AUTHOR INFORMATION

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Authored by Latha Chandran, MD, MPH, Associate Professor of Pediatrics, Associate Dean for Academic Affairs, Director, Division of General Pediatrics, State University of New York at Stony Brook School of Medicine

Latha Chandran, MD, MPH, is a member of the following medical societies: American Academy of Pediatrics

Edited by Elizabeth M Alderman, MD, Clinical Professor of Pediatrics, Albert Einstein College of Medicine, Yeshiva University; Consulting Staff, Montefiore Medical Center, Director of Fellowship Training, Division of Adolescent Medicine, Albert Einstein College of Medicine, Children's Hospital at Montefiore; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Wayne Wolfram, MD, MPH, Clinical Associate Professor, Departments of Pediatrics, Children's Hospital and University of Cincinnati; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Maureen Strafford, MD, Arnold P Gold Foundation Associate Professor, Departments of Anesthesiology and Pediatrics, Tufts University and Tufts-New England Medical Center

Author's Email:	Latha Chandran, MD, MPH
Editor's Email:	Elizabeth M Alderman, MD

eMedicine Journal, March 30 2006, VOLUME 7, Number 3

INTRODUCTION

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Background: Menstruation disorders are a common problem during adolescence. These disorders may cause significant anxiety for patients and their families. Physical and psychological factors contribute to the problem. In order to treat menstruation disorders, it is important to become familiar with the normal menstrual cycle.

For a regular menstrual cycle, the median age of menarche is 12.77 years. The average interval between thelarche and menarche is about 2 years, and 90% of females menstruate by the time they have Tanner IV breast and pubic hair development. Most cycles occur between 21-35 days with 3-10 days of bleeding and 30-40 mL of blood loss. Anovulatory cycles and irregular menstrual patterns are common within 24 months of menarche.

Classification of menstrual disorders

Amenorrhea and oligomenorrhea (lack of bleeding or too little bleeding)

Dysmenorrhea (painful menstruation)

Menorrhagia (excessive bleeding)

Amenorrhea

Amenorrhea may be primary (ie, never menstruated) or secondary (ie, menarche, but no periods for 3 consecutive months). Primary amenorrhea is the absence of menstruation by age 16 years in the presence of normal pubertal development or by age 14 years in the absence of normal pubertal development. Evaluating for breast and uterine development in patients with a menstruation disorder is important. Secondary amenorrhea is more common than primary amenorrhea. The most common etiology is dysfunction of the hypothalamic-pituitary-ovarian (HPO) axis.

Dysmenorrhea

Dysmenorrhea is a very common complaint and may be primary or secondary, though primary dysmenorrhea is more prevalent. Symptoms include crampy lower abdominal and pelvic pain radiating to the thighs and back without associated pelvic pathology. Dysmenorrhea is caused by prostaglandins during ovulatory cycles. Endometrial prostaglandin levels increase during the luteal and menstrual phases of the cycle, causing uterine contractions. Secondary dysmenorrhea is rare, and pain is associated with pelvic pathology (eg, bicornuate uterus, endometriosis, pelvic inflammatory disease, uterine fibroids).

Menorrhagia

Menstrual bleeding lasting more than 8-10 days and with blood loss of over 80 mL is considered excessive.

Pathophysiology:

Hormonal changes in the normal menstrual cycle

In the ovulatory cycle, the hypothalamus secretes gonadotrophin-releasing hormone (GnRH), which stimulates the pituitary to release follicle-stimulating hormone (FSH). This, in turn, causes an ovarian follicle to grow and mature. In mid cycle, a surge of luteinizing hormone (LH) occurs with a FSH surge resulting in ovulation. The developing follicle produces estrogen, which stimulates the endometrium to proliferate. After the ovum is released, FSH and LH levels fall, corpus luteum develops at the site of the ruptured follicle, and progesterone is secreted from the ovary. Progesterone causes the proliferating endometrium to differentiate and stabilize. Fourteen days after ovulation, menstruation results from endometrial shedding secondary to the rapid decline in the levels of estrogen and progesterone from the involuting corpus luteum.

Hormonal changes during anovulatory cycles

Anovulatory cycles are common in the first 2 years after menarche because of the immaturity of the HPO axis. They also can occur in a variety of pathological conditions.

In anovulatory cycles, the follicular growth occurs with the stimulation from FSH; however, due to lack of LH surge, ovulation fails to occur. Consequently, no corpus luteum is formed and no progesterone is secreted. The endometrium continues its proliferative phase excessively. When the follicle involutes, estrogen levels drop and estrogen withdrawal bleeding occurs. Most anovulatory cycles are regular with normal bleeding; however, the unstable proliferative endometrium can shed irregularly, resulting in prolonged heavy bleeding.

CLINICAL

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History:

• Amenorrhea


• • Detailed history of pubertal development
  
  
  
  • Family history of menarche, pubertal development
  
  
  
  • History of weight loss, stress, exercise
  
  
  
  • Detailed dietary history
  
  
  
  • History of contraception, medications
  
  
  
  • History suggestive of CNS disease (eg, headaches, visual changes)
  
  
  
  • History of chronic illnesses (eg, Crohn disease)
  
  
  
• Dysmenorrhea


• • Evaluation should include a detailed menstrual history and the relationship of the pain to the menstrual cycle.
  
  
  
  • Ask about a family history of endometriosis.
  
  
  
  • Ascertain the degree of incapacitation. If pain is mild and physical examination is normal, a pelvic examination is not indicated. If pain is severe and interferes with daily living, a pelvic examination is warranted. If a patient is sexually active, a pelvic examination is mandatory. Be suspicious of secondary dysmenorrhea if onset of dysmenorrhea occurs at menarche.
  
  
  
• Menorrhagia



• Date of menarche



• Menstrual calendar (invaluable)

• Sexual activity



• Use of hormones, such as oral contraceptive pills or depo-medroxyprogesterone acetate, and use of other medications such as Coumadin, aspirin



• Chronic illnesses



• Bleeding disorders, including family and personal history



• CNS symptoms



• Acne, hirsutism

Physical:

• Amenorrhea


• • Height, weight, and growth charts
  
  
  
  • Breast development, pubic hair
  
  
  
  • Syndromic appearance (eg, short stature, webbed neck)
  
  
  
  • Visual fields, thorough neurologic examination, optic fundi
  
  
  
  • Evidence of hyperandrogenism (eg, acne, hirsutism, clitoromegaly)
  
  
  
  • Evidence of thyroid disease
  
  
  
  • Evidence of chronic illnesses
  
  
  
  • Evidence of pregnancy
  
  
  
• Menorrhagia



• Growth percentiles



• Palpation of thyroid



• Breast examination for galactorrhea



• Evidence of bleeding elsewhere



• Pelvic examination, if sexually active

Causes:

• Primary amenorrhea with absent breast development and present uterus


• • Constitutional delay of puberty

  • Hypothalamic dysfunction (eg, stress, anorexia, chronic illness, exercise)

  • Pituitary failure

  • Gonadal failure

  • Gonadal dysgenesis (eg, Turner syndrome, Swyer syndrome)

  • Gonadotrophin deficiency (eg, Kallmann syndrome)
  
  
  
• Primary amenorrhea with breast development and present uterus


• • Hyperandrogenic amenorrhea

  • Hypothalamic amenorrhea

  • Hypothyroidism

  • Hyperprolactinemia

  • Outflow tract obstructions (eg, imperforate hymen, vaginal atresia)
  
  
  
• Primary amenorrhea with breast development and absent uterus



• Müllerian agenesis

• Androgen insensitivity



• Menorrhagia



• Anovulatory dysfunctional uterine bleeding (DUB)



• Immature HPO axis, adolescent DUB



• Hyperandrogenic chronic anovulation (eg, polycystic ovarian syndrome, adrenal hyperplasia)



• Pregnancy-related complications



• Sexually transmitted diseases



• Chronic illnesses



• Blood dyscrasia



• Trauma



• Drugs



• Endocrine disorders



• Neoplasms

DIFFERENTIALS

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Other Problems to be Considered:

Secondary amenorrhea and oligomenorrhea

Pregnancy
Hormonal contraception
Hypothalamic causes (eg, stress, exercise, eating disorder, chronic illness, drugs, tumor, obesity syndromes)
Pituitary causes (eg, hypopituitarism, tumor, infiltration, infarction)
Ovarian causes (eg, premature ovarian failure)
Androgen excess (eg, polycystic ovarian disease, adrenal hyperplasia, adrenal or ovarian tumor)
Other endocrine causes (eg, thyroid disease, Cushing disease)

WORKUP

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Lab Studies:

• Amenorrhea


• • Workup depends on patient history and physical findings.
  
  
  
  • No studies are necessary for constitutional growth delay.
  
  
  
  • Obtain a karyotype if the patient is syndromic or has evidence of ovarian failure.
  
  
  
  • Obtain serum FSH levels. Differentiating central from peripheral causes is important. High levels of FSH indicate ovarian failure or gonadal dysgenesis; low levels indicate hypothalamic or pituitary causes.
  
  
  
  • Obtain a bone age in primary amenorrhea.
  
  
  
  • Obtain a serum prolactin level.
  
  
  
  • Obtain thyroid function tests.
  
  
  
  • Obtain urine beta-human chorionic gonadotropin levels. This is mandatory for secondary amenorrhea.
  
  
  
• For secondary amenorrhea, consider testing serum LH, serum testosterone, dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone, and serum cortisol.



• Menorrhagia



• Test for gonorrhea and chlamydia if patient is sexually active.



• Obtain a urine pregnancy test.



• Obtain a CBC with reticulocyte count.



• Obtain coagulation studies.



• Obtain a blood type and cross-match in very severe cases.



• Also consider testing for thyroid-stimulating hormone (TSH) level, FSH level, serum prolactin, and serum androgens if clinical evidence of hyperandrogenism is present.

Imaging Studies:

• Amenorrhea


• • Consider MRI of the head if CNS symptoms or hyperprolactinemia are present.
  
  
  
  • Consider pelvic ultrasound if absent uterus or structural anomalies are suspected.
  
  
  
• Dysmenorrhea: Ultrasonography and MRI may be helpful if secondary cause of dysmenorrhea is suspected.



• Menorrhagia: Consider a pelvic ultrasound if a mass or structural anomaly is suspected.

TREATMENT

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Medical Care:

• Amenorrhea


• • Treatment depends on etiology. Direct therapy to the underlying cause.

  • If the patient has a completely normal physical examination with secondary amenorrhea, consider administering medroxyprogesterone 10 mg daily for 5-10 days to see if withdrawal bleeding occurs. If this occurs, it indicates adequate levels of endogenous estrogen and normal anatomy.
  
  
  
• Dysmenorrhea



• Provide symptomatic relief with nonsteroidal anti-inflammatory drugs (eg, naproxen, ibuprofen) at the first sign of cramps.

• If nonsteroidal anti-inflammatory therapy fails, consider oral contraceptive pills for 3-6 months.



• Menorrhagia



• Most cases of menorrhagia fall under the category of DUB. In situations where a specific etiology is identified, treatment of the underlying cause is necessary.

• For patients with mild DUB, provide reassurance and observation. Instruct the patient to keep a menstrual calendar. Consider iron supplementation and antiprostaglandin medications during bleeding episodes.

• For patients with moderate DUB, prescribe combination oral contraceptive pills beginning with 4 monophasic 45-microgram pills a day and tapering down. Oral contraceptive pills usually are continued for 6 months. Medroxyprogesterone alone also may be used. Also administer oral iron and folic acid supplements.

• For patients with severe DUB, consider hospitalization and coagulation studies. Administer intravenous Premarin every 4 hours until the bleeding stops, up to 4 doses. Simultaneously administer a monophasic 35-microgram oral contraceptive pill q6h for 24-48 hours and then bid to complete a 28-day course. If Premarin does not stop bleeding after 4 doses, consider pelvic pathology. Examination under anesthesia and dilatation and curettage may be necessary.

MEDICATION

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Medications used in the management of menstrual disorders depend on the type of disorder and the etiology of the disorder.

Drug Category: Hormones -- In patients with secondary amenorrhea who have a completely normal physical examination, medroxyprogesterone can be used to diagnose anovulation as the cause of amenorrhea (progesterone challenge test). Estrogens are effective in controlling acute, profuse bleeding. Estrogen also induces formation of progesterone receptors, making subsequent treatment with progestins more effective.

Drug Name	Medroxyprogesterone (Provera, Cycrin) -- Short-acting synthetic progestin. Progestin therapy in adolescents produces regular cyclic withdrawal bleeding until maturity of positive feedback system is achieved. Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. Typically does not stop acute bleeding episode but produces a normal bleeding episode following withdrawal.
Adult Dose	10 mg PO qd for 5-10 d
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; cerebral apoplexy, undiagnosed vaginal bleeding, thrombophlebitis, and liver dysfunction
Interactions	Aminoglutethimide increases hepatic metabolism of medroxyprogesterone
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in asthma, depression, renal or cardiac dysfunction, or thromboembolic disorders

Drug Name	Ethinyl estradiol and a progestin derivative (Ovral, Ortho-Novum, Ovcon, Genora) -- Combination pills of estrogen and progesterone in varying doses are used in the management of DUB. 21-day or 28-day cycles are used. Reduces secretion of LH and FSH from pituitary by decreasing amount of GnRH
Adult Dose	Dysmenorrhea: 21-day cycle: 1 tab PO qd for 21 d, do not take tablets for 7 d then resume 28-day cycle: 1 tab PO qd; last 7 tabs in cycle are placebo to help maintain compliance Menorrhagia, moderate: Initiate with 4 monophasic 45-mcg tab PO qid on day 1, then taper downward
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; thrombophlebitis, undiagnosed vaginal bleeding
Interactions	May reduce hypoprothrombinemic effects of anticoagulants; estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; an increase in corticosteroid levels may occur when administered concurrently with ethinyl estradiol; use of ethinyl estradiol with hydantoins may cause spotting, breakthrough bleeding, and pregnancy; increase in fluid retention caused by estrogen intake may reduce seizure control
Pregnancy	X - Contraindicated in pregnancy
Precautions	Exercise caution in hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, or thromboembolic disease

Drug Name	Conjugated equine estrogen (Premarin) -- Induces the synthesis of DNA, RNA, and various proteins in target tissues. Reduces the secretion of LH and FSH from the pituitary by decreasing amount of gonadotropin-releasing hormones.
Adult Dose	Severe DUB: 25 mg IV q4h until bleeding stops, up to 4 doses; concurrently administer 35-mcg oral combination contraceptive pill PO q6h for 24-48 h, then bid to complete a 28-day cycle
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; known or suspected pregnancy; breast cancer, undiagnosed abnormal genital bleeding, active thrombophlebitis or thromboembolic disorders; history of thrombophlebitis, thrombosis or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast or prostatic malignancy)
Interactions	May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic P450 enzyme; loss of seizure control has been noted when administered concurrently with hydantoins
Pregnancy	X - Contraindicated in pregnancy
Precautions	Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as, abnormal or excessive uterine bleeding or mastodynia; estrogens may cause some degree of fluid retention (exercise caution); prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs) -- Blocks formation of prostacyclin, an antagonist of thromboxane, which is a substance that accelerates platelet aggregation and initiates coagulation.

Drug Name	Naproxen (Aleve, Anaprox, Naprosyn) -- For relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.
Adult Dose	500 mg PO once, after 6 h initiate 250 mg PO q6-8h; not to exceed 1.25 g/d
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Drug Category: Mineral supplementation -- Used to provide adequate iron for hemoglobin synthesis and replenish body stores.

Drug Name	Iron sulfate (Feosol, Feratab, Fer-Iron, Slow-FE) -- A nutritionally essential inorganic substance.
Adult Dose	325 mg PO qd
Pediatric Dose	Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Absorption is enhanced by ascorbic acid; interferes with tetracycline absorption; food and antacids impair absorption
Pregnancy	A - Safe in pregnancy
Precautions	Gastrointestinal upset; iron toxicity is observed with ingestion of large amount and can be fatal especially in children; parenteral (IV) administration may cause several reactions, including headaches, malaise, fever, generalized lymphadenopathy, arthralgia, and urticaria; can cause severe anaphylaxis; others include phlebitis at infusion site

FOLLOW-UP

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Complications:

• Excessive or prolonged bleeding can result in anemia.



• Excessive stimulation of the endometrium by estrogens with chronic anovulation increases the risk of endometrial cancer. Treating patients intermittently with combination oral contraceptives or progestins is important.

Patient Education:

• Educate patients about proper maintenance of a menstrual calendar. This is an invaluable tool in the evaluation of menstrual disorders.



• For excellent patient education resources, visit eMedicine's Women's Health Center and Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Amenorrhea, Vaginal Bleeding, Female Sexual Problems, Birth Control Overview, and Birth Control FAQs.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Always rule out pregnancy in a female with abnormal bleeding who is sexually active.



• Remember that a coexisting infectious disease may be present.

TEST QUESTIONS

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CME Question 1: A 13-year-old adolescent presents with a history of excessive menstrual bleeding and normal physical examination findings. She experienced menarche at age 12 years. Which of the following is the most likely diagnosis?

A: Blood dyscrasia
B: Hypothyroidism
C: Pregnancy-related bleeding
D: Dysfunctional uterine bleeding (DUB)
E: Endometritis

The correct answer is D: In the first 2 years after menarche, an immature hypothalamic-pituitary-ovarian axis is common. This can result in irregular menstrual bleeding, and no pathology is associated.

CME Question 2: A patient presents with amenorrhea. Breast examination reveals galactorrhea, and the patient denies sexual activity. Which of the following is the next step?

A: Obtain a serum follicle-stimulating hormone level.
B: Obtain a serum prolactin level.
C: Obtain a radiograph of the sella turcica.
D: Obtain serum estradiol levels.
E: Obtain a pelvic ultrasound.

The correct answer is B: The next step in the investigation should be to obtain a serum prolactin level. Suspect a prolactin-secreting tumor and obtain MRI of the brain as the final step.

Pearl Question 1 (T/F): The average interval between thelarche and menarche is 2 years.

The correct answer is True: Menarche is a late event in the pubertal development of girls.

Pearl Question 2 (T/F): In a patient who presents with oligomenorrhea and hirsutism, blood tests reveal elevated luteinizing hormone (LH) levels. Turner syndrome is the most likely diagnosis.

The correct answer is False: Polycystic ovarian syndrome or ovarian hyperthecosis is the most likely diagnosis. Theca cells secrete excessive LH. Associated hyperandrogenism results in acne, hirsutism, and other virilization effects.

Pearl Question 3 (T/F): The most common cause of secondary amenorrhea in a female is pregnancy.

The correct answer is True: Always exclude this condition before performing any other workup.

Pearl Question 4 (T/F): A karyotype should be obtained in a 15-year-old adolescent patient with delayed growth, primary amenorrhea, and lack of breast development.

The correct answer is True: Growth failure and delayed pubertal development are clues that this patient may have Turner syndrome. Other physical stigmata of Turner syndrome may be present. Elevated gonadotrophins are found in this condition; however, karyotype is diagnostic.

BIBLIOGRAPHY

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• Bravender T, Emans J: Adolescent Gynecology , Part I- Common Disorders. Pediatric Clinics of North America 1999; 46(3): 519- 43.
• Braverman PK, Sondheimer SJ: Menstrual disorders. Pediatr Rev 1997 Jan; 18(1): 17-25; quiz 26[Medline].
• Cosgrove L, Riddle B: Constructions of femininity and experiences of menstrual distress. Women Health 2003; 38(3): 37-58[Medline].
• Emans JS, Laufer M, Goldstein DP: Delayed Puberty and Menstrual Irregularities. Pediatric and Adolescent Gynecology 1998; 4th ed: 163-261.
• Harlow SD, Campbell OM: Epidemiology of menstrual disorders in developing countries: a systematic review. BJOG 2004 Jan; 111(1): 6-16[Medline].
• Iglesias EA, Coupey SM: Menstrual cycle abnormalities: diagnosis and management. Adolesc Med 1999 Jun; 10(2): 255-73[Medline].
• Mitan L A P, Slap GB: Adolescent Menstrual Disorders: Update. Medical Clinics of North America 2000; 84(4): 851-68.
• Slap GB: Menstrual disorders in adolescence. Best Pract Res Clin Obstet Gynaecol 2003 Feb; 17(1): 75-92[Medline].

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