There are three general causes of secondary amenorrhea: hormonal disturbance leading to a lack of a normal menstrual cycle, physical damage to the endometrium which prevents its growth, or obstruction of the outflow path of the menstrual blood.
There are many potential causes of secondary amenorrhea. Hormonal causes include pregnancy, lactation, thyroid dysfunction, hyperprolactinemia, hyperandrogenism (including polycystic ovarian syndrome), hypogonadotropic hypogonadism (hypothalamic-pituitary dysfunction), and suppression of the endometrium by hormonal birth control. Structural causes include damage to the endometrium (Asherman’s syndrome) and obstruction of the outflow tract (cervical stenosis).
History in a patient with secondary amenorrhea should include a full menstrual history. It is important to ascertain what birth control method the patient is using, as the progestin-containing birth control methods (including combined oral contraceptive pills) suppress growth of the endometrium and may lead to secondary amenorrhea. The pattern of menses is also important - does the patient have a long history of infrequent and irregular periods (suggesting anovulation), or was the amenorrhea abrupt? Were there any inciting events before the onset of secondary amenorrhea, such as childbirth, surgery, trauma, pelvic infection, or D and C? Patients should be asked about headaches, vision changes, and galactorrhea to assess for hyperprolactinemia from pituitary prolactinoma. Thyroid symptoms should also be evaluated (fatigue, weight changes, skin/hair/nail changes, palpitations, tachycardia). Hirsutism and acne suggest PCOS, so patients should be asked about unwanted hair growth and acne. Patients should be asked about stressors and exercise routines, as excessive stress or exercise may lead to hypogonadotropic hypogonadism.
Physical examination should include calculation of body mass index (BMI), as well as assessment of acanthosis nigricans, hirsutism, acne, and virilization.
The first step in the evaluation of any patient with secondary amenorrhea is a urine pregnancy test. Every contraceptive method has a failure rate, and anyone who is menstruating is potentially fertile, regardless of age. 
If the pregnancy test is negative, consider the clinical picture: hirsutism, acne, and a long history of infrequent and irregular menses suggest polycystic ovarian syndrome. By the Rotterdam criteria, a patient may be diagnosed with PCOS if she has two of the following: clinical or chemical hyperandrogenism, oligo- or amenorrhea, or polycystic ovaries on ultrasound. So if a patient has evidence of hirsutism and oligo- or amenorrhea, she can be diagnosed with PCOS without further laboratory testing or imaging.
If history and physical exam are not consistent with PCOS, a TSH should be ordered. Both hyper- and hypothyroidism can lead to menstrual dysfunction.
If TSH is normal, check a serum prolactin. Elevated serum prolactin suggests prolactinoma.
If prolactin is normal, the next step is to perform a progestin challenge. The patient is given oral progesterone (typically medroxyprogesterone, Provera, 10mg PO qDay x10 days). After stopping the progesterone, the patient would be expected to have a withdrawal bleed. If there is no withdrawal bleed, this means that a) there is insufficient endogenous estrogen to stimulate the growth of the endometrium, b) the endometrium has been damaged and is unable to grow, or c) the outflow of menstrual blood has been obstructed.
If a patient who has a withdrawal bleed also has hirsutism, suspect PCOS, ovarian or adrenal tumors, or Cushing syndrome.
If the patient does not experience a withdrawal bleed after progestin challenge, the next step is an estrogen-progestin challenge, in which the patient is given combined estrogen and progesterone (such as combined oral contraceptives). If the endometrium is intact and the outflow is not obstructed, the estrogen from the oral contraceptives would be expected to trigger the growth of the endometrium, and stopping the oral contraceptives should lead to a withdrawal bleed. If a patient has a negative progestin challenge (no withdrawal bleed after progesterone treatment) but a positive estrogen-progestin challenge (bleeding after one month of combined oral contraceptives), suspect hypogonadism and check FSH and estradiol.
If FSH is elevated and estradiol is low, suspect ovarian failure. (The pituitary is yelling at the ovaries to make estrogen, but they are not responding.)
If FSH is low and estradiol is low, suspect hypothalamic-pituitary dysfunction, such as due to stress, exercise, or pituitary infarct (Sheehan’s syndrome).
If the estrogen-progesterone challenge is negative (no bleeding after a month of combined oral contraceptives), suspect damage to the endometrium (Asherman’s syndrome) or outflow obstruction, such as from cervical stenosis. Transvaginal ultrasound may be performed to evaluate for hematometra (trapped menstrual blood in the uterus). Hysteroscopy would be an appropriate next step to evaluate for Asherman’s syndrome. If trapped blood is evacuated during cervical dilation, this suggests cervical stenosis as the cause and is also potentially curative.
Always remember to order a urine pregnancy test!
Bear in mind that hormonal contraceptives inhibit the hypothalamic-pituitary axis, so patients must be off hormonal contraceptives for at least three months before testing FSH and estradiol. Standard estradiol assays do not detect ethinyl estradiol, the estrogen in birth control.
Remember that it is common and not pathologic for patients on hormonal contraception to be amenorrheic. Amenorrhea on birth control does not require further evaluation unless there are other concerning symptoms.
There are many causes of secondary amenorrhea and thus it is important to have a multidisciplinary team involved in the investigation and management of this disorder. The biggest concern today apart from infertility is the ongoing bone loss that occurs as a result of lack of sex hormones. Healthcare workers including nurse practitioners should educate the patient on the importance of bone health while they are being worked up for the cause of the secondary amenorrhea. Besides increasing calcium in the diet, the patient should participate in regular exercise. The loss of fertility in many women is also associated with significant emotional distress and hence a referral to a mental health counselor is recommended. The outcomes of women with secondary amenorrhea depend on the cause. 
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