A 38-year-old woman comes to the emergency department due to an acute episode of heavy menstrual bleeding. The patient has a history of menorrhagia, with monthly cycles lasting 7-10 days and brisk blood flow with the passage of large clots. Pelvic examination reveals an enlarged fibroid uterus, and she is found to have significant anemia due to blood loss. The patient is prescribed continuous leuprolide therapy. After several weeks, which of the following sustained hormonal changes are expected to have occurred as a result of the treatment?
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This patient has symptomatic uterine fibroids (ie, leiomyomas), which are benign, estrogen-dependent tumors that can cause bulk (eg, pelvic pressure, constipation) or bleeding symptoms such as heavy menses and blood loss anemia.
Patients with symptomatic fibroids may be treated with leuprolide, a GnRH receptor agonist that initially stimulates gonadotropin (ie, FSH, LH) secretion from the pituitary. However, unlike endogenous GnRH (which is released in a pulsatile fashion), continuous leuprolide therapy (eg, depot injection formulations) eventually causes desensitization and downregulation of pituitary GnRH receptors, leading to decreased FSH (hypogonadotropic) and decreased estrogen (hypogonadal) levels. Over time, leuprolide's feedback inhibition at the hypothalamic level also leads to decreased endogenous GnRH release.
The hypogonadotropic, hypogonadal state induced by leuprolide can shrink estrogen-dependent fibroids and induce amenorrhea, thereby improving bleeding symptoms.
(Choice A) Clomiphene, used for ovulation induction to treat infertility, acts on the hypothalamus by interfering with hypothalamic estrogen receptors, thereby inhibiting normal negative feedback from estrogen; this promotes GnRH and FSH secretion and stimulates ovulation.
(Choice B) Letrozole, an aromatase inhibitor, decreases peripheral (ie, adipose) and ovarian conversion of androgens to estrogens; the decreased estrogen level releases estrogenic negative feedback on the hypothalamus to increase GnRH and FSH secretion. Letrozole is used as adjuvant therapy for estrogen receptor–positive breast cancer in postmenopausal women (by decreasing estrogen levels) and for ovulation induction (by stimulating GnRH and FSH release).
(Choice C) Depot medroxyprogesterone acetate (DMPA), a progesterone contraceptive, inhibits pituitary secretion of gonadotropins (ie, FSH, LH) to prevent ovulation. The decrease in FSH causes increased hypothalamic GnRH secretion and suppressed ovarian estrogen production.
(Choice D) Exogenous estrogen–containing medications (eg, combined estrogen-progestin oral contraceptives, menopausal hormone therapy) increase estrogen levels, producing negative feedback at the hypothalamus and decreased GnRH and FSH levels.
Educational objective:
Leuprolide is a GnRH agonist used to treat symptomatic uterine fibroids (eg, heavy menses, anemia). When administered in a continuous fashion, leuprolide inhibits the release of endogenous hypothalamic GnRH and downregulates pituitary GnRH receptors, thereby decreasing GnRH, FSH, and estrogen levels (ie, hypogonadotropic hypogonadism).