A 30-year-old nulligravid woman and her 31-year-old husband come to the office for an infertility evaluation. They have been unable to conceive despite 2 years of unprotected intercourse. The patient has had irregular periods since menarche, ranging between 30 and 70 days each cycle. Her BMI is 34 kg/m². Examination shows a small, anteverted uterus and bilateral enlarged ovaries. A urine pregnancy test is negative. The patient is prescribed letrozole for ovulation induction therapy. Which of the following is the mechanism of action of this medication?

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11ec160b_3bc6_37d6_9249_7f65c260e257_MD0001_00 This patient with irregular menses and enlarged ovaries likely has polycystic ovary syndrome (PCOS), a common cause of infertility due to anovulation. Ovulation induction agents (eg, letrozole, clomiphene) can be used to treat anovulatory fertility by increasing gonadotropin levels (ie, FSH, LH), which stimulates ovulation. Letrozole and clomiphene stimulate gonadotropin release via manipulation of different targets on the hypothalamic-pituitary-ovarian (HPO) axis: (Choice A) Bromocriptine, a dopamine receptor agonist, decreases prolactin secretion. Prolactin normally inhibits FSH release, so patients with hyperprolactinemia (eg, lactotroph adenoma) often have infertility. In these patients, bromocriptine can normalize prolactin levels and restore FSH and estrogen levels. However, the etiology of infertility in PCOS is not elevated prolactin but rather abnormal gonadotropin activity. (Choice C) Increased endometrial proliferation, which increases the risk for endometrial hyperplasia or cancer, occurs with the use of unopposed estrogen (eg, estrogen-only hormone therapy) or certain selective estrogen receptor modulators (eg, tamoxifen). (Choice D) When administered continuously, leuprolide (GnRH agonist) downregulates pituitary GnRH receptors and decreases FSH and estrogen, causing a hypogonadotropic, hypogonadal state clinically similar to that of menopause. Educational objective: Polycystic ovary syndrome can present with irregular menses, enlarged ovaries, and anovulatory infertility. Letrozole, an aromatase inhibitor, acts on the ovary and peripheral adipose tissue to inhibit androgen-to-estrogen conversion by the enzyme aromatase; the subsequent decrease in estrogen production causes the pituitary to release more FSH and LH, thereby stimulating ovulation. __________ References: Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. (http://www.ncbi.nlm.nih.gov/pubmed/29797697) Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. (http://www.ncbi.nlm.nih.gov/pubmed/25006718)

A 30-Year-Old Nulligravid Woman and Her 31-Year-Old Husband Come to the Office