Roziana Ramli MD, Mmed(OBGYN)

HSNZ

•Estrogen causes increased blood flow to the endometrium

•Normal menses results from fluctuations in the circulating levels of estrogen and progesterone.

NORMAL MENSES• 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

CHARACTERISTICS OF NORMAL MENSES

NORMAL MENSTRUATION• Life Cycle

• Menarche

• 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)

• Characteristics• 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

DUB

• Two types: anovulatory and ovulatory

• Most women with DUB do not ovulate (ANOVULATION)• 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

• Anovulatory cycles:

• NO corpus luteum, therefore NO progesterone

• UNOPPOSED estrogen causes continuous endometrial proliferation

• endometrium may then OUTGROW its blood supply resulting in areas of necrosis

• 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

OVULATORY DUB• DUB without any attributable anatomic, organic, or

systemic cause BUT associated with regular ovulation (uncommon)

• Regular withdrawal menses every 24-35 days—BUT excessive blood loss

• Loss of local endometrial hemostasis• Ratio of PGE2 : PGF2

• Level of PGI2• Fibrinolytic activity

•

SO WHAT??

• (Too MUCH): Ward admission, fluid management, transfusion, Rx

• (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,

WHAT DO WE DO NEXT??

PHYSICAL EXAMINATION•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 clinical history

• Rule out uterine fibroids or polyps

• Rule out endometrial hyperplasia or carcinoma

PHYSICAL EXAMINATION

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

• Ultrasound

• Women in menopausal transition usually can be followed without an extensive hormonal evaluation.

HOW TO TREAT DUB?

• NSAID’s

• estrogens, progestins, or both

• antifibrinolytic agents

• GnRH agonists

TREATMENT OF DUB

Medical management Surgical management

• Ablative therapy

• Endometrial resection

• Hysterectomy

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

OR

• 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

ANTI-FIBRINOLYTICS

• 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

PROGESTINS• 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

• 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.

PROGESTINS

• 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 deficiency.

• Also, patients with thin, denuded endometrium occurring after several days of chronic bleeding might require induction of new endometrial proliferation by estrogen therapy first.

PROGESTIN

• Recurrent bleeding episodes

• Progesterone releasing IUD (Levonorgestrel IUD)

• 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

COCP• 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 control DUB.

COCP

• 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 very effective.

• 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 DUB

• Used for relief of mild to moderate pain.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

GNRH AGONISTS

• 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 MANAGEMENT•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.

SURGICAL MANAGEMENT

• 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

• HYSTERECTOMY

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 hormone therapy

•If medical therapy fails, patients should undergo further testing (eg, imaging or hysteroscopy)

•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 the endometrium

•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 Endometrium/Ca

• Minimum req: ultrasound for endometrial thickness and pelvic pathology

• ENDOMETRIAL SAMPLING

• Unlikely cancerous, Unlikely pelvic pathology related

• Treat only when DUB disturbs life (pt’s wishes, menses TOO LONG, TOO MUCH, TOO FREQUENT)

• REASSURANCE

TAKE HOME

Adolescent Older adult

• Reassure:

• Menses at least 3-4x/year

• Counsel:

• Fertility

• DM,IHD

• Ca endometrium

• Use ovulation induction drugs to prevent anovulation

PCOS? FERTILITY ISSUES?

THANK YOU ….