Differential Diagnosis

In primary amenorrhea, defined as failure for menstruation to begin, chromosomal or congenital abnormalities, such as gonadal dysgenesis, triple X syndrome, isochromosomal abnormalities, testicular feminization syndrome, and, rarely, true hermaphroditism, should be considered in addition to the conditions that cause secondary amenorrhea (Table 110-2). Elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) suggest primary gonadal failure, and chromosome analysis often elucidates its cause. When primary amenorrhea occurs with otherwise normal progression of pubertal development, a structural anomaly of the müllerian duct system (Chapter 548) should be suspected. Imperforate hymen is most the common disorder of müllerian duct descent and is associated with recurrent (monthly) abdominal pain and, after some time has passed, a midline, lower abdominal mass, which is the blood-filled vagina, and is called hematocolpos. Diagnosis is made by inspection of the introitus, revealing a bulging hymen with bluish discoloration. If the obstruction is at the level of the cervix, the blood-filled uterus (hematometrium) is apparent on bimanual examination or ultrasonography. Agenesis of the cervix or uterus is rare but occurs in association with sacral agenesis.

Primary or secondary amenorrhea may also be caused by chronic illness, particularly that associated with malnutrition or tissue hypoxia, such as diabetes mellitus, inflammatory bowel disease, cystic fibrosis, or cyanotic congenital heart disease. In most cases, the illness has been diagnosed previously, but, occasionally, the amenorrhea is its first manifestation. Pregnancy is a common cause of secondary and occasionally primary amenorrhea. Polycystic ovarian syndrome (PCOS) (Chapter 580.2) is one of the most common endocrine disorders affecting 4-6% of premenopausal women and presents with menstrual abnormalities that range from amenorrhea to dysfunctional uterine bleeding. The criterion for the diagnosis of PCOS is menstrual irregularity in the face of androgen excess with either hirsutism, acne, or increased serum androgens. When the androgen excess is coupled with insulin resistance and acanthosis nigricans, the term HAIR-AN syndrome is used. A central nervous system (CNS) tumor, most commonly a craniopharyngioma, may present with amenorrhea. Prolactinomas, although rare, are the most common pituitary tumor in adolescence. Abnormalities of the thyroid gland, typically hyperthyroidism, may first be suspected by delayed sexual maturation or amenorrhea, even in the absence of other signs and symptoms. Hypothyroidism may cause precocious puberty but may also be associated with delayed puberty or abnormal uterine bleeding. Anorexia nervosa, which may present with either primary or secondary amenorrhea, is occasionally confused with hyperthyroidism because of weight loss, hyperactivity, and personality changes seen in both entities. Amenorrhea is one of the components of the female athlete triad in association with disordered eating and low bone mass (Chapter 682). Ballerinas, gymnasts, and runners may be at disproportionate risk of this triad. Ingestion of drugs, both legal and illegal, may cause amenorrhea and, in the case of phenothiazines, even a false-positive urine pregnancy test. Some drugs, including phenothiazines and certain antihypertensive agents, may cause galactorrhea, further mimicking pregnancy. Pertinent findings on physical exam include signs of androgen excess, such as obesity, acne, hirsutism, and clitoromegaly, along with excessive thinness, galactorrhea, and thyromegaly. Adolescents with amenorrhea who diet, whether or not they meet diagnostic criteria for anorexia nervosa, are at risk for low bone density.

Laboratory Findings

The approach to the clinical evaluation of amenorrhea follows a stepwise progression initiated by the history and physical examination. The pregnancy test, usually a qualitative measure of urinary chorionic gonadotropin, is the key laboratory test to perform in the evaluation of amenorrhea regardless of the history or sexual activity given by the patient (Fig. 110-1). The next step for laboratory determinations follows the scheme in which gonadotropin levels. The measurement of FSH is critical in determining whether chromosomal abnormalities (with FSH elevation >25 mIU/mL) or other endocrinopathies or CNS tumors (with normal or low FSH <5 mIU/mL) are present. Prolonged amenorrhea (>6 mo) or persistent oligomenorrhea (<6 menses in past year) without an explanation should prompt the measurement of thyroid-stimulating hormone, FSH, LH, and prolactin levels, even in the face of a normal progesterone challenge. Elevated LH and normal FSH levels require the measurement of androgen excess even in the absence of virilization. An LH : FSH ratio >3 and elevated free testosterone and DHEAS (dihydroepiandrosterone sulfate) levels are common in adolescents with PCOS. Hyperinsulinemia is a characteristic feature of PCOS, and there is an increased risk of type 2 diabetes mellitus. Elevated DHEAS may indicate the source of excess androgen to disorders in the adrenal gland. An elevated prolactin level or other clinical features suggesting a CNS tumor should be followed up with cranial CT scan or, preferably, MRI.

Figure 110-1 Approach to the adolescent with amenorrhea. DHEAS, dihydroepiandrotestosterone sulfate; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PCOS, polycystic ovary syndrome; T, testosterone.

(From Slap GB: Menstrual disorders in adolescence, Best Pract Res Clin Obstet Gynaecol 17:75–92, 2003.)

Endometrial status can be assessed as part of the evaluation when other endocrinologic parameters are normal by a progesterone challenge in which 5 or 10 mg oral medroxyprogesterone acetate is given for 5-10 days. Withdrawal bleeding should occur 2-7 days thereafter when normal endometrium is present. If bleeding does not occur, one must consider insufficient estrogenic priming of the endometrium, an abnormal uterus, or an outflow tract obstruction.

Treatment

Determination of the cause of amenorrhea may permit the initiation of corrective intervention. When the disorder is not amenable to remediation, consideration should be given to establishing regular pseudomenses to allow the adolescent to feel like her peers (Table 110-3). Counseling the adolescent whose diagnosis will render her unable to conceive is especially challenging, and support and follow-up are important. If the result of a vaginal smear is positive for estrogen effect, regular cycling can be accomplished using medroxyprogesterone in a dose of 10 mg orally for 10-12 days at least every other month. Combination norgestimate- or drospirenone-containing oral contraceptives can also be used for this purpose in patients with PCOS. In a patient with gonadal dysgenesis, conjugated estrogens must be given first (Premarin in an oral dose of 0.3 mg and increased to 1.25 mg) for feminization to progress. This is followed by medroxyprogesterone, 10 mg orally on days 10-21 of the cycle. Lifestyle changes, particularly weight reduction and insulin sensitizers, specifically metformin, have been shown to re-establish menses and ovulation is some patients, but symptoms return when the medication is discontinued.

Differential Diagnosis

Most abnormal vaginal bleeding in adolescents results from anovulatory cycles. This is called dysfunctional uterine bleeding; this term is used when no demonstrable organic lesion is identified to account for the abnormal bleeding. When it occurs during the 1st 2 yr after menarche, dysfunctional uterine bleeding usually reflects an immaturity of the hypothalamic-pituitary-ovarian axis; specifically, the mid-cycle LH surge is not in place, leading to anovulation and, hence, potential for irregular bleeding.

Among U.S. adolescents admitted to the hospital for menorrhagia, anovulation was the most common cause (46%), followed by hematologic causes (33%), infection (11%), and chemotherapy (11%). In Sweden, a study among ~1,000 adolescents revealed that 73% had ≥1 episode of bleeding problems, with one third experiencing menorrhagia. Organic lesions are found in about 9% of 10-20 yr old young women; the most common include ectopic pregnancy, threatened abortion, and endometritis/salpingitis. The key distinguishing feature between anovulatory uterine bleeding and that due to organic disorders listed previously is that the latter are characterized by pain whereas anovulatory bleeding is usually painless. Table 110-4 lists the extensive differential diagnosis; studies of severe cases that require hospitalization report coagulation disorders (idiopathic thrombocytopenic purpura, von Willebrand disease, Glanzmann disease, leukemia), hypothyroidism, thalassemia major, Fanconi syndrome, and rheumatoid arthritis as the more frequent diagnoses. Medications may cause abnormal uterine bleeding; these include estrogens, progestins, androgens, prolactin, and drugs that cause prolactin release (estrogens, phenothiazines, tricyclic antidepressants, metoclopramide), and anticoagulants (heparin, warfarin, aspirin, and nonsteroidal antiinflammatory drugs [NSAIDs]).

Laboratory Findings

The hemoglobin and hematocrit are the most important elements in the initial evaluation. They establish the severity of the bleeding, with levels less than a hemoglobin of 9 g/dL or a hematocrit of 27% considered severe, 9-11 g/dL and 27-33% considered moderate, and >11 g/dL and >33% considered mild. Hospitalization is generally recommended for adolescents with a hemoglobin <7 g/dL or a hemoglobin <10 g/dL with significant postural blood pressure changes or excessive heavy bleeding. For sexually active teenagers, tests for gonorrhea, chlamydia, and pregnancy are also performed. The secondary evaluation should include liver and thyroid function studies, platelet count, prothrombin time, partial thromboplastin time, and tests for von Willebrand disease. If these studies are not performed at the first visit, they must be performed before any estrogen therapy is initiated that might interfere with interpreting the results.

Treatment

In mild cases, iron supplementation is recommended, and the patient should keep a menstrual calendar to follow the subsequent flow patterns. With moderate disturbances, cycling with oral contraceptives, barring any contraindications, should be considered along with monitoring the iron status and oral iron therapy. Severe bleeding, not requiring hospitalization, can usually be stopped with hormonal therapy, either medroxyprogesterone acetate (Provera) 10 mg/24 hr for 10-14 days or a combination oral contraceptive using 2-4 pills per day until the bleeding stops, and then 1 pill per day for the remainder of the cycle. Once a patient is hospitalized, Premarin 25 mg every 4 hr up to 2 to 3 doses given intravenously is required. At the same time, the combination oral contraceptive regimen or Depo-Provera (medroxyprogesterone acetate [DMPA]), 150 mg IM every 12 wk, required for maintenance, can be initiated. These estrogen doses are high, prompting some concern about the risk of thromboembolism, but no complications have been reported from short-term use. For severe cases, transfusion of packed red blood cells may be needed.

In the rare case of a patient whose bleeding cannot be controlled by one of these methods, an endometrial curettage may be indicated. Although this procedure is frequently undertaken in adult women with menometrorrhagia, the rarity of endometrial carcinoma and the usual efficacy of hormonal therapy in adolescence make this procedure unnecessarily invasive in this age group.