8th Edition APGO Objectives for Medical Students Normal and Abnormal Bleeding

Rationale The occurrence of bleeding at times other than expected menses is a common event. Accurate diagnosis of abnormal uterine bleeding is necessary for appropriate management.

Objectives The student will be able to: Describe endocrinology and physiology of the normal menstrual cycle Distinguish abnormal uterine bleeding from dysfunctional uterine bleeding List causes of abnormal uterine bleeding Evaluate and diagnose abnormal uterine bleeding Describe therapeutic options

Normal Menstrual Cycle Basic functional components Hypothalamic-pituitary unit Ovaries Uterus-endometrium

Normal Menstrual Cycle Normal parameters Cycle interval 28 days + 7 days Duration of menstrual flow - 4-7 days Average blood loss - 30-45 mL Ovulatory bleeding is cyclic and predictable

Normal Menstrual Cycle Follicular phase (days 1-13) Rapid endometrial growth due to stimulation by ovarian estrogen Regeneration in region of glandular stumps Maximum thickness in late follicular phase

Normal Menstrual Cycle Luteal phase (days 14-28) Dependent upon ovulation (day 14) and development of corpus luteum, progesterone production Progesterone inhibits further endometrial thickness Microvasculature becomes well-differentiated (spiral arterioles)

Normal Menstrual Cycle Menstrual phase Fall in progesterone as corpus luteum involutes Vasoconstriction → ischemia and hemorrhage Release of PGF2α Hemostasis Platelet plugs Vasoconstriction Regeneration of functional layer (estrogen stimulation)

Normal Menstrual Cycle Hormonal changes LH peaks day 14 FSH is slightly increased day 14 and day 27-28 Estradiol peaks day 12-13 Progesterone peaks day 18-22, then falls Inhibin increased in luteal phase

Normal Menstrual Cycle Pathways of ovarian steroidogenesis ∆ 4 → Estradiol, testosterone androstenedione ∆ 5 → Dehydroepiandrosterone; Dihydrotestosterone

Abnormal uterine bleeding Definition Excessive flow or prolonged bleeding Frequent bleeding episodes Prolonged intervals between bleeds Organic cause (structural or systemic) vs. hormonal dysfunction

Abnormal uterine bleeding Terminology Hypermenorrhea/menorrhagia Regular bleeding Prolonged bleeding >7 days Excessive bleeding >80 mL Metrorrhagia - irregular bleeding at frequent intervals Polymenorrhea - regular uterine bleeding at intervals <21 days Intermenstrual - bleeding between regular and identifiable periods Oligomenorrhea - bleeding at intervals >40 days

Menorrhagia Affects approximately 15% of adult women Etiology - pathologic conditions Bleeding disorders Leiomyomas Adenomyosis Thyroid dysfunction Chronic endometritis Endometrial polyps or hyperplasia Estrogen-producing tumors Cervical or endometrial cancer Intrauterine device Anovulation (dysfunctional uterine bleeding)

Menorrhagia Laboratory evaluation Urine pregnancy test CBC with platelets EMB (endometrial biopsy) Thyroid functions (TSH) Coagulation studies Pelvic sonography

Menorrhagia Medical management Prostaglandin synthetase inhibitors Combination hormonal contraceptives Progestins Correct medical conditions

Menorrhagia Surgical management D&C - if clinically indicated Myomectomy - if leiomyomata are cause and fertility desired Hysteroscopy with lesion resection Endometrial ablation Hysterectomy

Intermenstrual bleeding Unpredictable Generally associated with structural abnormalities Differential diagnosis Ovulatory (Mittelschmerz) Inflammatory - endometritis Structural Malignancy Leiomyomas Polyps Iatrogenic Oral contraceptives Hormone Replacement Therapy (HRT)

Anovulatory (dysfunctional) uterine bleeding Etiology Obesity Adrenal hyperplasia Polycystic ovary syndrome (PCO) - increased ovarian production of androgens, insulin resistance, chronic anovulation Increased circulating androgens aromatized to E1 (estrone) providing negative feedback to pituitary Low FSH (due to chronic elevation of estrogens) and high LH - static levels do not trigger ovulation

Anovulatory (dysfunctional) uterine bleeding Etiology Obesity Adrenal hyperplasia Polycystic ovary syndrome (PCO) - increased ovarian production of androgens, insulin resistance, chronic anovulation Increased circulating androgens aromatized to E1 (estrone) providing negative feedback to pituitary Low FSH (due to chronic elevation of estrogens) and high LH - static levels do not trigger ovulation

Anovulatory (dysfunctional) uterine bleeding Laboratory evaluation Urine pregnancy test CBC with platelets DHEAS and testosterone, if symptoms of hirsutism Endometrial biopsy (R/O neoplasia) Thyroid stimulating hormone (TSH)

Anovulatory (dysfunctional) uterine bleeding Medical management Combination hormonal contraceptives Progestins (cyclic or continuous) Weight reduction/exercises Metformin

References Buttram VC Jr, Reiter RC. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril 36:433-445, 1981. American College of Obstetricians and Gynecologists Practice Bulletin #16, Surgical Alternatives to Hysterectomy in the Management of Leiomyomas, ACOG: Washington, DC, May 2000. Adapted from Association of Professors of Gynecology and Obstetrics Medical Student Educational Objectives, 7th edition, copyright 1997

Normal and Abnormal Uterine Bleeding Clinical Case Normal and Abnormal Uterine Bleeding

Patient Presentation 41-year-old G2P0020 LMP=10 days ago presents with persistent heavy vaginal bleeding. She denies dizziness, but complains of feeling weak and fatigued. Her cycles have been heavy for a long time, but seem to be worsening over the last several months. Her cycles come every 28-35 days and she bleeds for 7-10 days. She describes bad cramps, passing clots and using 2 boxes of maxi pads each cycle. She is worried about losing her job if the bleeding is not better controlled. She only gets designated break times from the assembly line to use the bathroom. She takes Ibuprofen every 4-6 hours for cramps. She denies any bleeding disorders in the family. She uses condoms for contraception. She also complains of a pressure sensation and increased urinary frequency. Allergies: None; Medications: Ibuprofen as needed

Patient Presentation Ob-Gyn history Menarche 13/cycles 28-35 days/ 7-10 days. Normal pap smears. History of Gonorrhea once and treated 1 elective termination at 16-years-old and 1 miscarriage at 10 weeks, about 2 years ago Past medical history None Past surgical history D & C for miscarriage; tonsils and adenoids as a child Social history Nonsmoker. Occasional alcohol. No drugs. Works at a factory for machine parts assembly. Family history Hypertension in mother and father. Mother had 1 miscarriage and 3 sons. Her brothers are healthy and one has sickle trait. Her paternal grandfather died of lung cancer.

Patient presentation ROS Negative, except as noted above. Physical exam VS: BP=130/88; Pulse= 110; Respirations= 18; Ht=5’6’; Wt=150 pounds African-American women who appears pale and with bags under her eyes HEENT: NC and AT Lungs: clear to auscultation and percussion CV: rapid rate, no murmurs Breasts: Non-tender, no masses, no dimpling, retraction or discharge Abdomen: Non-tender, No hepatomegaly, firm palpable mass in the lower abdomen Extremities: Non-tender, no edema, 2+/= DTRs bilaterally Pelvic exam: Normal external genitalia; moist and pink vagina with rugae and dark blood in the vault; cervix is non-tender, no lesions, and nullipara; uterus is 16 weeks size, firm, mobile, non-tender; adnexae: non-tender, no palpable masses

Patient presentation Laboratory/studies Hbg: 9.0, HCT: 27% HCG: negative TSH: 3.5 uIU/mL (Normal range: 0.4-4.0) Prolactin: 19 ng/dl (Normal range <20) PT/PTT: normal Urinalysis: negative for infection Endometrial biopsy: Proliferative endometrium Pelvic Ultrasound: Multiple myomas (intramural and submucosal in location), Normal ovaries

Diagnoses Menorrhagia Anemia Leiomyomatous uterus Possible anovulation (when her cycles are greater than or equal to 35 days)

Treatment This patient was treated with GnRH analog for three months. Her hemoglobin increased to 12. She had some minor spotting during therapy. She complained of hot flushes and irritability. Her follow-up examination at 2.5 months of therapy showed a decrease in uterine size to 12-14 weeks size. Her repeat ultrasound confirmed these findings. She was counseled regarding medical management with oral contraceptives, progestins or continued GnRH analog with hormonal add-back. Given the presence of submucosal myomas, it is likely that this treatment may not be effective in the long run. However, she has had an optimal response thus far.

Treatment She was also counseled regarding surgical management. If she is interested in maintaining her fertility, her options include: hysteroscopic resection of submucosal myomas only or abdominal myomectomy. If fertility is not desired and she wants a definitive therapy, then a hysterectomy is indicated. Risks and benefits for these medications and surgeries were discussed. This patient is at increased risk for requiring a blood transfusion if the bleeding recurs and is heavy, or if the bleeding is significant during surgery. She will think about her options and decide over the next week.

Teaching points Leiomyomas occur with a high prevalence of 25-50% of women (Buttram and Reiter). They are more common in the African-American population. If this patient did not respond to the gonadotropin agonist therapy and the bleeding worsened, she would have been a candidate for high dose oral contraceptives, high-dose Premarin intravenously or a D&C to control her bleeding. If none of these options were effective, a uterine artery embolization or hypogastric artery ligation could be options prior to hysterectomy. In the near future, other medical therapies may become standard. Currently, gonadotropin-releasing hormone antagonists and progesterone antagonist mifepristone (RU 486) are under investigation. Gene therapies may be developed as we learn more about leiomyoma formation and growth.

Teaching points After a myomectomy, the recurrence rate of leiomyomas ranges from 27-51%. Approximately, 15% require another operative procedure. The incidence of re-operation is increased with multiple myomas (26%) as opposed to a single myoma (11%). It is important to rule out the other differential diagnoses in women with leiomyomas, i.e. pregnancy with possible incomplete abortion or ectopic, thyroid disease, endometrial cancer, etc). These disorders are also present in these women and we cannot assume we have the correct diagnosis unless tested.