Chapter 13: Menstrual Disorders

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

Irregularities in menstruation may manifest as complete absence of menses, dysfunctional uterine bleeding, dysmenorrhea, or premenstrual syndrome. Vaginal bleeding is addressed in Chapter 34. 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.

General Considerations

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.

Primary Amenorrhea

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.

Prevention

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

Clinical Findings

A. Signs and Symptoms

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.

B. Laboratory Findings

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.

C. Imaging Studies

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.

Treatment

A. 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 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.

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

C. 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

A. 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, striae, clitoromegaly, and hirsutism.

B. 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 (<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.

C. Imaging Studies

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.

Differential Diagnosis

The differential diagnosis of secondary amenorrhea can be broken down into those etiologies with and those without evidence of hyperandrogenism.

A. With Evidence of Hyperandrogenism

1. Polycystic ovary syndrome (PCOS)

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.

2. Autonomous hyperandrogenism

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.

3. Late-onset or mild congenital adrenal hyperplasia

This rare condition may be diagnosed with the finding of an increased 17-hydroxyprogesterone level in the setting of secondary amenorrhea and hyperandrogenism.

B. Without Evidence of Hyperandrogenism on Examination

1. Medication use

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.

2. Functional hypothalamic amenorrhea

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.

3. Hypergonadotropic hypogonadism

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).

4. Hyperprolactinemia

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.

5. Thyroid disease

Profound hypothyroidism or hyperthyroidism affects the feedback control of LH, FSH, and estradiol on the hypothalamus, causing menstrual irregularities.

6. Hypogonadotropic hypogonadism

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.

Treatment

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.

A. Treating the Underlying Causes of Amenorrhea

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.

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.

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.

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.

General Considerations

Dysmenorrhea is the most common gynecologic complaint and is a leading cause of morbidity in women of reproductive age, resulting in absence from work and school, as well as nonparticipation in sports.

Pathogenesis

Primary dysmenorrhea is caused by the release of prostaglandin F₂α from the endometrium at the time of menstruation, and rarely occurs until ovulatory menstrual cycles are established. Prostaglandins induce smooth-muscle contraction in the uterus, causing pressure within the uterus to exceed that of the systemic circulation. Ischemia ensues, causing an anginal equivalent in the uterus. The cause of secondary dysmenorrhea varies with the underlying disease.

Clinical Findings

A. Symptoms and Signs

Symptoms of primary dysmenorrhea include pain beginning with the onset of menstruation and lasting 12–72 hours, characterized as crampy and intermittent in nature, with radiation to the low back or upper thighs. Headache, nausea, vomiting, diarrhea, and fatigue may accompany the pain. Symptoms are usually worst on the first day of menses and then gradually resolve. The patient may report that her dysmenorrhea began gradually, with the first several years of menses, and then intensified as her periods became regular and consistently ovulatory. Conversely, patients with secondary amenorrhea report symptoms beginning after age 20, lasting 5–7 days, and progressive worsening of pain with time. These patients may also report pelvic pain that is not associated with menstruation.

B. Physical Findings

A pelvic examination with cervical smear and cultures should be performed in all patients presenting with a chief complaint of dysmenorrhea. Findings of cul-de-sac induration and uterosacral ligament nodularity on pelvic examination are indicative of endometriosis. Adenexal masses could indicate endometriosis, neoplasm, hydrosalpinx, or scarring from chronic pelvic inflammatory disease (PID). Likewise, uterine abnormalities or tenderness should raise the examiner’s index of suspicion for the underlying pathology as the cause for dysmenorrhea.

C. Laboratory Findings

Any woman with acute onset of pelvic pain should have a pregnancy test. Women with a history consistent with primary dysmenorrhea do not require additional initial labs. In those who fail to respond to therapy for primary dysmenorrhea or in those whom a diagnosis of secondary dysmenorrhea is suspected, a complete blood count (CBC) and an erythrocyte sedimentation rate (ESR) may help in detection of the underlying infection or inflammation.

D. Imaging Studies

Patients with abnormal findings on pelvic examination who do not respond to therapy for primary dysmenorrhea or who have a history suggestive of pelvic pathology should undergo pelvic ultrasound.

E. Special Examinations

In patients whom endometriosis is suggested, diagnostic laparoscopy may be indicated. Because of the high rates of treatment and diagnostic failure with laparoscopy, some authors recommend empirically treating patients with a presumptive diagnosis of endometriosis with GnRH analogs for 3 months. Proponents argue that this provides both diagnostic and therapeutic functions, while forgoing surgical complications.

Treatment

A. Medical Therapies

Treatment for primary dysmenorrhea focuses on reducing endometrial prostaglandin production. This can be accomplished with NSAIDs (nonsteroidal anti-inflammatory drugs), which inhibit prostaglandin synthesis, or with contraceptives that suppress ovulation. It is recommended to allow at least three full cycles to assess efficacy of either of these approaches. In patients who do not experience success with these means, an alternate diagnosis, such as endometriosis, should be considered. Medical therapies are listed in Table 13-4 with respect to their degree of efficacy.

B. Physical Modalities

Physical modalities utilizing heat, acupuncture/acupressure, and spinal manipulation have been proposed for inclusion in the treatment of dysmenorrhea. A heated abdominal patch was demonstrated to have efficacy similar to ibuprofen (400 mg) for the treatment of dysmenorrhea, with quicker, but not greater, relief observed with the combination of ibuprofen and heat. Acupuncture relieved pain in 91% of patients with dysmenorrhea, compared to 36% relief for control patients in a study with sham acupuncture. A systematic review of spinal manipulation in the treatment of dysmenorrhea failed to find evidence for the effectiveness of this approach.

C. Supplements and Herbals

A number of supplements and herbal formulations have been touted as relieving the symptoms of dysmenorrhea. While some small trials have showed promising results, the data are not strong enough at this time to recommend widespread use. A systematic review of Chinese herbal therapy for treatment of dysmenorrhea showed promising results with self-designed formulas in small studies, but not with commonly used herbal health products. Results were limited by poor methodological quality and small sample size.

D. Behavior Modification

Strenuous exercise and caffeine intake are both lifestyle factors that can modulate prostaglandin-induced uterine contractions. Strenuous exercise can increase uterine tone, resulting in increased periods of uterine “angina” with accompanying increases in prostaglandins. Decreasing strenuous exercise in the first few days of a woman’s menses may reduce her dysmenorrhea. Conversely, caffeine decreases uterine tone by increasing uterine cyclic adenosine monophosphate levels.

E. Surgical Therapy

If a patient continues to have significant dysmenorrhea with this treatment, further testing for causes of secondary dysmenorrhea should be considered, and surgical options, such as interruption of pelvic nerve pathways, should be explored when applicable.

General Considerations

While 40% of women experience PMS symptoms significant enough to interfere with daily life, 5% of women experience severe impairment. Evaluation, diagnosis, and treatment of PMS should be undertaken prudently, as it is often mistaken for other disorders, and sometimes treated with counterproductive and even harmful approaches. The clinician must be sensitive in addressing issues of reduced self-worth, frustration, and depression that may be present in women suffering from this condition.

Pathogenesis

Premenstrual syndrome is assumed to be secondary to interactions between the ovarian hormones, estrogen and progesterone, and central neurotransmitters. Serotonin is the central neurotransmitter most often implicated in the manifestations of PMS. This would explain the cyclical mood changes that are synchronized with the changes in ovarian hormone levels. Systemic symptoms, such as bloating, may be produced through the peripheral effects of these hormones. Trace elements and nutrients are also speculated to have a role in the pathogenesis of PMS symptoms, but their role is less clear.

Clinical Findings

A. Symptoms and Signs

Symptoms may include irritability, bloating, depression, food cravings, aggressiveness, and mood swings. Abraham’s classification of premenstrual syndrome (Table 13-5) helps the clinician to organize history taking for patients with PMS.

Factors associated with an increased risk of PMS include stress, alcohol use, exercise, smoking, and the use of certain medications. It is not clear whether some of these factors are causative or are forms of self-medication used by sufferers. A prospective symptom diary kept for at least 2 months is helpful in assessing the relation of symptoms to the luteal phase of menses. The absence of a symptom-free week early in the follicular phase, the time period just after menses, suggests that a chronic psychiatric disorder may be present. A record of symptoms that are temporally clustered before menses and that decline or diminish 2–3 days after the start of menses is highly suggestive of PMS. Patients with PMS experience fluid retention and fluctuating weight gain in relation to their menses. Mild edema may or may not be evident on physical examination.

B. Laboratory Findings

There are no laboratory evaluations recommended in the diagnosis of PMS. Nutrient deficiency tests are not recommended, as they do not adequately assess the patient’s physiologic state.

C. Radiologic Studies

There are no radiologic studies recommended in the assessment of PMS.

Treatment

The treatment goals for PMS are to minimize symptoms and functional impairment while optimizing the patient’s overall health and sense of well-being. Therapy should take an integrative approach, including education, psychological support, exercise, diet, and pharmacological intervention, if necessary. By providing education about the prevalence and treatability of PMS, the clinician can destigmatize the disease and encourage the patient to take ownership of the treatment plan.

Many first-line treatments for PMS, although not based on well-designed prospective trials, also have general health benefits, are inexpensive, and have few side effects. These include dietary modifications, as recommended by the American Heart Association and moderate exercise at least 3 times a week. Patients should begin to see the results of these lifestyle changes 2–3 months after initiation. Patients should be counseled to expect improvement in their symptoms, rather than cure. Multiple approaches may be required before finding the optimal treatment.

For those patients with continued symptoms, secondary treatment strategies may be employed. Dietary supplements, specifically vitamin B₆, calcium, and magnesium, have been suggested to correct possible deficiencies. Current therapies are listed in Table 13-6, with their levels of supporting evidence, primary benefits, and potential side effects.

Alternative therapies include herbal medicine, dietary supplements, relaxation, message, reflexology, manipulative therapy, and biofeedback. Although some small trials have shown promising results, there is no compelling evidence from well-designed studies supporting the use of these therapies in the treatment of PMS.