Learning Outcome

1. Describe the causes of amenorrhea.
2. Recall the presentation of amenorrhea.
3. Summarize the evaluation of amenorrhea.

Introduction

Typically, the female menstrual cycle comprises a 28 to 30-day cycle containing 2 phases: the proliferative and secretory phases. The uterine lining sheds at the end of the cycle, known as menstruation.[1][2][3] Throughout each stage of a woman's reproductive life cycle, from menarche to menopause, there may be variations in their menstrual cycle's length and amount secondary to many causes. This variation may be within the normal range or pathologic. Particularly during stages of the reproductive cycle (eg, menarche and perimenopause), when longer intervals between menstrual cycles commonly occur, clinicians may be unsure of the appropriate diagnostic studies or whether an evaluation is even indicated.

Amenorrhea is abnormal uterine bleeding characterized by the absence of menstruation in a female of reproductive age, 12 to 52 years on average.[4] It can be classified as either primary or secondary amenorrhea. Primary amenorrhea is defined as having no history of menstruation by the age of 15 years or 3 years after thelarche; secondary amenorrhea is defined as the absence of menses for ≥3 months in a woman with previously regular menstrual cycles or ≥6 months in any woman with at least one previous spontaneous menstruation.[4][5] Patients meeting the criteria for either primary or secondary amenorrhea warrant an evaluation. However, an evaluation for delayed puberty is indicated in adolescents aged 13 years with primary amenorrhea and no breast development.[6][7]

There are numerous potential etiologies of amenorrhea. Most underlying causes can be classified into general groups: outflow tract abnormalities; primary ovarian insufficiency; hypothalamic or pituitary disorders; other endocrine gland disorders; and physiologic or medication induced.[8][9] When evaluating a patient with amenorrhea, a systematic approach should be used to consider each potential etiology. The initial work-up usually includes a comprehensive history and physical examination, a urine pregnancy test, serum hormone testing, and pelvic imaging. Additional testing may also be indicated based on the clinical presentation.[6][8][9] Treatment depends on the underlying etiology and may include lifestyle interventions, hormone therapy or other medications, surgery, and mental health services.

Nursing Diagnosis

• Cessation of menstruation
• Anxiety
• Low self-esteem
• Sexual dysfunction

Causes

Amenorrhea is the absence of menstruation in a female of reproductive age. It can be classified as either primary or secondary amenorrhea. Primary amenorrhea is defined as having no history of menstruation by the age of 15 years or 3 years after thelarche; secondary amenorrhea is defined as the absence of menses for ≥3 months in a woman with previously regular menstrual cycles or ≥6 months in any woman with at least one previous spontaneous menstruation. Patients meeting the criteria for either primary or secondary amenorrhea warrant an evaluation. Additionally, an assessment for delayed puberty is indicated in adolescents aged 13 years and younger without initial breast development.

Congenital or anatomic abnormalities are most commonly the cause of primary amenorrhea. However, any etiology of secondary amenorrhea may also present as primary amenorrhea. Determining the underlying cause of amenorrhea will assist in guiding management decisions.[9] Menstruation is controlled by hormones secreted from the hypothalamus, pituitary gland, and ovary. Dysfunction in any of these three organs can result in amenorrhea; therefore, numerous potential etiologies exist. Most underlying causes can be classified into general groups: outflow tract abnormalities; primary ovarian insufficiency; hypothalamic or pituitary disorders; other endocrine gland disorders; and physiologic or medication induced.[8][9] When evaluating a patient with amenorrhea, a systematic approach should be used to consider each potential etiology. 

Risk Factors

Amenorrhea is not life-threatening, but the loss of the menstrual cycle can indicate severe underlying pathology. The ovarian hormone estrogen helps promote bone mineral density; therefore, if the underlying abnormality results in low estrogen, the patient has a higher risk of osteoporosis and fractures.

Assessment

During the history and physical examination, clinicians first need to ask about the patient's age and at what age the patient started menses during puberty (ie, menarche). This information is important to determine and differentiate between primary and secondary amenorrhea. If the patient was not menstruating, it must be primary amenorrhea. All other cases will be secondary amenorrhea.[10][11] 

It is essential to ask about symptoms that may suggest a potential cause for the patient's amenorrhea. One of the most crucial causes to rule out is pregnancy. Pregnancy symptoms include nausea, vomiting, fatigue, constipation, and breast tenderness. 

Clinical evidence that may suggest a hypothalamic disorder includes a low body mass index, a restrictive diet or eating disorder, and intense athletic training. A rare hypothalamic cause of amenorrhea is called Kallman syndrome, which results from an absence of specific neurons in the brain, resulting in amenorrhea and anosmia (ie, an inability to smell).

One of the most common pituitary causes of amenorrhea is a prolactin-secreting pituitary gland tumor called prolactinoma. Prolactin is the hormone responsible for producing breast milk. It is elevated naturally during lactation. Abnormal elevations in prolactin from a prolactinoma can result in milky nipple discharge in nonbreastfeeding patients, known as galactorrhea. Additionally, pituitary tumors can compress the optic chiasm and lead to visual disturbances or headaches.

Ovarian abnormalities include primary ovarian insufficiency (POI) and gonadal dysgenesis (ie, abnormal formation of the gonads). If the ovaries are unable to produce estrogen and progesterone, the endometrium will not be stimulated; menses will not occur. Signs of low estrogen include vaginal dryness, painful intercourse, hot flashes, and mood swings. Menopause naturally occurs in the early 50s but may occur in the 40s as well. POI refers to ovarian dysfunction resulting in cessation of menses before age 40. Patients with a history of autoimmune disease, chemotherapy, or radiation are at increased risk for POI.

Other endocrine disorders may also affect the HPO axis. The most common condition is polycystic ovary syndrome (PCOS). These patients have abnormally high levels of androgens (eg, testosterone), which can lead to male-pattern hair growth (eg, facial hair, chest hair) and acne.

A history of medication use is significant because antipsychotics are one of the most common causes of high prolactin levels, which lead to amenorrhea. The use of hormonal contraception, cocaine, opioids, and antiepileptics can also cause the failure of menstruation. Infiltrative diseases (eg, neurosarcoidosis, hemochromatosis, or cancer) and any chronic illness could also be causing amenorrhea.

Physical examination includes the general physical examination, which can be used to look for etiologic clues. The examination also should consist of the following:

• Measuring height, weight, and vital signs
• Calculation of body mass index (BMI) 
• Skin assessment for hirsutism, hair loss, or acne to investigate possible hyperandrogenemia
• Heart and lung exam for evidence of chronic disease
• Abdominal exam for signs of chronic illness or pelvic masses
• A breast exam for signs of nipple discharge; in adolescents, the maturation of the breasts should be noted (eg, Tanner staging)
• A pelvic exam for anatomic abnormalities; the outflow tract should be assessed for patency, and maturation of the external genitals and pubic hair should be noted.

Evaluation

Diagnostic studies should include the following:

• Beta hCG to exclude pregnancy 
• Prolactin level to exclude prolactinoma
• Testosterone and dehydroepiandrosterone sulfate (DHEAS) for exclusion of hyperandrogenism
• Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol to evaluate HPO axis function
• Pelvic ultrasound to assess the internal pelvic organs, including the uterus and ovaries
• Karyotyping if clinical suspicion for Turner syndrome, gonadal dysgenesis, müllerian agenesis (ie, absent uterus), or a disorder of sexual development (eg, complete androgen insensitivity syndrome)

Medical Management

Treatment mainly depends on the cause of amenorrhea. If the cause of amenorrhea is premature ovarian insufficiency (POI) or permanent HPO axis dysfunction, hormone replacement therapy (HRT) is indicated. Anatomic obstructions of the menstrual outflow tract require surgical correction. If amenorrhea is due to malnutrition, a proper diet plan can cure the patient successfully. For anorexia nervosa and stress-induced amenorrhea, cognitive-behavioral therapy and antidepressants can help. Dopamine agonist drugs like cabergoline can treat prolactinoma; if large, surgery can be curative. PCOS is typically treated with lifestyle modifications and combined oral contraceptive pills (OCPs), which help regulate menstruation and reduce hyperandrogenemia.[12][13][14]

Nursing Management

• Provide support.
• Encourage increased nutritional intake if the patient has a low body weight.
• Educate patients on the causes of amenorrhea.
• Educate patients that amenorrhea not intentionally induced by contraceptive medications (eg, continuous OCPs) may indicate a severe underlying condition.

When To Seek Help

Consultation with the appropriate specialized clinician should be sought for any of the following:

• Menarche has not occurred by age 15
• Menarche has not occurred within 3 years of initial breast development
• No signs of puberty by age 13
• No menstrual for 3 cycle lengths if previous cycles were regular or if no cycle in over 6 months if previous cycles were previously irregular
• Galactorrhea
• Vision changes, neurologic deficits, or headache symptoms
• Evidence of bone fracture
• Signs of mental health disorder (eg, depression)

Outcome Identification

• Achieve regular menstrual cycles.
• Resume fertility.

Monitoring

• Menstrual patterns
• Weight and BMI
• Bone mineral density (BMD) monitoring in patients with longstanding hypothalamic dysfunction
• Vital signs and cholesterol levels in patients with PCOS or at high risk for metabolic diseases (eg, hypertension and diabetes mellitus)
• Mood

Coordination of Care

Amenorrhea is a common problem at some point in the life of most females. After ruling out pregnancy, however, determining the cause can be a challenge. Aside from the gynecologist, the disorder is best managed by a multidisciplinary team of healthcare workers, including an endocrinologist, dietitian, internist, mental health worker, and fertility expert. The outcomes in women with amenorrhea depend on the cause. Some women with PCOS need lifelong treatment as they are at high risk for adverse cardiac events and metabolic syndrome. Patient education is vital, and the patient should be encouraged to pay attention to factors that affect bone density. In addition, these women need to eat a healthy diet fortified with calcium and participate in regular exercise.[2][15] 

Health Teaching and Health Promotion

• Eat a healthy diet.
• Instruct athletic patients that increased caloric intake requires intense, vigorous training.
• Instruct patients with a higher risk of osteoporosis to take vitamin D and calcium supplements.

Pearls and Other issues

The causes of amenorrhea are diverse, and an interprofessional approach is required. Premenopausal patients must be followed up for several years to ensure the menstrual cycle has returned.