Approach to secondary amenorrhea: Clinical sciences

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Introduction0:00–0:45

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.

Assess for Pregnancy 0:45–1:41

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.

Other causes of amenorrhea1:41–2:14

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.

Primary ovarian insufficiency2:14–3:30

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.

PCOS3:30–5:45

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.

Functional Hypothalamic Amenorrhea 5:45–7:09

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.
Time for another clinical pearl! The female athlete’s triad is a type of functional hypothalamic amenorrhea that was first diagnosed among competitive athletes and is defined by disordered eating, amenorrhea, and osteopenia or osteoporosis.
Consider bone density testing for all patients with amenorrhea who are exercising intensely and have disordered eating.Next, let’s go over thyroid gland dysfunction.

Hypothyroidism7:09–7:36

These patients may report fatigue, lethargy, and cold intolerance. The pelvic examination is normal, while labs show elevated TSH, normal prolactin, and normal estradiol levels.
At this point, you can consider thyroid gland dysfunction and obtain a free thyroxine, or free T4, level. If it’s low the diagnosis is hypothyroidism.
Moving on, let’s talk about anatomic obstruction. In this case, the history reveals prior intrauterine surgery and possibly cyclic pelvic pain or recurrent pregnancy loss.

Asherman syndrome 7:36–8:29

The pelvic exam will be normal, but the cervical os might be stenotic. The TSH, prolactin, and estradiol levels are normal.
With these findings, consider anatomic obstruction and obtain a pelvic ultrasound. The ultrasound may show heterogeneous endometrial irregularity, and endometrial fluid keeping with hematometra, as well as bridging synechia.
The next step is to perform a diagnostic hysteroscopy and evaluate for intrauterine synechiae or adhesions. If they are present, the diagnosis is Asherman syndrome.So let’s move on to secondary amenorrhea with low FSH levels, generally less than five.

Pituitary adenoma8:29–10:02

starting with pituitary gland tumors. The patient may report headaches; impaired vision such as diplopia, decreased visual acuity or subjective visual field loss; and the presence of galactorrhea.
The physical examination may confirm visual field loss or diminished visual acuity and the pelvic exam will be normal. The labs will demonstrate normal TSH and elevated prolactin.
The estradiol level is usually low but may be normal or elevated. A prolactin level greater than twenty is abnormal but suppression of menses does not usually occur until the prolactin is above fifty.
With prolactin greater than fifty, consider a pituitary tumor, repeat the prolactin level, and perform an MRI to see the sella turcica.
If the repeat prolactin is greater than fifty and the imaging demonstrates a pituitary mass, the diagnosis is a pituitary adenoma.
Here’s one more high-yield fact! Pituitary adenomas are classified by size.
Macroadenomas are greater than 10 mm and microadenomas are less than 10mm. Both types of masses can cause hyperprolactinemia but the larger masses are more likely to cause headaches as well as visual changes due to compression of the optic chiasm.
Finally, let's discuss anterior pituitary necrosis. These patients have a history of severe postpartum hemorrhage requiring a blood transfusion.

Sheehan syndrome10:02–11:40

They also report the inability to lactate and may describe fatigue, constipation, cold intolerance, and vasomotor symptoms.
Symptoms are often mild and may not appear for several months or even years after childbirth. The physical exam findings might include weight loss and loss of axillary and pubic hair.
Labs may demonstrate a low TSH, as well as a low prolactin and estradiol. With these findings, consider anterior pituitary necrosis.
Obtain a CBC, BMP, cortisol, and growth hormone levels; as well as an MRI of the sella turcica. The lab results may demonstrate anemia, hyponatremia, and hypoglycemia, which are indicators of adrenal insufficiency, as well as low cortisol and low growth hormone levels.
The MRI may demonstrate an empty sella, or small pituitary gland, confirming that the diagnosis is Sheehan syndrome.Let’s take a break with a clinical pearl!
Due to advances in obstetrical care, Sheehan syndrome has become less common. However, any patient with severe postpartum hemorrhage should be evaluated for adrenal insufficiency immediately postpartum and assessed for other signs of hypopituitarism in the following 4 to 6 weeks.
After considering and assessing for these causes of secondary amenorrhea, consider and assess for alternative diagnoses.

Assess for alternative diagnoses11:40–12:01

These include an androgen-secreting tumor, non-classical congenital adrenal hyperplasia, lactational amenorrhea, hormonal contraceptives, and menopause.
Alright as a quick recap… Secondary amenorrhea is defined as the absence of menses for three months in a patient with a history of regular menses, or six months in a patient with a history of irregular cycles.

Review12:01–12:31

Common causes include primary ovarian insufficiency, PCOS, functional hypothalamic amenorrhea, and hyperprolactinemia, as seen with a pituitary adenoma.
Other causes include hypothyroidism, Asherman syndrome,