A 34-year-old woman comes to the office for evaluation of amenorrhea. Last year the patient had a missed abortion that was surgically managed with suction curettage. At her follow-up visit a few weeks later she had a copper-releasing intrauterine device placed. Her menstrual periods were initially irregular and heavy, but the bleeding became increasingly lighter. Now the patient has not had a menstrual period in 6 months. Prior to the intrauterine device placement she had regular menses. The patient has had no weight changes, changes in vision, or galactorrhea. She has generalized anxiety disorder. Her older brother has severe intellectual disability due to fragile X syndrome. Vital signs are normal. BMI is 22 kg/m². Pelvic examination shows a small, mobile uterus with no adnexal masses. There is no tenderness over the perineum with speculum examination. Pregnancy test is negative. TSH is normal and FSH is elevated. A progesterone challenge is performed and the patient has no withdrawal bleeding. Which of the following is the most likely diagnosis in this patient?

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11ec25c8_d99e_7454_bc81_5fb60ee10d3c_MD0003_00 This patient has secondary amenorrhea (lack of menses ≥6 months in a patient with previously irregular cycles) and an elevated FSH level suggestive of ovarian failure. In women age <40, this is consistent with the diagnosis of primary ovarian insufficiency (POI). In POI, the lack of ovarian function results in low estrogen levels, evidenced by a lack of withdrawal bleeding after a progesterone stimulation challenge. In these patients, the low estrogen levels limit endometrial proliferation; therefore, there is no endometrium to slough off with progesterone stimulation. POI is common in women who are fragile X syndrome (FMR1 gene) premutation carriers (ie, those with 50-200 CGG repeats). These women often have associated neurobehavioral clinical features (eg, generalized anxiety disorder, autism) and a family history of fragile X syndrome, as seen in this patient. This premutation causes an FMR1 mRNA overexpression, which is hypothesized to have a cytotoxic effect on ovarian primordial follicles and result in accelerated follicle depletion. Due to this association, women with ovarian failure at age <40 and no other obvious cause for POI (eg, Turner syndrome) are tested for FMR1 gene mutations. Management of POI includes estrogen-containing therapy to reduce the risk of comorbidities associated with low estrogen levels (eg, osteoporosis, cardiovascular disease). (Choice A) Functional hypothalamic amenorrhea typically occurs in women with a relative caloric deficiency (eg, athletes, eating disorders) due to decreased GnRH secretion. Patients have no withdrawal bleeding after a progesterone challenge due to low estrogen levels; however, FSH levels are low. (Choice B) Intrauterine adhesions (Asherman syndrome) can cause secondary amenorrhea in patients who undergo intrauterine procedures (eg, suction curettage) due to endometrial damage and fibrous tissue formation. Patients with intrauterine adhesions have no withdrawal bleeding on a progesterone challenge; however, they have normal FSH levels, making this diagnosis less likely. (Choice C) Levonorgestrel-releasing intrauterine devices (IUDs) can cause amenorrhea by thinning the endometrium. In contrast, copper-releasing IUDs can cause heavy menstrual bleeding and dysmenorrhea. FSH levels are normal in both. (Choice D) Polycystic ovary syndrome can present with abnormal uterine bleeding and secondary amenorrhea. This diagnosis is unlikely because these patients have normal estrogen levels and, therefore, would have withdrawal bleeding after a progesterone challenge. Educational objective: Primary ovarian insufficiency (POI) occurs due to accelerated ovarian follicle depletion in women age <40, resulting in secondary amenorrhea, elevated FSH, and low estrogen levels. A risk factor for POI is FMR1 gene premutation for fragile X syndrome. References: Genetics of primary ovarian insufficiency: a review. (http://www.ncbi.nlm.nih.gov/pubmed/25227694) Primary ovarian insufficiency. (http://www.ncbi.nlm.nih.gov/pubmed/20708256) Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency. (http://www.ncbi.nlm.nih.gov/pubmed/23703681)

A 34-Year-Old Woman Comes to the Office for Evaluation of Amenorrhea