Dysfunctional Uterine Bleeding

Diagnosis & Management of Abnormal Uterine Bleeding

Paul H. Taylor, PA- C Department of Gyn/Ob Emory University Atlanta, Georgia

Abnormal uterine bleeding without organic cause. R/O pregnancy, tumor, infection coagulopathy, and pelvic or systemic disease Virtually all women will experience bleeding that she considers abnormal Interference with work, home and sex life; causes emotional, medical, and functional burdens Ineffective management may drain health care and financial resources; however, anemia, missed serious pathology, and even hysterectomy may result

Background
Dysfunctional uterine bleeding (DUB) is the most common cause of abnormal vaginal bleeding during a woman's reproductive years. The diagnosis of DUB should be used only when other organic and structural causes for abnormal vaginal bleeding have been ruled out DUB comprises one third of all out-patient gynecologic visits, is the most common cause of iron-deficiency anemia in the developed world This lecture focuses on understanding the pathophysiology and principles of management

The Menstrual Cycle

A normal menstrual cycle occurs every 23-39 ( average of 29 ) days with menstruation for 2-7 days. Blood loss ranges from 25- 69 mL total, with average being 40 ml. This represents 8 or fewer soaked pads per day with usually no more than 2 heavy days. Loss of 80 ml or more of blood during a cycle is considered excessive

The Menstrual Cycle

The menstrual phase usually lasts 4 days and involves the disintegration and sloughing of the functionalis layer of the endometrium. The proliferation ( follicular) phase extends from day 5 to day 14 of the typical cycle. It is marked by endometrial proliferation brought on by estrogen stimulation. The estrogen is produced by the developing ovarian follicles under the influence of follicle-stimulating hormone (FSH). Cellular proliferation of the endometrium is marked, and the length and convolutedness of the spiral arteries increases. This phase ends as estrogen production peaks, triggering the FSH and luteinizing hormone (LH) surge. Rupture of the ovarian follicle follows, with release of the ovum (ovulation). The secretory (luteal ) phase is marked by production of progesterone and less potent estrogens by the corpus luteum. It extends from day 15 to day 28 of the typical cycle. The functionalis layer of the endometrium increases in thickness, and the stroma becomes edematous. If pregnancy does not occur, the estrogen and progesterone feedback to the hypothalamus, and FSH and LH production falls. The spiral arteries become coiled and have decreased flow. At the end of the cycle, they alternately contract and relax, causing a breakdown of the functionalis layer and menses to begin.

Etiology of DUB
Approximately 90% of DUB results from anovulation, and 10% occur with ovulatory cycles. During an anovulatory cycle, the corpus luteum fails to form, which causes failure of normal cyclical progesterone secretion ( low progesterone levels ). This results in continuous unopposed production of estradiol, stimulating overgrowth of the endometrium. Without progesterone, the endometrium proliferates and eventually outgrows its vascular support, leading to necrosis: conditions such as polycystic ovarian syndrome and obesity stimulate continual growth. Conversely, there may be minimal bleeding if the estrogen level is not high enough to stimulate endometrial growth, as in amenorrhea associated with stress exercise, or weight loss.

Ovulatory DUB
In ovulatory DUB,women have heavy menstrual bleeding, yet no serious cause is found. They have normal levels of progesterone and other hormones. Experts do not fully understand ovulatory dysfunctional bleeding, and what causes it. Ovulatory DUB is thought to be secondary to defects in local hemostasis?

Dysfunctional Bleeding from the Uterus Can be Described as Follows:

Prevalence of Ovulatory DUB

Menorrhagia - Prolonged (>7 d) or excessive (>80 mL daily)

In

the US: As many as 10% of women with normal ovulatory cycles reportedly have experienced DUB. Obese females tend to have irregularities in their menstrual cycles due to nonovarian endogenous production of estrogen often related to their degree of adipose tissue. This usually results in prolonged cycles of amenorrhea that alternate with cycles of metrorrhagia or menometrorrhagia

uterine bleeding occurring at regular intervals Metrorrhagia - Uterine bleeding occurring at irregular and more frequent than normal intervals Menometrorrhagia - Prolonged or excessive uterine bleeding occurring at irregular and more frequent than normal intervals Intermenstrual bleeding (spotting) - Uterine bleeding of variable amounts occurring between regular menstrual periods Polymenorrhea - Uterine bleeding occurring at regular intervals of less than 21 days Oligomenorrhea - Uterine bleeding occurring at intervals of 35 days to 6 months Amenorrhea - No uterine bleeding for 6 months or longer

Estrogen Breakthrough Bleeding

Anovulatory

Estrogen Withdrawal Bleeding

This frequently occurs in women approaching the end of

cycles have no corpus luteal formation. Progesterone is not produced. The endometrium continues to proliferate under the influence of unopposed estrogen. Eventually, this out-of-phase endometrium is shed in an irregular manner that might be prolonged and heavy. This pattern is known as estrogen breakthrough bleeding and occurs in the absence of estrogen decline

reproductive life.
In older women, the mean length of menstrual cycle is

shortened significantly due to aberrant follicular recruitment, resulting in a shortened proliferative phase. Ovarian follicles in these women secrete less estradiol . Fluctuating estradiol levels might lead to insufficient endometrial proliferation with irregular menstrual shedding. This bleeding might be experienced as light, irregular spotting. Eventually, the duration of the luteal phase shortens, and, finally, ovulation stops. Dyssynchronous endometrial histology with irregular menstrual shedding and eventual amenorrhea result

Oral contraceptives, progestin-only preparations, or postmenopausal steroid replacement therapy

Treatment with oral contraceptives, progestin-only preparations, or

Adolescents with DUB

The primary defect in the anovulatory bleeding of adolescents is

postmenopausal steroid replacement therapy might be associated with iatrogenicallyinduced uterine bleeding. Progesterone breakthrough bleeding occurs in the presence of an unfavorably high ratio of progestin to estrogen. Intermittent bleeding of variable duration can occur with progestin only oral contraceptives, depo-medroxyprogesterone , and depolevonorgestrel . Progesterone withdrawal bleeding can occur if the endometrium initially has been primed with endogenous or exogenous estrogen, exposed to progestin, and then withdrawn from progestin . Such a pattern is seen in cyclic hormonal replacement therapy

failure to mount an ovulatory luteinizing hormone (LH) surge in response to rising estradiol levels. Failure occurs secondary to delayed maturation of the hypothalamic-pituitary axis. Because a corpus luteum is not formed, progesterone levels remain low. The existing estrogen primed endometrium does not become secretory. Instead, the endometrium continues to proliferate under the influence of unopposed estrogen. Eventually, this out- of-phase endometrium is shed in an irregular manner that might be prolonged and heavy, such as that seen in estrogen breakthrough bleeding.

Climacteric

Endometrial Cancer

Anovulatory bleeding in menopausal transition is related to declining ovarian follicular function. Estradiol levels will vary with the quality and state of follicular recruitment and growth.

In patients who are 40 years or older, the number and quality of ovarian follicles diminishes. Follicles continue to develop but do not produce enough estrogen in response to FSH to trigger ovulation. The estrogen that is produced usually results in latecycle estrogen breakthrough bleeding

One of the most important goals in work-up of DUB is to rule out endometrial cancer, especially in older women. Development of endometrial cancer is related to estrogen stimulation and endometrial hyperplasia. Bleeding prevalence may be as high as 1/3 of cases, and the presence of uterine myomas should NOT delay appropriate work-up .

Bleeding might be light or heavy depending on the individual cycle response.

Mortality/Morbidity Risk Factors for Endometrial Cancer

Age - 75% of cases occur after menopause

DUB in itself is rarely fatal, distinguishing this presentation from that of endometrial cancer is important. Development of endometrial cancer is related to estrogen stimulation and endometrial hyperplasia . Race: DUB has no predilection for race; however, black women have a higher incidence of leiomyomas and higher levels of estrogen. As a result, they are prone to experiencing more episodes of abnormal vaginal bleeding. Age: DUB is most common at the extreme ages of a woman's reproductive years, either at the beginning or near the end
Most

with peak incidence in the late 60s.

Obesity - especially upper body fat. This may

be secondary to increased estrogen production and bioavailability.

Polycystic ovary disease. Unopposed exogenous estrogen.

When progestins are added (oral contraceptives or with replacement therapy), relative risk is less than for the general population. Diabetes (all types grouped). Personal or family history of ovarian or breast cancer. Women who are overweight and have had breast cancer are at even greater risk. Nulliparity . Late menopause. Tamoxifen therapy - Use for greater than one year is an independent risk factor.

severe cases of DUB occur in adolescent girls during the first 18 months after the onset of menstruation, when their immature hypothalamic-pituitary axis may fail to respond to estrogen and progesterone, resulting in anovulation .
In

the perimenopausal period, DUB may be an early manifestation of ovarian failure causing decreased hormone levels or responsiveness to hormones, thus also leading to anovulatory cycles.

Physcial Exam Findings Physical Examination

Initial
Uterine or ovarian structural abnormalities may be noted on bimanual

evaluation should be directed at assessing patient's volume status and degree of anemia. Examine for pallor and absence of conjunctival vessels to gauge anemia. Patients who are hemodynamically stable require a pelvic speculum and bimanual examination to define the etiology of vaginal bleeding. The examination should look for the following: Trauma to the vaginal walls or cervix Foreign body Cervical or vaginal laceration Bleeding from the os

examination, but a negative examination is insensitive for finding abnormalities.

Patients with hematologic pathology also may have cutaneous

evidence of bleeding diathesis. Physical findings include petechiae, purpura, and mucosal bleeding (eg, gums) in addition to vaginal bleeding.
Patients with liver disease that has resulted in a coagulopathymay

manifest additional symptomatologybecause of abnormal hepatic function. Evaluate patients for spider angioma, palmar erythema, splenomegaly, ascites, jaundice, and asterixis. Women with polycystic ovary disease present with signs of hyperandrogenism, including hirsutism, obesity, and palpable enlarged ovaries.
Hyperactive and hypoactive thyroid can cause menstrual

irregularities. Patients may have varying degrees of characteristic vital sign abnormalities, eye findings, tremors, changes in skin textu re, and weight change. Goiter may be present

Etiology of DUB
thrombocytopenia, hypothyroidism, hyperthyroidism, Cushing disease, liver disease, hypertension, diabetes mellitus, and adrenal disorders
Pregnancy

Causes of Dysfunctional Uterine Bleeding

Infections Endocrine chlamydia Cushing's disease gonorrhea immature hypothalamin -pituitary axis PID Medications hyperprolacinemia hormonal agents hypothyroidism low-dose oral contraceptive pills menopause (OCPs) obesity nonprogestin-containing IUDs polycystic ovary disease nonsteroidal anti -inflammatory premature ovarian failure drugs Stuctural lesions (NSAIDS) adenomyosis Norplant System coagulopathies progestin-only contraceptive condyloma acuminata dysplastic or malignant lesion of the tamoxifen cervix or vagina warfarin endometiosis Pregnancy endometrial cancer ectopic pregnancy uterine or cervical polyps incomplete abortion uterine leiomyomata pregnancy complications trauma

may be associated with vaginal bleeding Trauma to the cervix, vulva, or vagina may cause abnormal bleedi ng. Carcinomas of the vagina, cervix, uterus, and ovaries always mus t be considered Other causes of DUB include structural disorders, such as functi onal ovarian cysts, cervicitis, endometritis, salpingitis , and leiomyomas. Polycystic ovary disease, vaginal infection, polyps, ectopic pregnancy, hydatidiform mole, blood dyscrasias, excessive weight gain, increased exercise performance, or stress may also contribute to DUB. Breakthrough bleeding may occur in patients taking oral contraceptives
The

most common drug interactions with OCPs occur with phenobarbital, carbamazepine, some penicillins, tetracycline, and trimethoprim-sulfamethoxazole.
An iatrogenic

cause of DUB is the use of progestin-only compounds for birth control. Medroxyprogesterone acetate (Depo-Provera), a long -acting injection given every 3 months, inhibits ovulation. Contraceptive intrauterine devices (IUDs) can cause variable vaginal bleeding for the first few cycles after placement and intermittent spotting subsequently. The progesterone impregnated IUD (Mirena) is associated with less menometrorrhagia and usually results in secondary amenorrhea

Differential Diagnosis
Abdominal Trauma,
Hypothyroidism and

Other Problems to be Considered:

Advanced liver disease Anabolic steroids Cervical cancer Cervicitis Cervical polyps Cirrhosis Endometrial cancer Leiomyoma Leukemia Postcoital bleeding Salpingitis Thrombocytopenia Uterine cancer Uterine leiomyomas Vaginal lacerations Von Willebrand disease

Penetrating Abortion, Complete Abortion, Complications Abortion, Incomplete Abortion, Inevitable Abortion, Missed Abortion, Septic Abortion, Threatened Abruptio Placentae Anemia, Acute Anemia, Chronic Endometriosis

Myxedema Coma Idiopathic Thrombocytopenic Purpura Ovarian Cysts Ovarian Torsion Pelvic Inflammatory Disease Pregnancy, Ectopic Pregnancy, Postpartum Hemorrhage Pregnancy, Trauma Shock, Hemorrhagic Shock, Hypovolemic Thrombocytopenic Purpura

Laboratory Tests

Presentation Suggestive of Hyper-androgenism?

urine pregnancy test CBC PT/PTT Pap smear* FSH / LH liver function tests TSH Prolactin level DHEASO4

Rule out pregnancy Anemia? coagulpathy cervical cancer > 40 IU/L menopausal? Liver disease Thyroid disease pituitary adenoma polycystic ovary disease

Dehydroepiandrosterone sulfate

Additional Labs: thyrotropin, free T4, testosterone, 17- OH progesterone, and fasting insulin and glucose Anovulation is most common, which results from a disturbance in the hypothalamic pituitary-ovarian axis. Ovulatory DUB is thought to be secondary to defects in local hemostatis , no disturbance in the HPO axis occurs, nor are there abnormalities in the steroid hormone profiles

Imaging Studies: Ultrasound

Generally, patients with DUB can be managed appropriately

without the use of expensive imaging studies. In obese patients with suboptimal pelvic examination or in patients with suspected ovarian tumors, pelvic ultrasound evaluation might be most helpful. Pelvic ultrasound also might be confirmatory for polycystic ovaries (PCO). The absence of the traditional string of pearls appearanc e does not exclude polycystic ovarian syndrome diagnosis. Confirmation of PCO by imaging is not mandatory for the diagnosis. Ultrasound can be used to examine the status of the endometrium. Endometrial hyperplasia, endometrial carcinoma, endometrial polyps, and uterine fibroids can be identified easily by this technology

Endometrial Biopsy

Risk of endometrial cancer increases with age, ACOG recommends endometrial biopsy in all women > 35 who have a change in bleeding pattern Biopsy is also indicated for patients aged 1835 years with risk factors for endometrial cancer; such as being anovulatory for at least one year

Dilation & Curettage with Hysteroscopy

Treatment
There are medical, surgical, and combined methods of treating DUB. The choice of approach depends on the cause, severity of bleeding, patient's fertility status, need for contraception, and treatment options available at the care site

If contraindications to endometrial sampling

such as acute PID, cervical stricture, or bleeding disorders, or if EMS was inadaquate, or is symptoms continue despite medical management This procedure is expensive and invasive, but is considered the Gold Standard to obtain histopathologic diagnosis Visualize endometrium polyps, lesions, etc It is sometimes avoided in adolescents because of concerns about possible infertility. Repeated procedures may result in intrauterine adhesions.

Treatment Goals
In

women of childbearing age, treatment is aimed at achieving regular menstrual cycles, prevent future episodes, replenish iron stores, prevent serious long term consequences of anovulation, preserve desired fertility. Oral contraceptives or progestogen therapy are frequently used for this purpose. If anemia is present, iron supplementation may be recommended. If pregnancy is desired, ovulation induction may be attempted with medication. Women whose symptoms are severe and resistant to medical therapy may choose surgical treatments including endometrial ablation (a procedure that burns or removes the lining of the uterus) or hysterectomy

Drug Therapy Acute Heavy Bleeding

Cases

Treatment Regimens
Chronic Anovulatory DUB

of acute, heavy, uncontrolled bleeding should be treated with intravenous estrogen, 25mg every 4 hours, to a maximum of 3 doses or until bleeding stops. Oral conjugated estrogen also may be given in divided doses up to 10mg per day, although this regimen often causes nausea and vomiting Oral Contraceptives 3-4 tabs of monophasic pill per day ( 35 mcg EE tab ), in one week one pill per day until pack finished Upon completion, use cyclic OCPs for the following 3-4 cycles for endometrial support

Cyclic Regulation

Oral Medroxyprogesterone 5-10 mg/d x 5- 14 days month Oral Norethindrone acetate 1- 10 mg x 5-14 days per month Oral Norethindrone 5-15 mg/d x 10 days per month Oral micronized progesterone 200-300 mg/d x 10- 12 days per month IM Medroxprogestrone 150mg q 3 months ( monthly? ) Levonorgestrel IUS Combined Oral contraceptives or Transdermal patch Clomiphene 50 mg/d x 5 days

Contraception

Induction of Ovulation

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Treatment Regimens
Chronic Ovulatory DUB / Menorrhagia

Reduction in amount and duration of menstrual flow

Ibuprofen 800 mg Q 8 hr Naproxen sodium 275 mg q 6hr after loading dose of 550 mg Diclofenac, indomethacin, etc.. Mefenamic (Ponstel ) FDA approved for menorrhagia 500 - 1,500 mg/d in divided doses Depo Provera and Mirena I U S

Reduction in menstrual flow and contraception

These drugs are safe for long-term usage, and the long-term effects are well studied. Aspirin does not appear to be effective

In cases of moderately heavy DUB, oral contraceptive pills (OCPs) may be given up to four times a day for 5 to 7 days or until bleeding stops. 2, 3 The rest of the pills may then be taken once a day until the pack is finished and withdrawal bleeding oc curs. In anovulatory patients, this is followed by an additional 2 months of OCPs as usually prescribed. This regimen will stabilize the epithelium, slough excessive build-up, and provide contraception. OCPs may also be started initially at one pill every day in milder cases of DUB.2 - 4, 7 If the patient is already on OCPs and experiencing DUB, a change to a higher estrogen activity OPC is indicated. 3 Medroxyprogesterone (Provera) at 10mg PO per day for 10 to 12 days has traditionally been one of the most common methods used to control DUB. This "medical curettage" works well to correct midcycle spotting and when the EMB demonstrates proliferative endometruim. 1 - 3 Depomedroxyprogesterone (150mg) or progesterone in oil (100 - 200mg) may be given intramuscularly to achieve similar effects. 2, 3 The progestin-only contraceptive pills also work well and, like depo-Provera, have the added benefit of providing contraception. 3 Breast tenderness and mood swings are possible side -effects of therapy. These regimens work especially well with chronic or milder acute DUB. Progestin-containing IUDs, together with oral or transdermal estrogen, may control DUB in postmenopausal patients. 26, 27 Nonsteroidal anti-inflammatory drugs (NSAIDS) can decrease DUB, probably through inihibition of prostaglandin synthesis. 27 Naproxen (Naprosyn ) 500mg twice daily, mefenamic acid (Ponstel) 500mg three times daily, or ethamsylate 500mg four times a day has been shown to decrease menstrual flow. 28 - 30 Once bleeding is controlled, NSAIDS need only be used during menstruation. 27

Endometrial Ablation Refractory to Conventional Treatment

The androgenic synthetic steroid danazol (Danocrine) , which is

Keeping Uterus / Loss of Fertility

Neodymium:yttrium-aluminum-garnet (Nd:YAG) laser endometrial ablation Success rate of approximately 85% and is more effective in patents over the age of 35 years. Amenorrhea may occur in 29% of patients. There is some concern that cancers could be missed, since no tissue is available for pathologic stu dy. Possible risks include fluid overload, endometritis, and uterine perforation. Laser equipment is expensive and requires special safety precautions. Hysteroscopic transcervical resection of the endometrium (TCRE) makes use of an electrocautery loop or ball to remove or coagulate the endometrium to stop DUB. It may reduce the need for hysterectomy by up to 90%, and has been shown to have a lower overall procedure cost (including retreatment costs and eventual hysterectomies) than immediate hysterectomy for more severe DUB. The goal is to ablate the endometrium and encourage endometrial adhesions resulting in hypo-or amenorrhea. The hysteroscope is considerably less expensive to buy and maintain than the las er but carries the risks of fluid overload, endometritis, and uterine perforation. The enometrium may also be hysteroscopicallyablated via the insertion of a thermal uterine balloon. The system consists of a control system attached to a 16cm by 5mm catheter with a latex balloon on the end that houses a heating element. A sterile 5%dextrose solution is instilled until the pressure reaches between 160 and 180mmHg. The solution is heated to 87 degrees C. for 8 minutes and then the device is removed. The treatment has been found to be as efficacious as roller-ball ablation with less complications

traditionally used to treat endometriosis, can be used to treat DUB. Similarly, the GnRH agonists goserelin acetate ( Zoladex ,) leuprolide acetate ( Lupron,) or nafarelin acetate ( Syneral) induce a hypogonadotropic state which stops dysfunctional bleeding. , They all produce hypogonadism and induce ammenorrhea. Because of their side effects, these drugs are used when hormonal methods have failed or are contraindicated. These agents are primarily used to thin the endometrium prior to surgical intervention. Research involving estrogen and progesterone "add back" therapy may provide a means of overcoming the long - and short-term sideeffects. DUB will recur in up to 50% of women treated.

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Hysterectomy
Hysterectomy remains the most absolutely curative treatment for DUB. Elective hysterectomy has a mortality rate of six per 10,000 operations. One randomized study found that hysterectomy was associated with more morbidity and much longer healing times than endometrial ablation. Another recent study found that sexual functioning improved overall after hysterectomy with an increase in sexual activity and a decrease in problems with sexual functioning.

Summary DUB

There is a wide range of normal menstruation during the reproductive years, this fact alone may alleviate stress and unnecessary visits to Gyn Educating the patient about underlying causes of DUB and the rational for treatment is a challenge The majority of DUB is anovulatory

Hyper- estrogen states increase the risk of developing endometrial cancer

Women of all ages should be assessed for endometrial carcinoma risk factors and educated appropriately

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