Approach to primary amenorrhea: Clinical sciences

Primary amenorrhea is defined as the absence of menses by age fifteen in a patient with normal growth and secondary sexual characteristics. However, the absence of menses by age thirteen in a patient without secondary sexual characteristics also requires evaluation. The most common causes of primary amenorrhea are genetic or anatomic, but it is also caused by pituitary or hypothalamic dysfunction.

Once a diagnosis is established, psychosocial and emotional support are an essential part of patient care, as the treatment may be complex and lifelong, particularly if the underlying condition can not be corrected.

When assessing a patient who presents with primary amenorrhea, your first step is to obtain a focused history and physical exam, as well as an hCG to asses for pregnancy. If the hCG is positive, the patient is pregnant, so that’s your diagnosis.

On the other hand, if the patient isn’t pregnant, your next step is to assess secondary sexual characteristics. Let’s say your patient is 13 years old but has not developed secondary sexual characteristics like breast development, defined as breast Tanner Stage 1, and pubic hair Tanner Stage 2 to 3. In this case, you can continue your evaluation with FSH level.

Here’s a high-yield fact! Lack of breast development implies lack of estrogen, since estrogen is needed for thelarche, meaning breast development. So, estrogen is not being made either because the pituitary is not instructing the ovary to do so, or the ovary is not responding to it.

If the FSH is greater than twenty, the problem is likely gonadal. So, consider hypergonadotropic hypogonadism and order a chromosome analysis.

If the genotype is 46,XX, think about ovarian dysfunction and obtain prolactin and estradiol levels. With normal prolactin and low estradiol, the diagnosis is primary ovarian insufficiency.

Here is a clinical pearl! The etiology of primary ovarian insufficiency is often unknown but it is associated with other endocrinopathies, chemotherapy, radiation, infiltrative or inflammatory processes, and chromosomal translocations, as well as having a premutation in the Fragile X Messenger Ribonucleoprotein-1, or FMR-1 gene.

Okay, let’s go back to a chromosome analysis. If the genotype is 45,X, the diagnosis is Turner syndrome. Keep in mind that the genotype may also be one of many mosaic patterns such as 45,X/46,XX. Turner syndrome is often diagnosed at a young age because of the classic phenotype of short stature, webbed neck, and low hairline. However, there is a wide variation in phenotypic expression, and many patients are diagnosed at puberty or beyond.

Finally, if the genotype is 46,XY, the diagnosis is Swyer syndrome, also known as pure gonadal dysgenesis. This can be caused by mutations of the sex-determining region, or SRY gene, on the Y chromosome, or by a deletion of the segment of the Y chromosome containing the SRY gene. These patients have complete gonadal dysgenesis with streak gonads, female genitalia, and an intact mullerian system. This means that they do have a small uterus and fallopian tubes, as the streak gonads do not produce anti-Mullerian hormone.

Here’s a clinical pearl! These patients likely do not have breast development, but do have external and internal female genital tracts. Keep in mind that these streak gonads should be removed due to their high malignant potential.

Time for another clinical pearl! The initial management of patients with hypergonadotropic hypogonadism relates to pubertal development and possibly issues with gender identity. Later, patients may need counseling regarding fertility and long-term hormone replacement to decrease the risks of osteoporosis and cardiovascular disease.

Now that we’ve diagnosed patients with an elevated FSH, let’s move on to patients with a low or normal FSH. If the FSH is less than five, or if it is normal, the source of dysfunction is not gonadal but related to the hypothalamus or pituitary gland. Therefore, consider hypogonadotropic hypogonadism, and check a prolactin level.

When the prolactin is greater than fifty, your history and physical exam will help you reach a diagnosis. Some patients may report headaches and impaired vision including diplopia or a subjective decrease in visual fields or visual acuity, as well as galactorrhea. The physical examination may confirm visual field loss and decreased visual acuity. If this is the case, consider a pituitary gland tumor and check TSH and estradiol levels, and repeat the prolactin level. Also, obtain an MRI to see the sella turcica. In this situation, the TSH will be normal and the prolactin will be above fifty. The estradiol will probably be low but might be normal or even elevated. However, if the MRI demonstrates a pituitary mass, the diagnosis is a pituitary adenoma. More specifically, a microadenoma is less than 10 mm in size, and a macroadenoma is greater than 10 mm.

Now let’s talk about patients with a normal prolactin level, starting with hypothalamic dysfunction. The patient may report a history of weight loss, disordered eating, high-performance exercise, excess psychological stress, or chronic illness. Physical examination may reveal a BMI of less than 20. If you see these findings, consider hypothalamic dysfunction and obtain an FSH and LH, and perform a progestin challenge. A progestin challenge involves administering oral medroxyprogesterone acetate to the patient for five to ten days and monitoring for a withdrawal bleed. If the FSH is normal and the LH is low, and there is no withdrawal bleed after the progestin challenge, the diagnosis is functional hypothalamic amenorrhea.