A 16-Year-Old With Amenorrhea and Delayed Breast Development

Varshini Chakravarthy, MD; Sehar Ejaz, MD

Disclosures

January 14, 2020

Discussion

The case patient is a 16-year-old girl who has yet to reach menarche, 3.5 years after the start of breast development. Primary amenorrhea is defined as the lack of menses by age 15 years or more than 3 years after the initiation of secondary characteristics. As such, this patient meets the criteria for primary amenorrhea. The likely differential diagnosis for this presentation includes constitutional delay of puberty; structural defects, such as imperforate hymen or an absent uterus (as in Mayer-Rokitansky-Küster-Hauser syndrome); hormonal disorders, such as congenital adrenal hyperplasia, hypothyroidism, hypopituitarism, and premature ovarian insufficiency; and chromosomal anomalies, such as Turner syndrome.[1]

The patient in this case has high levels of follicle-stimulating hormone and luteinizing hormone, with low levels of estrogen, inhibin A, and anti-Müllerian hormone, suggesting premature ovarian insufficiency. This should be suspected in patients who present with hypergonadotropic hypogonadism associated with primary amenorrhea or secondary amenorrhea, defined as the absence of menses for 6 months before 40 years of age. In mild cases, it may also present with oligomenorrhea and low estrogen levels, such as hot flashes.

This complex diagnosis has a multitude of proposed causes, with many etiologies yet to be discovered. The known causes of this disorder can be roughly categorized as iatrogenic and sporadic. Iatrogenic causes include radiation, chemotherapy, or surgery. Sporadic etiologies can be further categorized as autoimmune, idiopathic, genetic (eg, galactosemia, X-linked disorders), or infectious (eg, cytomegalovirus, varicella). Roughly 20%-25% of premature ovarian insufficiency cases can be attributed to chromosomal disorders, such as Turner syndrome, which afflicts 1 in 2500 females.[2] Other genetic disorders (eg, X chromosome microdeletions or translocations, fragile X syndrome) and carriers of FMR1 premutation are also associated with premature ovarian failure. Many other genes, such as STAG3, BRCA2, ESR2, and NOBOX, play an important role in ovarian formation and function. Mutations in these genes and several other transcription factors, such as BMP15, are associated with 46,XX gonadal dysgenesis.[3]

Autoimmune disorders (eg, syndrome of polyglandular autoimmune failure type 1 and II) often present with premature ovarian failure. These patients usually present with a history of autoimmune thyroid and adrenal disorders. Positive findings for autoantibodies against adrenal and thyroid tissue should raise suspicion.[2] The presence of antiovarian antibodies confirms the diagnosis.

The patient in this case did not have anything in her history suggestive of iatrogenic causes of premature ovarian insufficiency. She also did not have antiovarian antibodies, ruling out autoimmune etiology of dysfunctional ovaries. Karyotyping and genetic workup resulted in her diagnosis.

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