Approach to secondary amenorrhea: Clinical sciences

Secondary amenorrhea is defined as the absence of menses for more than 3 months in a patient who has a history of regular menstrual cycles; or greater than 6 months in a patient with a history of irregular menstrual cycles. Secondary amenorrhea can be caused by dysfunction of the hypothalamus, pituitary, ovaries, thyroid, or uterus. Secondary amenorrhea is important because it can be a sign of systemic illness; it is associated with infertility; and, in some cases, can lead to an increased risk of endometrial cancer, osteoporosis, or cardiovascular disease.

The first step in evaluating a patient who presents with secondary amenorrhea is to perform a focused history and physical examination. You should also obtain some labs, including hCG, FSH, estradiol, prolactin, and TSH. The first test you should always look at when evaluating menstrual abnormalities is the hCG because if it’s positive, you have a diagnosis of pregnancy, which is a common cause of secondary amenorrhea.

Here’s a clinical pearl! Many hormonal contraceptives, such as continuous oral contraceptives or progestin-containing intrauterine devices, have the desired side effect of amenorrhea. This effect can persist for several months after discontinuation of these medications, and can also affect the assessment of hormone levels. Be sure to keep this in mind when evaluating a patient for amenorrhea.

Once you have ruled out pregnancy, consider and assess for other causes of secondary amenorrhea. The FSH level is a useful tool to triage patients as it helps to determine where the dysfunction lies along the hypothalamic-pituitary-ovarian axis. Remember that an elevated FSH indicates that the ovaries are not producing enough estradiol, while a low FSH indicates that there might be dysfunction at the level of the hypothalamus or pituitary gland.

Let’s start with ovarian dysfunction. In this case, the FSH is greater than twenty and history reveals a patient under the age of forty, with vasomotor symptoms, vaginal dryness, and possibly mood changes, or a history of chemotherapy or radiation therapy. The physical exam reveals vulvovaginal atrophy, and the labs demonstrate a normal TSH and prolactin, with low estradiol.

In this case, consider ovarian dysfunction and repeat the FSH and estradiol in 2-4 weeks. It is important to repeat these tests, since the values can fluctuate significantly throughout the menstrual cycle and can be difficult to interpret when a patient has amenorrhea. If the second set of labs confirms an FSH greater than twenty and a persistently low estradiol, that’s primary ovarian insufficiency.

Here’s a high-yield fact! If patients with primary ovarian insufficiency, formerly called premature menopause, are not treated with systemic hormone therapy, they are at increased risk for osteoporosis and cardiovascular disease.

Next, let’s talk about normal FSH levels in the setting of hyperandrogenism. The patient may present with a history of weight gain and will confirm that they are not taking exogenous androgens. The physical exam may reveal a body mass index greater than twenty five, hypertension, acne, hirsutism, or acanthosis nigricans; while the pelvic exam is normal. In addition, the TSH, prolactin, and estradiol are within normal range.

If this is the case, think about hyperandrogenism and obtain a total testosterone; 17- Hydroxyprogesterone, or 17-OHP; dehydroepiandrosterone sulfate, or DHEA-S, and a pelvic ultrasound. The testosterone and DHEA-S may be elevated and the 17-OHP will be normal. The pelvic ultrasound may show polycystic appearing ovaries, which is defined as twenty or more follicles measuring two to nine millimeters in diameter, or as an increased ovarian volume, greater than ten centimeters cubed, on either ovary. With these findings, you have the diagnosis of polycystic ovary syndrome or PCOS.

Here’s a clinical pearl! Traditionally, PCOS is diagnosed based on clinical features, like the Rotterdam Criteria. The 3 criteria are: ovulatory dysfunction, such as irregular cycles, hyperandrogenism, and polycystic ovarian appearance on pelvic ultrasound. If 2 out of the 3 Rotterdam criteria are met, then the diagnosis is PCOS.

And now another high-yield fact! Patients with PCOS who have prolonged amenorrhea are at risk for endometrial intraepithelial neoplasia, also known as endometrial hyperplasia and endometrial carcinoma. These patients have normal estrogen levels but chronic anovulation and relatively low progesterone, which causes endometrial proliferation without shedding, leading to endometrial thickening, glandular crowding, and malignancy.

Now let’s consider hypothalamic dysfunction. History might reveal weight loss, disordered eating, high-performance exercise, chronic illness, or excess psychological stress. Physical examination may reveal a body mass index of less than 20, vulvovaginal atrophy, and breast atrophy. The lab values will show normal TSH, normal prolactin, and low estradiol.

In this case, consider hypothalamic dysfunction and check FSH and LH levels. Also perform a progestin challenge test, which involves prescribing oral medroxyprogesterone acetate to the patient for 5 to 10 days, and monitoring for a withdrawal bleed. If the FSH is normal and LH is low, and there is no withdrawal bleeding after the progestin challenge, the diagnosis is functional hypothalamic amenorrhea.