studies that indicate IV estrogen acts quicker or is more effective than high dose oral estrogen. After treatment is finished, all medications are stopped and the patient is allowed to have withdrawal bleeding. This can be heavy so warn patients, but it is rarely prolonged
A third option is high dose estrogen-progestin therapy This is the preferred method for many physicians One study suggested progestins may not be as successful because simultaneous use of a progestin can inhibit the synthesis of estrogen receptors and increase Estradiol dehydrogenase in the endometrial cell. The actions of progestins serving to interfere with the rapid growth-promoting effects of unopposed high dose estrogen. Once the bleeding episode has been controlled, you can continue standard dose OCP regimens using one tablet per day for 21 days or medroxyprogesterone acetate, 10 mg each day for the first 10 days of each month.
Because fibrinolysis plays an important role in hemostasis of the bleeding menstrual endometrium, the use of antifibrinolytics has been evaluated in the treatment of women with AUB. In particular, tranexamic acid (TA) and its precursors have been found to be particularly effective in reducing menstrual blood loss. In clinical trials, TA reduced menstrual blood loss by 45% to 54%. In light of such favorable data, it is easy to see why antifibrinolytics are a mainstay for treatment of ovulatory AUB in most of the world, but it is puzzling to understand why these agents are rarely administered in North America. One author proposed that North American physicians may be mistakenly concerned about an increased risk of thromboembolic events in women receiving antifibrinolytics. This concern is largely unwarranted, and one retrospective study in a large cohort of women at enhanced risk for thromboembolic disease failed to show an associated between administration of TA and thromboembolic events.
The progesterone IUD has been used successfully to treat women with ovulatory DUB. Bergqvist et al. Reported a decrease in MBL from an average of 138ml to 49 ml in 12 women with one year of IUD usage. Milson et al. used the levonorgestral IUD to treat DUB and reported an 80% reduction in the MBL at 3 months and 100% reduction at the end of the first year of use. It has a duration of action of 7 years or more.
Acute bleeding episodes are best controlled by high dose estrogen therapy; recurrent episodes by progestin therapy. Progestin therapy may be the first choice for chronic anovulatory DUB and it has been used to manage ovulatory DUB. However MBL usually is reduced by only 15% or less in these patients. There are other options for patients with ovulatory DUB. NSAIDs Prostacyclin is a vasodilator that inhibits platelet aggregation. The precise mechanism is unclear as NSAIDS generally inhibit thromboxane formation as well. Ideally, to control bleeding, inhibiting the synthesis of prostacyclin without altering thromboxane formation is desired. Currently no NSAID possesses this unique activity. Naproxen, ibuprofen, mefenamic acid, and meclogenamite sodium all studied. Most effective in women with the greatest amount of pretreatment blood loss. (decrease 20 to 50%) Treatment results in a sustained reduction in blood loss and an increase in ferritin indicating increased iron stores Usually added to hormonal therapy to achieve a greater decrease in blood loss.
The usual causes of AUB vary over a woman’s lifetime, as shown on this slide. Anovulatory uterine bleeding and irregular periods are common during the first few years after menarche. This primarily due to immaturity of the HPO axis, which renders it incapable of naturally responding to estrogen with a LH surge. Regular ovulatory bleeding is usually established within 2-3 years after menarche, and persistence of irregular periods beyond this time warrants further investigation. Coagulation disorders are not uncommon in adolescent women. Such disorders may be noted by unusual bleeding from the gums, prolonged bleeding after minor cuts, and easy bruising. In one study, 19% of adolescent patients evaluated for AUB were found to have coagulation disorders. This incidence was even higher if the hemoglobin was <10 g/dL (in approximately 25%) or if hospitalization was required (approximately 50%). Coagulation disorders in the adolescent may include von Willebrand disease, thalassemia major, Fanconi anemia, prothrombin deficiency, and other disorders. In addition, psychosocial stress, including that associated with eating disorders, may contribute to irregular periods in adolescents. It is common for women of reproductive age to suffer from occasional and self-limited AUB. The reasons are unclear, but the process of normal menstruation is complex and easily deranged. Pregnancy and related complications are a common cause of bleeding in women of reproductive age and must not be overlooked. Sexually transmitted diseases can cause pelvic infections associated with vaginal bleeding. Abnormal bleeding can also be caused by endometrial polyps or submucous myomas. Although the cause of abnormal bleeding in women of reproductive age is often benign, malignancy is always a possibility, particularly if the woman is obese or has a history of chronic oligoovulation or anovulation. Anovulatory uterine bleeding is also common in women of reproductive age and may be due to various causes. By far, the most common endocrinopathy is PCOS, affecting 6% of all women of reproductive age. Perimenopausal women have an increased incidence of anovulatory cycles due to depletion of the store of ovarian oocytes. With aging, endometrial hyperplasia, cancer, polyps, or submucosal fibroids become more prevalent, and pathologic endometrial tissue should be suspected in the perimenopausal woman with abnormal bleeding. Risk factors such as obesity, hypertension, diabetes mellitus, and chronic anovulation are significantly associated with cancer in perimenopausal women. Any vaginal bleeding in menopausal women should be considered abnormal. Up to 10% of these women have been found to have cancer. A large percentage of postmenopausal women (up to 80%) may have endometrial pathology such as hyperplasia, polyps, or submucous fibroids, particularly if the bleeding occurs after 1 year of amenorrhea or persists with hormone replacement therapy.
Dub gynae seminar
Roziana Ramli MD, Mmed(OBGYN)
•Estrogen causes increased blood flow to the endometrium
•Normal menses results from fluctuations in the circulating levels of estrogen and
• Estradiol and progesterone levels decrease several days
prior to the onset of menses.
• Endometrial blood flow decreases
• Endometrial height decreases and vascular stasis occurs.
• Tissue ischemia occurs.
• Arterial relaxation
• Sloughing of the endometrium.
• Uterine bleeding occurs
CESSATION OF MENSES
• Two main mechanisms:
• Formation of the platelet plug
• important in the functional endometrium
• Prostaglandin dependent vasoconstriction
• important in the basalis layer
• Life Cycle
• 5-7 years of relatively long cycles
• Increasing regularity of cycles
• In the 40’s cycles begin to increase in length with increasing
episodes of anovulation (2-8 years “perimenopause”)
• Menopause (average age = 51)
• By age 25, 40% of women have cycles between 25-28 days
• Age 25-35, 60% of women have 25-28 day cycles.
• Overall 15% have 28 day cycles
• 5% have cycles < 21days
• 9% have cycles >35 days
•Dysfunctional uterine bleeding (DUB) is defined as ABNORMAL
uterine bleeding that occurs in the absence of any pathology,
pregnancy or medical illnesses.
•Diagnosis of EXCLUSION
•Abnormal bleeding: (excessively heavy or light, prolonged, frequent, or random)
•DUB occurs most often shortly after menarche and at the end of
the reproductive years.
–20% of cases are adolescents
–50% of cases in 40-50 year olds
• Two types: anovulatory and ovulatory
• Most women with DUB do not ovulate
• Most common: either ESTROGEN BREAKTHROUGH
bleeding OR ESTROGEN WITHDRAWAL bleeding
• Ovulatory DUB occurs most commonly after the
adolescent years and before the perimenopausal years.
• Incidence in these patients may be as high as 10%
WHAT WENT WRONG IN DUB?
ESTROGEN BREAKTHROUGH BLEEDING
• NO corpus luteum, therefore NO progesterone
• UNOPPOSED estrogen causes continuous endometrial proliferation
• endometrium may then OUTGROW its blood supply resulting in areas of
• endometrial shedding will be irregular manner without uniform sloughing of
the basalis layer
• subsequent endometrial healing: irregular and dyssynchronous
• RESULT: EXCESSIVE AND IRREGULAR UTERINE BLEEDING
ESTROGEN WITHDRAWAL BLEEDING
• Frequently: at the end of reproductive life.
• SHORT CYCLE due to aberrant follicular recruitment
• LESS ESTRADIOL causing insufficient endometrial
proliferation and irregular menstrual shedding.
• RESULT: LIGHT, IRREGULAR SPOTTING
• DUB without any attributable anatomic, organic, or
systemic cause BUT associated with regular ovulation
• Regular withdrawal menses every 24-35 days—BUT
excessive blood loss
• Loss of local endometrial hemostasis
• ↑ Ratio of PGE2α : PGF2α
• ↑ Level of PGI2
• ↑ Fibrinolytic activity
• (Too MUCH): Ward admission, fluid management,
• (Too FREQUENT): Iron deficiency anemia (30%). Mainly
adolescents (20% might have a disorder of hemostasis)
• (Too LONG): Chronic unopposed estrogenic stimulation of
the endometrial lining increases the risk of both endometrial
hyperplasia and endometrial carcinoma. (1-2% of women with
improperly managed anovulatory bleeding)
• (Too BAD): Infertility associated with chronic anovulation,
•Assess hemodynamic stability (vital signs) and proceed with evaluation
of the following:
• Obesity (BMI)
• Signs of androgen excess (hirsutism, acne)
• Goitre or manifestations of hyper/hypothyroidism
• Galactorrhea (may suggest hyperprolactinemia)
• Ecchymosis, purpura (signs of bleeding disorder)
• Signs of anemia or chronic blood loss
• VAGINAL EXAMINATION and Pap smear
• The hallmark of DUB: -ve pelvic examination despite the
• Rule out uterine fibroids or polyps
• Rule out endometrial hyperplasia or carcinoma
INVESTIGATIONS (CASE TO CASE BASIS)
• UPT / HCG
• Complete blood count .
• Pap smear
• Endometrial sampling
• Thyroid function tests and prolactin
• Coagulation factors
• Other hormone assays as indicated for PCOS, 21 hydroxylase
deficiency, or ovarian or adrenal tumors
• Women in menopausal transition usually can be followed without an
extensive hormonal evaluation.
progestins, or both
• GnRH agonists
TREATMENT OF DUB
Medical management Surgical management
• Ablative therapy
TREATMENT OF DUB ACUTE BLEEDING
• Estrogen therapy promotes rapid regrowth of the endometrium over denuded epithelial
surface, exerts vasospastic action on capillary bleeding by affecting the level of fibrinogen, factor IV, and
factor X in blood, as well as platelet aggregation and capillary permeability.
• Oral conjugated equine estrogens
• 10mg a day in four divided doses
• treat for 21 to 25 days
• medroxyprogesterone acetate, 10 mg per day for the last 7
days of the treatment estrogen induces formation of progesterone receptors,
making subsequent treatment with progestins more effective.
• if bleeding not controlled, consider organic cause
• 25 mg IV every 4 to 12 hours for 24 hours, then switch to
oral treatment as above.
• Bleeding usually diminishes within 24 hours
TREATMENT OF DUB ACUTE BLEEDING
• Acute bleeding (continued)
• High dose estrogen-progestin therapy
• use combination OCP’s containing <=35 mics of ethinylestradiol
• four tablets per day
• treat for one week after bleeding stops
• may not be as successful as high dose estrogen treatment
• Fibrinolysis-endometrial hemostasis
• Tranexamic acid (TA) and precursors effective in reducing
menstrual blood loss (54%)
• Concern about thromboembolic events may be unwarranted
based on retrospective data
• Drug of choice in anovulatory DUB.
• Can be used alone after acute bleeding episode, in pts with adequate
amounts of endogenous estrogen to cause endometrial growth.
• Progestin therapy in adolescents produces regular cyclic withdrawal
bleeding until positive feedback system matures.
• Occasional anovulatory bleeding that is not profuse or prolonged can be
treated with progestins.
• Progestins inhibit estrogen receptor replenishment and activate 17-
OHsteroid dehydrogenase in endometrial cells, converting estradiol to
the less active estrone.
• Stops endometrial cell proliferation, allowing organized sloughing of
cells after withdrawal.
• Synthetic progestins have an antimitotic effect, allowing
the endometrium to become atrophic if administered
continuously (effective in cases of endometrial hyperplasia)
• Some perimenopausal patients will not respond well to
progestin therapy because of an inherent estrogen
• Also, patients with thin, denuded endometrium occurring
after several days of chronic bleeding might require
induction of new endometrial proliferation by estrogen
• Recurrent bleeding episodes
• Progesterone releasing IUD (Levonorgestrel
• Avoids systemic side effects
• 80% reduction of blood loss at 3 months
• 100% reduction at 1 year
• found to be superior to antifibrinolytic agents and
prostaglandin synthetase inhibitors
• Oral contraceptive pills (OCPs) suppress endometrial development,
reestablish predictable bleeding patterns, decrease menstrual flow,
and lower the risk of iron deficiency anemia.
• Acute episodes of heavy bleeding suggest an environment of
prolonged estrogenic exposure and buildup of the lining.
• Prolonged uterine bleeding suggests the epithelial lining of the
cavity has become denuded over time. In this setting, a progestin is
unlikely to control bleeding. Estrogen alone will induce return to
normal endometrial growth rapidly
• OCPs can be used effectively in a cyclic or continuous regimen to
• Bleeding usually is controlled within the first 24 hours, as the overgrown
endometrium becomes pseudodecidualized.
• Contraceptive pills containing estrogen and progestin have been advocated for
patients with DUB who desire contraception.
• When progestin is present it takes longer to induce endometrial proliferation.
• In long-term management of DUB, combination oral contraceptives are
• Cyclooxygenase inhibitor, inhibits prostacyclin formation(accelerates
platelet aggregation and initiates coagulation)
• Administered t/out the duration of bleeding/first 3/7 of menses
• Most effective: menorrhagia in ovulatory cycles, not effective for the
• Used for relief of mild to moderate pain.
• Reduce concentration of GnRH receptors in the pituitary
• Initial gonadotropin release associated with rising estradiol, gonadotropin
levels fall to castrate levels, with resultant hypogonadism.
• Very effective in inducing amenorrhea
• Prolonged therapy: osteoporosis and other postmenopausal side effects
• Expensive, not used as a first line approach but for short-term relief,
particularly in patients with renal failure or blood dyscrasia.
•Surgical measures including Hysterectomy: when medical therapy has
failed, symptomatic anemia, and a disruption in the quality of life from
persistent, unscheduled bleeding.
•D&C is an appropriate diagnostic (not therapeutic as not shown to be efficacous)
step in a patient who fails to respond to hormonal management.
• The addition of hysteroscopy will aid in the treatment of
endometrial polyps or the performance of directed uterine biopsies.
• Endometrial ablation: alternative to avoid
hysterectomy or pt not fit for major surgery.
• Ablation techniques: laser, rollerball,
resectoscope, or thermal destruction
• Pretreat with agent to thin the endometrium.
• Shorter recovery time.
• May fail treatment
ESSENTIAL UPDATE: NEW ACOG TREATMENT
GUIDELINES FOR ABNORMAL UTERINE BLEEDING
•Either low-dose COCP or progestin therapy is generally effective in women aged
19-39 years; high-dose estrogen may benefit patients with an extremely heavy
menstrual flow or hemodynamic instability
•Medical treatment for women >=40 can, prior to menopause, consist of cyclic
progestin therapy, low-dose oral contraceptive pills, the LNGIUS, or cyclic
•If medical therapy fails, patients should undergo further testing (eg, imaging or
•An in-office endometrial biopsy is preferable to (D&C) when examining a patient
for endometrial hyperplasia or cancer
•If medical therapy fails in a woman in whom childbearing is complete,
hysterectomy may be considered
•Surgery only in patients in whom medical treatment has failed, cannot be
tolerated, or is contraindicated
•Endometrial ablation is not acceptable as a primary therapy, because the
procedure can hamper the later use of other common methods for monitoring
•Regardless of patient age, progestin therapy with the levonorgestrel
intrauterine device should be considered; contraceptives containing a
combination of estrogen and progesterone also provide effective treatment
•Low-dose combination hormonal contraceptive therapy (20-35 μg ethinyl
estradiol) is the mainstay of treatment for adolescents up to age 18 years
ESSENTIAL UPDATE: NEW ACOG TREATMENT
GUIDELINES FOR ABNORMAL UTERINE BLEEDING
USUAL CAUSES OF BLEEDING
THROUGHOUT A WOMAN’S LIFETIME
• Must rule out Hyperplastic
• Minimum req: ultrasound for
endometrial thickness and
• ENDOMETRIAL SAMPLING
• Unlikely cancerous, Unlikely pelvic
• Treat only when DUB disturbs
life (pt’s wishes, menses TOO
LONG, TOO MUCH, TOO
• Menses at least 3-4x/year
• Ca endometrium
• Use ovulation induction
drugs to prevent
PCOS? FERTILITY ISSUES?