Approach to primary amenorrhea: Clinical sciences

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Introduction0:00–0:49

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.

History and physical examination0:49–1:58

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.

Hypergonadotropic hypogonadism1:58–2:12

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.

Primary ovarian insufficiency2:12–2:54

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.

Turner syndrome2:54–3:28

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.

Swyer syndrome3:28–4:51

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.

Hypogonadotropic hypogonadism4:51–5:18

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.

Pituitary adenoma5:18–6:24

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.

Functional hypothalamic amenorrhea6:24–7:53

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.
Here's a high-yield fact! Failure to have a withdrawal bleed signifies hypoestrogenism, since estrogen is required to make a proliferative endometrial lining.
The progestin challenge mimics ovulation and development of a corpus luteum, which would secrete progesterone during a normal menstrual cycle.
After 5 to 10 days, the progestin is stopped, which mimics involution of the corpus luteum, and should trigger a withdrawal bleed if the patient’s endometrium has been exposed to estrogen.Okay, let’s switch gears and consider Kallman syndrome, which is a congenital form of hypogonadotropic hypogonadism.

Kallman syndrome7:53–9:03

These patients present with a history of decreased or absent sense of smell which is referred to as hyposmia or anosmia.
In addition, the physical examination may be positive for color blindness and hearing loss. At this point, you should consider a genetic abnormality and obtain a genetic analysis.
If it is positive for the genetic mutation ANOS1, formerly known as KAL1, or another related mutation, the patient has Kallman syndrome.
Here is a high-yield fact! Kallman syndrome is part of a family of genetic disorders associated with abnormalities in the production or function of gonadotropin-releasing hormone, or GnRH.
There are many genotypic and phenotypic variations associated with isolated GnRH deficiency. Patients with Kallman syndrome have hyposmia or anosmia, but patients with other mutations have a normal sense of smell.After assessing for causes of primary amenorrhea, consider alternative diagnoses.

Consider alternate diagnoses9:03–9:24

These include constitutional delay of puberty, congenital adrenal hyperplasia, polycystic ovary syndrome, and hypothyroidism.Alright, now let’s go back to our initial assessment of secondary sexual characteristics.

Assess secondary sexual characteristics9:24–10:01

If the patient has not had menarche by age fifteen, but has normal secondary sexual characteristics like appropriate breast development, defined as breast Tanner stage 2 to 4, and pubic hair Tanner stage 2 to 3, then the next step is to obtain a pelvic ultrasound.
Here’s a high-yield fact! Remember, breast development means there’s estrogen present, so the ovaries should be working.If you see that a uterus is present on ultrasound and the patient reports lower abdominal pain, back pain, chronic constipation, and possible urinary retention, consider an outflow anatomic obstruction, which could be either cervical or vaginal.

Consider anatomic obstruction10:01–10:48

In cases when a physical exam reveals a shortened vagina with or without a palpable cervix, the diagnosis is a transverse vaginal septum.
On the other hand, if the physical exam shows a blue bulge at the introitus, the diagnosis is an imperforate hymen.Here’s one more clinical pearl!
Outflow anatomic obstructions can be managed by surgery alone and is unlikely to require other interventions. On the flip side, if the ultrasound shows that the uterus is absent, consider a chromosome abnormality and order a chromosome analysis.

Consider chromosome abnormality10:48–10:57

If the genotype is 46,XY, the diagnosis is androgen insensitivity syndrome. In addition to medical management, individuals with androgen insensitivity syndrome need psychosocial counseling and support as they may question their gender identity and often have symptoms of anxiety and depression.Here's a high-yield fact!

Androgen insensitivity syndrome10:57–11:40

Patients with androgen insensitivity syndrome have breast development but no internal female genital structures, while patients with Swyer syndrome do not have breasts but do have internal female genital structures.
However, both have external female-appearing genitalia.However, if the genotype is 46,XX, the diagnosis is Mullerian agenesis.

Mullerian agenesis11:40–12:20

Although the diagnosis of an absent uterus can be made by ultrasound, an MRI is often indicated to evaluate for rudimentary Mullerian structures, which are present in 90% of these patients.Here is a final high-yield fact!
Patients with Mullerian agenesis can have agenesis or atresia of the uterus, vagina, or both. Also, there is a high percentage of renal, skeletal, and abdominal wall anomalies associated with it.
So, keep this in mind when assessing patients.Alright, as a quick recap… Primary amenorrhea is the absence of menses by age fifteen in patients with normal growth and secondary sexual characteristics.

Review12:20–13:06

However, the absence of menses by age thirteen in a patient without secondary sexual characteristics also requires evaluation.
There are many causes of primary amenorrhea ranging from primary ovarian insufficiency, Turner syndrome, and Swyer syndrome to pituitary adenomas, functional hypothalamic amenorrhea, and Kallman syndrome.
In addition, some causes are associated with anatomic abnormalities such as a transverse vaginal septum or imperforate hymen, or the absence of the uterus such as androgen insensitivity
Approach to primary amenorrhea: Video, Steps, Uses | Osmosis