Menstrual disorders are a heterogeneous group of conditions that are both physically and psychologically debilitating. Though they were once considered nuisance problems, it is now recognized that menstrual disorders take a significant toll on society, both in days lost from work, as well as the pain and suffering experienced by individual women. These disorders may arise from physiologic (ie, pregnancy), pathologic (ie, endocrine abnormalities), or iatrogenic (ie, secondary to contraceptive use) conditions.

Irregularities in menstruation may manifest as complete absence of menses, dysfunctional uterine bleeding, dysmenorrhea, or premenstrual syndrome. Since it is essential to know what is normal in order to define that which is abnormal, normal menstrual parameters are listed in Table 13-1.

Essentials of Diagnosis

• Primary amenorrhea: the absence of menses by 16 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 mense, or at least 12 months or six cycles without a period in a woman with previously irregular menses.

General Considerations

Amenorrhea is a symptom, not a diagnosis, and may occur secondary to a number of endocrine and anatomic abnormalities. Classifying amenorrhea into primary and secondary amenorrhea can aid in evaluation and simplify diagnosis.

Primary Amenorrhea

The patient with primary amenorrhea is often brought to the physician by her mother who is concerned about the patient’s delay in reaching developmental milestones. 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 are gonadal dysgenesis, hypothalamic hypogonadism, and anatomic abnormality.

Prevention

Amenorrhea may be prevented by maintaining an appropriate body weight and treating the underlying conditions.

Clinical Findings

Signs and Symptoms

Key elements of the history are listed in Table 13-2. This targeted history will help to 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. The clinician should be careful to allay patient fears, as this will often be her first pelvic examination. 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.

Laboratory Findings

Choice of laboratory examination should be guided based on history and physical findings and are listed here based on etiology. A pregnancy test should be performed on all individuals presenting for primary amenorrhea that have secondary sexual characteristics and functional anatomy. Though 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 have 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 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 normal 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 is listed in Table 13-3.

Imaging Studies

Radiographic studies are targeted toward the diagnosis suggested by history, physical, and laboratory studies. Magnetic resonance imaging (MRI) is indicated in patients whom pituitary pathology is suspected. Computerized visual field testing may be added if examination or MRI indicates optic chiasm compression. Pelvic ultrasound should be performed in patients with suspected pelvic anomalies.

Treatment

Medical Therapy

Successful treatment of primary amenorrhea is based on correct diagnosis of the underlying etiology. The patient should be counseled as to the cause of their amenorrhea, implications for future fertility, and treatment options. Patients with functional hypothalamic amenorrhea due to physical or psychological stress can have this reversed 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, being cautious to avoid over replacement. 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 those 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.

Surgical Intervention

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 patient with Y chromosome material to prevent the development of subsequent gonadal neoplasia.

Behavioral Modification

Patients with hypothalamic failure due to rapid weight loss, excessive exercise, or stress should receive counseling to address the underlying cause of these problems.

Secondary Amenorrhea

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.

Clinical Findings

Signs and Symptoms

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, and hirsutism.

Laboratory Findings

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, less than 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, especially in a woman with clinical features of virilization. If the LH level is normal, an LH to FSH ratio should be determined. This ratio is elevated, greater than 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 to 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.