A 15-year-old girl is brought to the clinic because her mother is worried the patient has not yet had her period. The patient’s older sister had her first period at age 14. The mother had her first period at age 13. The patient reports she is doing well in school and is on the varsity basketball team. Her medical history is significant for asthma and atopic dermatitis. Her medications include albuterol and topical triamcinolone. Her temperature is 98°F (36.7°C), blood pressure is 111/72 mmHg, pulse is 65/min, and respirations are 14/min with an oxygen saturation of 99% on room air. Her body mass index (BMI) is 19 kg/m^2. Physical exam shows absent breast development and external genitalia at Tanner stage 1. Serum follicle-stimulating hormone (FSH) level is measured to be 38 mIU/mL. Which of the following is the most appropriate next diagnostic step?
CYP17 gene work-up
Gonadotrophin-releasing hormone stimulation test
Karotype
Luteinizing hormone levels
Karotype
The patient is presenting with primary amenorrhea and an increased follicle-stimulating hormone (FSH) level, suggesting a gonadal abnormality and making karyotyping the most appropriate next step in management.

Primary amenorrhea can be diagnosed if a patient has normal secondary sex characteristics but no menarche by age 16, or if she has no secondary sex characteristics and no menarche as early as age 14. Primary amenorrhea is caused by either hypothalamic/pituitary (central) or gonadal (peripheral) abnormalities. Increased FSH indicates a peripheral cause or hypergonadotropic hypogonadism. Karyotyping would be the most appropriate next diagnostic step because these disorders can include Turner syndrome and androgen insensitivity syndrome.

Gravholt et al. review the evidence regarding the diagnosis and treatment of Turner syndrome. They discuss how this disease presents with hypergonadotropic hypogonadism. They recommend growth hormone therapy and hormone replacement therapy in these patients.

Incorrect Answers:
Answer A: CYP17 gene work-up should be done in patients with primary amenorrhea, an absence of secondary sex characteristics, elevated FSH, and hypertension. Alterations in the CYP17 gene can cause congenital adrenal hyperplasia due to 17-hydroxylase deficiency. The resulting excess of deoxycorticosterone is associated with hypertension and hypokalemia. Treatment is with hormone repletion therapy.

Answer B: Estrogen levels would be low in this patient as evidenced by her absence of breast development. Therefore, measuring estrogen levels would provide no additional diagnostic information. Estrogen levels may be useful in cases of peripheral gonadotropin resistance but these are rare.

Answer C: Gonadotropin-releasing hormone (GnRH) stimulation test would be the next diagnostic step if FSH were decreased. A decrease in FSH indicates a central cause or hypogonadotropic hypogonadism. A GnRH stimulation test is used to assess whether the central abnormality is due to the hypothalamus or the pituitary.

Answer E: Luteinizing hormone (LH) levels with a repeat FSH level may be helpful if FSH is low or normal. Low or normal FSH levels indicate hypogonadotropic hypogonadism as caused by hypothalamic-pituitary axis abnormalities. Cases of high FSH represent a different diagnostic entity as adequate gonadotropins are produced.

Bullet Summary:
In a patient with primary amenorrhea and an increased FSH, the next step in management is karyotyping.