Amenorrhea (Case 42)

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Amenorrhea (Case 42)

Amy Rogstad MD

Case: A 28-year-old woman presents with amenorrhea after discontinuing her oral contraceptive pills (OCPs). She desires pregnancy but has not conceived after 9 months of unprotected intercourse with her husband. Further questioning reveals a history of menarche at 13 years of age and normal development of secondary sexual characteristics. She believes breast development began around age 11 years. The patient’s menses were initially irregular; during the first year following menarche, she had fluctuations in cycle length and intermittently light and heavy menses. By the age of 15 years, however, her menses had become regular, occurring every 28 to 30 days and lasting about 5 days. She started OCPs when she was 20 years old both for contraception and to help with premenstrual cramping and mood swings. She continued on combination estrogen-progestin OCPs until the age of 27 years. Since stopping her OCPs, she has not had any regular menstrual cycles, with only two occasions of light bleeding lasting about 2 days each.

The patient has been feeling anxious about her inability to conceive and about her absent menses. Her husband has been evaluated and has been found to have a normal semen analysis. The patient reports that she has a history of headaches that began while she was in college but have worsened in the past 2 years. Currently she has headaches almost daily that are retro-orbital, dull, and aching. She denies any recent vision problems but has noticed occasional discharge from her breasts, which sometimes has a white, milky appearance. She has maintained a stable weight and is eating a balanced diet. She has not been sleeping well for the past 3 months, which she attributes to stress, and often feels fatigued during her workday as a high school teacher. She becomes tearful during the interview, and her husband, who accompanied her to the visit, holds her hand throughout the evaluation.

Differential Diagnosis

Hypothalamic amenorrhea (HA)


Pituitary adenoma

Primary ovarian insufficiency (POI)





Speaking Intelligently

Amenorrhea refers to the absence or abnormal cessation of the menstrual cycle. Evaluation for primary amenorrhea, the absence of menarche, should be initiated when there is failure to menstruate by 15 years of age in the presence of normal secondary sexual characteristics or within 5 years after breast development if that occurs before 10 years of age.

Secondary amenorrhea, cessation of menses after menarche that lasts 3 months or more, should be evaluated, but sometimes it should be evaluated after 1 to 2 weeks in patients with regular cycles to exclude pregnancy. Oligomenorrhea, less than nine menstrual cycles per year, also requires investigation. Pregnancy, lactation, and menopause account for about 96% to 97% of secondary amenorrhea. Of the remaining 3% to 4%, most will have one of several common causes for amenorrhea including hypothalamic-pituitary-ovarian (HPO) axis disorders, structural abnormalities, and disorders of androgen excess.


Clinical Thinking

• When evaluating a patient for amenorrhea, determine whether the problem is genetic, structural, or hormonal.

• In many patients with primary amenorrhea, chromosomal abnormalities or other genetic defects cause anovulation and amenorrhea.

• The presence or absence of breast tissue and uterine development can help the physician determine which of these disorders are most likely.

• Secondary amenorrhea usually occurs in patients with normal breast and uterine development and often involves an acquired or progressive disease process that halts or prevents regular menstrual cycles.

• When considering a patient with secondary amenorrhea, determine whether there is a hypothalamic, pituitary, or ovarian problem, or abnormal menses due to a hormonal excess or deficiency outside of the HPO axis.


• A detailed review of the patient’s menstrual history will help determine whether she has a primary or secondary problem.

• If the patient has never had menstrual cycles, review of secondary sexual characteristic development is particularly important. In a younger patient, parents may need to assist in this portion of the history.

• If the patient has experienced menarche, her subsequent menstrual pattern must be reviewed to determine whether she has achieved regular cycles or has had persistently irregular menses for months or years following menarche.

• In the case of secondary amenorrhea, the physician must determine whether the patient has any signs or symptoms suggestive of any of the etiologies listed above.

• The presence of headache, visual changes, galactorrhea, hirsutism, acne, weight changes, heat or cold intolerance, diarrhea or constipation, palpitations, or menopausal symptoms may help the physician focus the evaluation.

• The patient’s past medical, family, social, and psychiatric history should be reviewed, with special attention paid to any potential physical or psychological stressors.

• Careful review of the patient’s medication list is also important to assess for any agents that may impact hormone levels and/or signal underlying medical problems that have not been mentioned by the patient.

Physical Examination

• An external and internal genital exam is critical in all patients presenting with amenorrhea.

• Assess secondary sexual characteristics including breast development and axillary and pubic hair.

• The exam should specifically target the findings that could signal an underlying cause. For example, short stature, dysmorphic facial features, wide-set nipples, low hairline, or low-set ears should increase suspicion for Turner syndrome, one of the more common genetic causes for amenorrhea.

• Other physical findings that could relate to an underlying cause for amenorrhea include abnormal BMI or body habitus, neurologic defects (especially impaired visual fields), an abnormal thyroid exam, expressible breast discharge, acne, hirsutism, abnormal body fat distribution, abdominal striae, and abnormal reflexes.

Tests for Consideration

• A pregnancy test should be the first study obtained in patients presenting with amenorrhea, because pregnancy is the most common cause for secondary amenorrhea and should also be considered even when the amenorrhea seems to be primary.


Follicle-stimulating hormone (FSH) level: Assessment of the FSH level will help localize a hormonal problem in the HPO axis. If amenorrhea originates from an ovarian problem, the FSH should be elevated as the body tries to stimulate the ovaries to produce estrogen. If there is a hypothalamic or pituitary problem, however, the FSH may be low as a result of either decreased production in the pituitary or blunted stimulation of FSH from the hypothalamus.


Estrogen and luteinizing hormone (LH) levels:
In concert with the FSH level, estrogen and LH levels can help further delineate the location of a hormonal problem. Estrogen levels can be low in patients with high, low, or normal FSH. The FSH/LH ratio can point to hypothalamic dysfunction if elevated or a state of androgen excess (i.e., PCOS) if decreased.

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TSH: Will be decreased in hyperthyroidism and elevated in hypothyroidism, both of which can lead to menstrual irregularities.


Serum prolactin: Will be increased in the setting of prolactinoma.


Serum testosterone: Elevations in serum testosterone and other androgen hormones can indicate PCOS.


Karyotype analysis: If a chromosomal abnormality is suspected, a karyotype analysis may be necessary. Additional genetic testing may also be indicated, particularly in patients with primary amenorrhea.




→ Pelvic and/or transvaginal ultrasound: To evaluate the uterus and ovaries if internal genital exam is not possible or is inconclusive.


→ MRI of the brain and/or pituitary: To evaluate for mass lesions or other abnormalities.


→ CT scan of the abdomen and pelvis: To evaluate the adrenal glands and ovaries if there is a concern for adrenal Cushing syndrome, nonclassical CAH, or an androgen-secreting tumor in the adrenal gland or ovary.



Clinical Entities Medical Knowledge

Hypothalamic Amenorrhea

Amenorrhea caused by hypothalamic dysfunction probably represents a spectrum of related disorders including functional hypothalamic amenorrhea (FHA), amenorrhea in the female athlete, and amenorrhea associated with eating disorders. The precise mechanism of these disorders is not known, but all share a reduction in hypothalamic gonadotropin-releasing hormone (GnRH) production. FHA accounts for about 15% to 35% of cases of amenorrhea, making it one of the most common causes. The blunted GnRH release pattern leads to decreased FSH and LH but an increased FSH/LH ratio similar to that seen before puberty. Estradiol levels are also decreased, and patients are usually anovulatory. Leptin, an adipocyte hormone that acts as a satiety factor and a cofactor in the maturation of the reproductive system, has been implicated in the development of HA. Leptin can stimulate GnRH pulsatility and gonadotropin secretion and is decreased in patients across the spectrum of HA.


Amenorrhea in the female athlete is part of the “female athlete triad,” which also includes disordered eating and osteoporosis. Elite athletes in sports such as gymnastics, diving, and marathon running, as well as ballet dancers, are particularly vulnerable to this triad. In these patients, body fat often is below the 10th percentile.

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