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ESSENTIALS OF DIAGNOSIS
Primary amenorrhea: the absence of menses by 15 years of age in patient with secondary sex characteristics, or absence of menses by 13 years of age in a patient without secondary sex characteristics.
Secondary amenorrhea: absence of menses for at least 6 months in a woman with previously normal menses, or at least 12 months or six cycles without a period in a woman with previously irregular menses.
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General Considerations
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Amenorrhea is a symptom, not a diagnosis, and may occur secondary to a number of endocrine, physiologic, and anatomic abnormalities. Classifying amenorrhea into primary and secondary amenorrhea can aid in evaluation and simplify diagnosis.
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The clinician must be sensitive to the fact that the adolescent patient may be uncomfortable discussing her sexuality, especially in the presence of a parent. The most common causes of primary amenorrhea are gonadal dysgenesis, hypothalamic hypogonadism, pituitary disease, and anatomic abnormality.
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Primary amenorrhea may be prevented by maintaining an appropriate body weight and treating the underlying conditions.
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A. Signs and Symptoms
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The history and physical exam (H&PE) are the most important steps in diagnosing primary amenorrhea. Key elements of the history are listed in Table 13-2. This targeted history will help narrow the differential and eliminate unnecessary testing. Physical examination should focus on appearance of secondary sexual characteristics and pelvic examination findings—specifically the presence or absence of a uterus. BMI should also be calculated and compared with prior visits to assess both for rapid weight loss or weight gain. Presence or absence of breast development and presence or absence of the uterus and cervix are decision points for further testing and diagnostic categories.
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B. Laboratory Findings
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Choice of laboratory examination should be guided by history and physical findings and are listed here on the basis of etiology. A pregnancy test should be performed on all individuals presenting for primary amenorrhea that have secondary sexual characteristics and functional anatomy. Although the initial cycles after menarche are often anovulatory, pregnancy can occur before the first recognized menstrual cycle. Patients with a normal pelvic examination but absent breast development should receive serum FSH (follicle-stimulating hormone) measured to distinguish peripheral (gonadal) from central (pituitary or hypothalamic) causes of amenorrhea. A high FSH suggests gonadal dysgenesis. A karyotype should be performed to differentiate patients with Turner’s syndrome (45 X) that is most common from other variations. It is important to identify patients with a 46 XY karyotype, since these individuals have a high peripubertal risk for gonadoblastoma and dysgerminoma. If the uterus is absent, serum testosterone and karyotype should be performed. Elevated testosterone in the presence of a Y chromosome indicates presence of functional testicular tissue that should be excised to prevent later neoplastic transformation. In patients with both normal breast development and a pelvic examination, serum prolactin and TSH should be measured to rule out hyperprolactinemia and hypothyroidism. If these values are in the normal range, investigation should proceed according to the secondary amenorrhea algorithm. The etiologies for primary amenorrhea are listed in Table 13-3.
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Radiographic studies are targeted toward the diagnosis suggested by history, physical, and laboratory studies. Magnetic resonance imaging (MRI) is indicated in patients with suspected pituitary pathology. Computerized visual field testing may be added if examination or MRI indicates optic chiasm compression. Pelvic imaging should be performed in patients with suspected pelvic anomalies. Transverse vaginal septum, imperforate hymen, or vaginal agenesis can be detected or confirmed through imaging.
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Successful treatment of primary amenorrhea is based on correct diagnosis of the underlying etiology. The patient should be counseled as to the cause of her amenorrhea, implications for future fertility, risks of malignancy (if applicable), and treatment options. Patients with functional hypothalamic amenorrhea due to physical or psychological stress can reverse this by weight gain, resolution of emotional issues, or decrease in intensity of exercise. For patients with hypothyroidism, thyroid replacement should be started at a low dose and titrated up, with caution to avoid overreplacement. Patients with pituitary adenomas should be treated with the dopamine agonists bromocriptine or cabergoline, the former having the best established safety record and approved for use in pregnancy. Metformin can be used in patients with polycystic ovarian syndrome (PCOS) who are insulin-resistant. Cyclical estrogen-progesterone and combined estrogen-progesterone oral contraceptive pills, patches, or vaginal ring can be used in patients with gonadal dysgenesis or hypoestrogenic state. Only providers experienced in this field should perform induction of puberty in patients with constitutional delay. Estrogen is responsible for epiphyseal closure as well as the adolescent growth spurt; mistimed administration could have significant effects on the final achieved height in these patients. For patients who desire fertility, ovulation induction with clomiphene citrate, exogenous gonadotropins, or pulsatile GnRH (gonadotropin-releasing hormone) may be required.
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B. Surgical Intervention
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Structural anomalies should be addressed surgically. In those patients with congenital absence of a uterus, investigation should be undertaken for associated renal anomalies. Gonadectomy should be performed after puberty in patients with Y chromosome material to prevent the development of subsequent gonadal neoplasia.
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C. Behavioral Modification
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Patients with hypothalamic failure due to rapid weight loss, excessive exercise, or stress should receive counseling to address the underlying cause of these problems.
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The most common type of amenorrhea, secondary amenorrhea, is diagnosed when a woman with previously normal menses goes at least 6 months without a period, or when a woman with previously irregular menses goes at least 12 months or at least six cycles without a period.
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A. Signs and Symptoms
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Pertinent history in the evaluation of secondary amenorrhea includes: (1) previous menstrual history (timing and quality of menses), (2) pregnancies (to include terminations and complicated deliveries), (3) symptoms of endocrine disease, (4) medication history, (5) weight loss or gain, (6) exercise level, (7) history of instrumentation or surgery to genital tract, and (8) masculinizing characteristics noticed by patient or family. Physical examination should assess pubertal development and secondary sexual characteristics while looking for evidence of hyperandrogenism. These latter findings may include oily skin, acne, striae, clitoromegaly, and hirsutism.
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B. Laboratory Findings
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After the exclusion of pregnancy, initial labs should include fasting glucose, thyroid-stimulating hormone (TSH), and prolactin levels. In the absence of significant abnormalities in these values, a progestin challenge test should be performed to assess the patient’s estrogen status. FSH should be measured on women who do not experience withdrawal bleeding within 2 weeks. A high FSH value (>30 IU/L) is indicative of ovarian failure, whereas normal or low values indicate either an acquired uterine anomaly (Asherman syndrome) or hypothalamic-pituitary failure. Ovarian failure is confirmed with a low serum estradiol level (<30 pg/mL). A serum luteinizing hormone (LH) and FSH should be drawn on women who do not experience withdrawal bleeding after the progesterone challenge and have a normal estrogen level. An elevated LH value is highly suggestive of PCOS (polycystic ovary syndrome), especially in a woman with clinical features of virilization. If the LH level is normal, an LH/FSH ratio should be determined. This ratio is elevated (>2.5) in women with PCOS even when FSH and LH values are within normal limits. This diagnosis can be confirmed by measurement of serum testosterone and dehydroepiandrosterone sulfate (DHEA-S), which should be normal or just mildly elevated in PCOS. An increased testosterone/DHEA-S ratio is suggestive of an adrenal source. This finding warrants further study with determination of 17-hydroxyprogesterone. This level is elevated in late-onset congenital adrenal hyperplasia and Cushing syndrome. Cushing syndrome may be excluded with a 24-hour urinary free cortisol and dexamethasone suppression testing.
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Hysterosalpingogram is indicated with history of uterine instrumentation and/or suggestion of anatomic anomaly as source of amenorrhea. Computed tomographic (CT) scanning of the adrenal glands and ultrasound of the ovaries should be performed in women with clinical features of virilization and increased testosterone (>200 ng/dL) or DHEAS-S (>7 μg/mL). A CT or MRI of the pituitary should be performed if pituitary pathology is suspected.
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Differential Diagnosis
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The differential diagnosis of secondary amenorrhea can be broken down into those etiologies with and those without evidence of hyperandrogenism.
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A. With Evidence of Hyperandrogenism
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1. Polycystic ovary syndrome (PCOS)
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Responsible for 20% of secondary amenorrhea, PCOS is the most common reproductive female endocrine disorder, occurring in 5–7% of women. PCOS is associated with an increased risk of type 2 diabetes, abdominal obesity, hypertension, hypertriglyceridemia, and cardiovascular events.
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2. Autonomous hyperandrogenism
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Tumors of adrenal or ovarian origin may secrete androgens. Virilization is more pronounced than in PCOS and may manifest as frontal balding, increased muscle bulk, deep voice, clitoromegaly, and severe hirsutism.
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3. Late-onset or mild congenital adrenal hyperplasia
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This rare condition may be diagnosed with the finding of an increased 17-hydroxyprogesterone level in the setting of secondary amenorrhea and hyperandrogenism.
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B. Without Evidence of Hyperandrogenism on Examination
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History should be reviewed for use of contraceptives, particularly progesterone-only preparations. These may take the form of oral contraceptives (OCPs), implants, injectables, or intrauterine devices. It is important to inform women on progestin-only pills that 20% of patients will become amenorrheic within the first year of use. Rates are even higher for those using injectable progesterone, with 55% of women at 1 year and 68% of women at 2 years reporting amenorrhea.
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2. Functional hypothalamic amenorrhea
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Amenorrhea in this setting, seen in patients who have experienced rapid weight loss, severely restricted calorie intake, stress or rigorous exercise, may be part of the female athlete triad of amenorrhea, disordered eating, and osteoporosis.
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3. Hypergonadotropic hypogonadism
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Premature ovarian failure (cessation of ovarian function before 40 years of age) may be autoimmune or idiopathic, or may occur secondarily to radiotherapy or chemotherapy (cyclophosphamide is associated with destruction of oocytes).
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4. Hyperprolactinemia
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Pituitary adenomas may present with amenorrhea and galactorrhea, and are responsible for 20% of cases of secondary amenorrhea. Prolactin secreted by these tumors acts directly on the hypothalamus to suppress GnRH secretion. Dopamine receptor–blocking agents, hypothalamic masses, and hypothyroidism are less common causes of hyperprolactinemia.
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Profound hypothyroidism or hyperthyroidism affects the feedback control of LH, FSH, and estradiol on the hypothalamus, causing menstrual irregularities.
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6. Hypogonadotropic hypogonadism
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Head trauma, severe hypotension (shock), infiltrative or inflammatory processes, pituitary adenoma, or craniopharyngioma may damage the pituitary, resulting in decreased or absent gonadotropin (LH and FSH) release. These patients will often display symptoms relating to deficiency of other pituitary hormones as well.
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Treatment depends on correct diagnosis of the underlying etiology. As in primary amenorrhea, the goals of treatment are to establish a firm diagnosis, to restore ovulatory cycles and treat infertility (when possible), to treat hypoestrogenemia and hyperandrogensim, and to assess and address risks associate with a persistent hypoestrogenemic state.
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A. Treating the Underlying Causes of Amenorrhea
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Patients with identified hypothyroidism should be treated with thyroxine replacement. Patients with hyperprolactinemia secondary to prolactinoma may be treated with either surgical resection or dopamine agonist therapy. Bromocriptine is often used in women who desire to conceive, since there is no increased incidence of congenital malformations, and it has been used successfully for over 20 years. Patients found to have empty sella or Sheehan syndrome should be treated with replacement of pituitary hormones.
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Women whose amenorrhea is secondary to absent ovarian function before 40 years of age have premature ovarian failure. Those who experience ovarian failure before 30 years of age should undergo karyotype testing to screen for Y chromosome elements, which are associated with malignancies. These patients are at a high risk of osteoporosis and cardiovascular disease because of their hypoestrogenemic state. Estrogen replacement should be considered, with progesterone for those patients with an intact uterus, to prevent these sequelae.
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Women with adrenal or ovarian androgen-secreting tumors should undergo appropriate surgical intervention. Likewise, women found to have Asherman syndrome as a cause for their amenorrhea should undergo lysis of adhesions followed by endometrial stimulation with estrogen. These patients are at increased risk of placenta accreta in subsequent pregnancies.
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Patients with PCOS may achieve resumption of menses with weight loss. The assistance of a registered dietician should be sought to improve success rates in this daunting task. Metformin, a biguanide insulin sensitizer, has been used to treat PCOS, with reports of success in both inducing ovulation and improving laboratory markers for cardiovascular risk.