Menstrual flow on progestin withdrawal indicates normal estrogen production

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A 26-year-old woman is evaluated for a 4-month history of amenorrhea. Menses began at age 13 years. At age 18 years, the patient was placed on an oral contraceptive pill to control heavy bleeding. She discontinued the oral contraceptive pill 4 months ago because she and her husband want to become pregnant, and she has had no menses since then. There is no family history of infertility or premature menopause.

On physical examination, vital signs are normal, and BMI is 24. There is no acne, hirsutism, or galactorrhea. Examination of the thyroid gland and visual field testing yield normal findings. Pelvic examination findings are also normal. An office pregnancy test is negative.

Laboratory studies:

Follicle-stimulating hormone	2 mU/mL (2 U/L)
Prolactin	17 ng/mL (17 µg/L)
Thyroid-stimulating hormone	1.1 µU/mL (1.1 mU/L)
Thyroxine (T₄), free	1.0 ng/dL (12.9 pmol/L)

Which of the following is the most appropriate next diagnostic test?

A) Measurement of the plasma dehydroepiandrosterone sulfate level
B) Measurement of serum estradiol level
C) MRI of the pituitary gland
D) Progestin withdrawal challenge

Answer and critique

The correct answer is D) Progestin withdrawal challenge. This item is available to MKSAP 15 subscribers as item 5 in the Endocrinology and Metabolism section.

The next step in the evaluation of this patient with secondary amenorrhea after stopping her oral contraceptive pill is a progestin withdrawal challenge. At one time, the use of oral contraceptives was thought to be associated with an increased risk of developing amenorrhea once the oral contraceptive pill was discontinued. Studies have since shown that the incidence of amenorrhea and other endocrinologic findings in women who discontinue oral contraceptive use is no different from that in women with spontaneous amenorrhea. Therefore, women who stop oral contraceptive use are evaluated in the same way as women who have secondary amenorrhea and have never used oral contraceptives.

This patient has an unremarkable personal and family medical history and no evidence of androgen excess. Results of her screening laboratory studies are negative for thyroid disorders, ovarian dysfunction, and hyperprolactinemia. Given these data, the differential diagnosis of this patient’s secondary amenorrhea includes anatomic defects and chronic anovulation, with or without estrogen. The differential diagnosis can be narrowed most effectively with a progestin withdrawal challenge. Menses after challenge excludes anatomic defects and chronic anovulation without estrogen. Therefore, a progestin withdrawal challenge is the most appropriate next step.

Polycystic ovary syndrome (PCOS) affects 6% of women of child-bearing age and typically presents with oligomenorrhea and signs of androgen excess (hirsutism, acne, and, occasionally, alopecia). Insulin resistance is a major feature of the disorder, as is overweight and obesity (although only 50% of women with PCOS are obese). Typically, testosterone and dehydroepiandrosterone sulfate levels are mildly elevated, and the luteinizing hormone to follicle-stimulating hormone ratio is greater than 2:1.

Measurement of dehydroepiandrosterone sulfate is rarely clinically useful. Positive withdrawal bleeding after the progestin withdrawal challenge suggests an estradiol level of greater than 40 pg/mL (146.8 pmol/L) and thus obviates the need for measurement of serum estradiol levels. An MRI of the pituitary gland is unnecessary at this point because her follicle-stimulating hormone, prolactin, and thyroid levels are all normal.

Key Point

Menstrual flow on progestin withdrawal indicates relatively normal estrogen production and a patent outflow tract, which limits the differential diagnosis of secondary amenorrhea to chronic anovulation with estrogen present.

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