Symposium on Menstrual Disorders

Educational Objectives

The goals of this program are to improve the management of menorrhagia, dysfunctional uterine bleeding (DUB), and other common menstrual disorders in adolescents. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the hormonal changes in puberty that lead to menarche, and the characteristics of normal menarche and menstrual cycles in young women.

2.   List possible causes of abnormal bleeding in adolescents.

3.   Perform an effective work-up of the patient who presents with signs of menorrhagia or DUB.

4.   Evaluate and treat common menstrual problems, including dysmenorrhea, premenstrual syndrome, premen­strual dysphoric disorder, and amenorrhea.

5.   Discuss the relationships between athletics, eating disorders, and menses.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of in­terest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Simms-Cendan spoke at 25th Annual Care of the Sick Child Conference, held November 12-15, 2008, in Orlando, FL, and sponsored by Orlando Health, the Arnold Palmer Hospital for Children, and the College of Medicine, Florida State University. Dr. Neinstein was recorded at 50th Annual Pediatrics Symposium, held October 31 to November 2, 2008, in Palm Springs, CA, and sponsored by Kaiser Permanente. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Menorrhagia and Dysfunctional Uterine Bleeding in Adolescents 

  Judith Simms-Cendan, MD, Clinical Associate Professor, Department of Obstetrics and Gynecology, Univer­sity of Florida College of Medicine, Gainesville

Hormonal changes leading to menarche: multiple factors stimulate higher cortical and limbic systems to trigger pulsatile release of gonadotropin-releasing hormone (GnRH) from hypothalamus; GnRH binds to anterior pituitary gonadotrophs and stimulates release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which cause maturation of germinal epithelium and regulate sex steroid production

Menstrual physiology: chain of events  —  generation of FSH; FSH generates production of estrogen; estrogen causes formation of dominant follicle and leads to buildup of endometrial lining; when sufficient estrogen level reached, surge of LH triggered, which results in ovulation, formation of corpus luteum cyst, production of progesterone and more estrogen, and stabilization of endometrium; if no conception, estrogen and progesterone levels decline and lining shed; cycle restarts

Normal menarche: 95% of girls menstruate before 14 yr of age; evaluate for primary amenorrhea when  —  menses have not started within 3 yr of thelarche or by 15 yr of age; signs of polycystic ovary syndrome (PCOS), eating dis­order or excessive exercise present, or congenital anomaly suspected

Normal menstrual cycles in young girls: menses may be irregular during first 2 yr after menarche, but 90% of girls have cycles of 21 to 42 days; length of flow should be 2 to 8 days; interval between menarche and establishment of regular cycles »14 mo; girl should use £3 to 6 tampons or pads per day; indications for evaluation  —  cycles <21 days or >45 days; cycles initially regular but become irregular; flow lasting >7 days; excessively heavy flow (re­quiring change of pad every 1-2 hr)

Causes of abnormal bleeding in adolescents: gynecologic  —anovulation (due to immaturity of hypothalamic-pitu­itary-ovarian (HPO) axis; PCOS); pregnancy; molar pregnancy; infections; neoplasms (rare); trauma; nongynecologic  —coagulation disorders; systemic disease; iatrogenic causes

Abnormal bleeding from anovulation: in immature HPO axis, pituitary may fail to suppress FSH production; im­paired negative feedback results in continued stimulation of estrogen production, which leads to dilation of spiral arterioles and abnormal endometrial height without structural support; this causes spontaneous superficial shedding of endometrium, which in turn causes random asynchronous bleeding; persistent estrogen elevation eventually re­sults in decrease in FSH, which causes collapse of thickened hyperplastic epithelium and profuse bleeding

Abnormal uterine bleeding (AUB) and Chlamydia trachomatis: rates of chlamydial infection increasing (highest in southern United States and in girls 15-19 yr of age); in 70% of cases, progression from lower genital tract to as­ymptomatic upper genital tract infection seen; recent study of endometrial biopsy specimens of women with AUB detected C trachomatis in »50% of samples

Comments: von Willebrand disease (vWD)  —  most common inherited bleeding disorder (occurs in »1% of popula­tion); 3 types; other platelet function disorders  —  Bernard-Soulier syndrome; Glanzmann’s thrombasthenia

Platelet function assay (PFA): determines time to aggregation; normal results 117 to 209 sec; if aggregation time longer, test with  —  ristocetin to detect type 1 vWD or Bernard-Soulier syndrome; epinephrine (detects abnormality due to excessive use of aspirin or nonsteroidal anti-inflammatory drugs [NSAIDs]); adenosine diphospate to detect Glanzmann’s thrombasthenia; 2005 study  —  looked at prevalence of bleeding disorders in women with menorrha­gia; 44% of subjects <19 yr of age had abnormal PFA and 48% overall had detectable hemostatic abnormality (re­sults support role of PFA in evaluation of adolescents with menorrhagia)

Acute adolescent menorrhagia: in 1981 study looking at 59 adolescents admitted for menorrhagia, 20% had pri­mary coagulation disorder; 50% of patients who presented at menarche and 33% of those requiring transfusion had underlying coagulation disorder

Patient #1: 13-yr-old girl; bleeding 21 days/mo for past 6 mo; complains of daily headaches and fatigue; menarche at 12 yr of age; menses always irregular; no history of bleeding after surgery; never sexually active; no past medical history; family history unremarkable

Work-up: physical examination (PE)  —  document Tanner staging, height, and weight; examine for bruising; defer pelvic examination unless patient complains of pain; if patient complains of pain, order ultrasonography (US); lab­oratory studies  —thyrotropin (TSH) test; complete blood count (CBC) with platelets; consider urine tests for Neis­seria gonorrhoeae and C trachomatis if infection suspected; order bleeding studies if hemoglobin (Hb) <10 g/dL; bleeding studies must be done before starting hormonal therapy; if hirsuitism, acne, obesity, or acanthosis present, PCOS work-up required

Treatment of anovulatory bleeding: mild to moderate symptoms  —  start combination oral contraceptives (OCs) with first generation progesterone (eg, ethinyl estradiol plus levonorgestrel or norgestrel [eg, Lo/Ovral]); counsel patient that first menses on OCs will be heavy; use iron supplements for first 2 mo; continue OCs for ³6 mo; add mefenamic acid (Ponstel; older NSAID) to help reduce bleeding; heavy bleeding in hemodynamically stable patient  —  start combination OC 4 times/day for 3 days, then 3 times/day for 3 days, then 2 times/day for 3 days; if breakthrough bleeding occurs when weaned to once daily, maintain at twice daily for 21 days; allow bleeding, then restart OCs; continue for ³6 mo

Treatment in patients with contraindications to estrogens: options include cyclic oral medroxyprogesterone ace­tate (MPA) 20 mg/day for days 14 to 28 of cycle (difficult for patients to follow regimen correctly); use continuous oral MPA to create amenorrhea (side effects include weight gain, mood changes, and headaches); norethindrone (Aygestin; can give 15 mg/day continuously or cyclically; much better tolerated than progesterone); avoid depo-MPA (eg, Depo-Provera) in cases of abnormal bleeding (can cause bleeding)

Treatment of severe anovulatory bleeding: hospitalize if Hb <9 g/dL, or patient hemodynamically unstable or ac­tively bleeding heavily; volume expand with crystalloid; give intravenous (IV) conjugated estrogen (eg, Premarin) »25 mg every 4 hr for 4 to 6 doses; switch to OCs when bleeding stops; continue for ³6 mo

Patient #2: 14-yr-old girl presents to emergency department (ED) bleeding heavily (changes pad hourly); periods heavy since menarche; bled for 3 hr after tooth extraction

ED evaluation: PE  —  document orthostatic blood pressure and pulse; check for easy bruising; do pelvic examination as tolerated; order US; laboratory studies  —  Hb; platelets; prothrombin time; partial thromboplastin time; PFA; vWD panel (if PFA abnormal)

Treatment of acute menorrhagia: IV estrogen  —  critical; has hemostatic effect on endothelial cells; increases circu­lating factors VIII, VII, and fibrinogen; aminocaproic acid (Amicar)  —  inhibitor of fibrinolysis; oral and IV forms available; dilation and curettage  —  last resort

Management of menses in patient with type 1 vWD: maintain on continuous combination OCs; desmopressin (DDAVP)— give on first 3 days of cycle; stimulates endogenous release of von Willebrand factor; designated or­phan drug by Food and Drug Administration (FDA) for treatment of type 1 vWF; give therapeutic challenge to de­termine whether patient is responder; can be combined with Amicar; use DDAVP nasal spray (eg, Stimate) in 150 µg/0.1-mL dose

Levonorgestrel-releasing intrauterine system (Mirena): use in adolescents slightly controversial, but approved by American College of Obstetricians and Gynecologists (ACOG); can be used in patients with heavy bleeding; risk for pelvic inflammatory disease increases only if patient has active bacterial infection at time of insertion; associ­ated with greater reduction in menstrual blood loss than antifibrinolytics, OCs, or NSAIDs

Prevention of severe menorrhagia in oncology patients: 2006 study of depo-MPA vs GnRH agonist (leuprolide [eg, Lupron]) in young female patients on chemotherapy; 0% incidence of severe or moderate menorrhagia seen in leuprolide group; also some early data indicating that leuprolide use in these patients can protect fertility

Diagnosis and Treatment of Common Menstrual Disorders in Adolescents

Lawrence S. Neinstein, MD, Professor of Pediatrics and Medicine and Chief, Division of College Health, Keck School of Medicine, University of Southern California; Executive Director, USC University Park Health Center, Los Angeles

Normal growth and development in puberty: in 66% of adolescent girls, menarche is late pubertal event, occurring at sexual maturity rating (SMR) of 4; peak height velocity (PHV) is early event; girl who has passed PHV and men­arche and remains below average height unlikely to have significant further growth; conversely, 15-yr-old girl with normal development and SMR of 3 has high likelihood of reaching menarche in next 6 to 12 mo; in first 6 to 18 mo after menarche, menses may occur more frequently; subsequently, regulatory ovulatory cycles occur with increased production of FSH (stimulates follicular development); follicles secrete estrogen, which causes endometrium to be­come proliferative; positive feedback from FSH levels leads to ovulation; corpus luteum produces estrogen and progesterone; endometrium becomes secretory; prostaglandins produced, some of which aid in vasoconstriction and myometrial contractility (stop uterine bleeding during menstrual cycles); without ovulatory cycles, progester­one and prostaglandins not produced; menstrual cycle likely to be longer, but less painful (because dysmenorrhea caused and exacerbated by vasoconstriction and myometrial contractility)

Dysmenorrhea: most common menstrual disorder; typically presents with spasmodic cramping lower abdominal pain; »50% have systemic symptoms (nausea and vomiting, dizziness, diarrhea, and headaches); evaluation  —  patient history (should include sexual activity and sexually transmitted diseases (STDs); menstrual history; contra­ception; review of systems; medications tried and used; family myths about menarche and menses; PE (Papanico­laou [Pap] test recommended 3 yr after onset of sexual activity; pelvic examination not indicated in adolescent unless STD  suspected); treatment  —  reassurance and education about physiology and cause of symptoms; if con­traception needed or dysmenorrhea severe and refractory, ovulation can be inhibited with OCs; analgesics (particu­larly NSAIDs [eg, naproxen, ibuprofen]) effective

Premenstrual syndrome (PMS): tends to occur in slightly older group than dysmenorrhea; many presentations (eg, edematous changes, swelling of breasts, abdominal distention, emotional symptoms [depression, irritability], con­stipation, headaches, changes in appetite); theories about causation  —  hormonal changes; neurotransmitter changes; vitamin deficiencies; alterations in metabolism; pharmacologic approaches  —  pyridoxine (vitamin B₆); nontoxic in doses of 50 to 100 mg per day; ³200 mg can cause peripheral neuropathy; diuretics if edema present; NSAIDs; OCs (especially drosperinone and ethinyl estradiol [YAZ]); cyclic progesterone; fluoxetine (particularly for irritability or mental health issues); nonpharmacologic treatments  —  stress reduction; exercise; reduction of al­cohol intake; diet

Premenstrual dysphoric disorder: psychiatric terminology; diagnosis requires  —  presence of ³5 characteristic symptoms (including 1 of 4 mental health symptoms) during last week of luteal phase; pattern of symptoms persist­ing for most of past 12 mo; symptoms usually disappear after onset of menses and occur at or soon after ovulation; more severe than PMS

Evaluation of dysfunctional uterine bleeding (DUB): menstrual history  —  ask about changes in frequency of pad changes or type of protection (eg, regular vs super) needed; accidental breakthroughs or floodings

AUB vs DUB: different by strict definition; DUB due to anovulatory cycles; causes of AUB  —  complications of preg­nancy; local pathology (rare cause of heavy bleeding in adolescents); systemic disease (more common, particularly in hospitalized patients with AUB or DUB); iatrogenic (OCs [occasionally], many tranquilizers, and intrauterine devices)

Treatment of DUB: nonsevere  —  MPA alone for 7 to 10 days or combination OCs for 1 to 2 mo (can start with 2-4 pills/day and taper to 1 pill/day, if necessary); recurrent  —  cycle patient on MPA or OCs; severe  —  give IV conju­gated estrogens and start OCs at same time; recent study comparing results of treatments reported more success with combination OCs or sequential therapy than with progesterone (norethindrone) alone, and found that recurrent DUB slightly less common with sequential therapies than with combination OCs; studies show that treatment with NSAIDs decreases menstrual blood loss (due to suppression of prostaglandins)

Amenorrhea: secondary amenorrhea most common, especially amenorrhea associated with involvement in athletics; assuming patient not pregnant, hirsute or virilized, or cushingoid, and does not have galactorrhea (which requires appropriate work-up), can give MPA and attempt to induce withdrawal bleeding; if successful, uterus intact and ovaries producing estrogen; if patient does not bleed, get FSH level (if high, ovarian problem indicated; if normal or low, central nervous system work-up required)

Amenorrhea in athletes: girls involved in intense athletic training and activity at early age who have low percentage body fat at much higher risk for menstrual disorders, particularly amenorrhea; intensity of training and low body weight synergistic (eg, women who weigh <60 kg or run >60 miles/wk have »60% incidence); consequences of low body weight  —studies have shown that runners with amenorrhea have significantly lower spine density than runners with regular periods and »50% incidence of stress fractures (vs almost 0% in runners with regular cycles); eating disorders  —  compound problems of bone density; study of competitive women athletes found 32% engaged in ³1 eating disorder behavior daily for ³1 mo; other factors  —neurotransmitters and stress believed to be involved; summary  —  must evaluate these patients for organic etiology; weight changes seem to be additive with exercise; amenorrhea reversible with decrease in exercise; no reason to avoid exercise during menses; patient should increase calcium intake; if patient estrogen-depleted, prescribe estrogen replacement (eg, OCs)

Suggested Reading

Claessens EA, Cowell CA: Acute adolescent menorrhagia. Am J Obstet Gynecol 139:277, 1981; Frishman GN: Evaluation and treatment of menorrhagia in an adolescent population. J Minim Invasive Gynecol 15:682, 2008; Gold MA, Johnson LM: Intra­uterine devices and adolescents. Curr Opin Obstet Gynecol 20:464, 2008; Golden NH, Carlson JL: The pathophysiology of amenorrhea in the adolescent. Ann N Y Acad Sci 1135:163, 2008; Goodman LR, Warren MP: The female athlete and menstrual function. Curr Opin Obstet Gynecol 17:466, 2005; Grover S: Bleeding disorders and heavy menses in adolescents. Curr Opin Obstet Gynecol 19:415, 2007; Harel Z: Dysmenorrhea in adolescents and young adults: from pathophysiology to pharmacologi­cal treatments and management strategies. Expert Opin Pharmacother 9:2661, 2008; James AH: Bleeding disorders in adoles­cents. Obstet Gynecol Clin North Am 36:153, 2009; Kulp JL et al: Screening for coagulation disorders in adolescents with abnormal uterine bleeding. J Pediatr Adolesc Gynecol 21:27, 2008; Meirow D et al: Prevention of severe menorrhagia in oncol­ogy patients with treatment-induced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxypro­gesterone acetate. Cancer 107:1634, 2006; Philipp CS et al: Age and the prevalence of bleeding disorders in women with menorrhagia. Obstet Gynecol 105:61, 2005; Rapkin AJ: YAZ in the treatment of premenstrual dysphoric disorder. J Reprod Med 53:729, 2008; Rapkin AJ, Mikacich JA: Premenstrual syndrome and premenstrual dysphoric disorder in adolescents. Curr Opin Obstet Gynecol 20:455, 2008; Rodeghiero F: Management of menorrhagia in women with inherited bleeding disorders: general principles and use of desmopressin. Haemophilia 14 Suppl 1:21, 2008; Sanfilippo J, Erb T: Evaluation and management of dys­menorrhea in adolescents. Clin Obstet Gynecol 51:257, 2008; Toth M et al: Association between Chlamydia trachomatis and ab­normal uterine bleeding. Am J Reprod Immunol 57:361, 2007; Vercellini P et al: The role of the levonorgestrel-releasing intrauterine device in the management of symptomatic endometriosis. Curr Opin Obstet Gynecol 17:359, 2005; Warren MP, Chua AT: Exercise-induced amenorrhea and bone health in the adolescent athlete. Ann N Y Acad Sci 1135:244, 2008.