A group of premenopausal women participate in a clinical trial for a medication used to treat endometriosis. Prior to initiation of the medication, all the women had normal premenopausal levels of gonadotropin-releasing hormone (GnRH), FSH, and estrogen. The medication is administered as an intramuscular depot that results in unchanging steady-state serum drug levels. The participants' hormone levels are recorded over the next two months, with the results shown below:
| Day 3 | Day 60 | |
| GnRH | Normal | Low |
| FSH | High | Low |
| Estrogen | High | Low |
The observed hormone levels are most consistent with administration of which of the following medications?
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Patients with endometriosis have painful menses due to extrauterine endometrial implants, which shed with menses and cause intraperitoneal irritation. Treatment aims to suppress menstruation by decreasing the activity of the hypothalamic-pituitary-ovarian axis (HPO axis).
Leuprolide is a GnRH receptor agonist (ie, GnRH analogue) that can be administered in either a pulsatile (mimicking endogenous GnRH secretion) or continuous fashion. Leuprolide, when administered continuously and over a prolonged duration, produces 2 distinct hormonal patterns:
Initially (ie, day 3), the GnRH receptor agonist effect of leuprolide stimulates the HPO axis; this causes increased FSH and estrogen secretion without a significant change in GnRH levels.
With prolonged use (ie, day 60), leuprolide causes desensitization and downregulation of pituitary GnRH receptors, which eventually leads to low FSH and estrogen levels. Because leuprolide is an exogenous GnRH analogue, its prolonged use also decreases endogenous GnRH levels.
The resulting hypogonadotropic, hypogonadal state induces amenorrhea, thereby improving dysmenorrhea associated with endometriosis.
(Choice A) Clomiphene competitively binds to hypothalamic estrogen receptors, which prevents estrogenic negative feedback. Therefore, GnRH, FSH, and estrogen levels are all elevated following treatment.
(Choice B) Danazol is primarily an androgen receptor agonist but can also suppress FSH and LH release from the anterior pituitary. Therefore, both FSH and estrogen would be low, and GnRH levels may be elevated due to reduced feedback inhibition.
(Choices C and D) Ethinyl estradiol and etonogestrel are a synthetic estrogen and progestin, respectively. These medications suppress both the hypothalamus and anterior pituitary gland, resulting in decreased GnRH, FSH, and estrogen levels. In this case, the study participants' initially elevated FSH and estrogen levels are more consistent with administration of a GnRH analogue.
(Choice E) Letrozole, an aromatase inhibitor, inhibits androgen-to-estrogen conversion. Therefore, estrogen levels are low initially, which stimulates high GnRH and FSH levels. Over time, high FSH levels eventually stimulate increased estrogen production, which mostly restores estrogenic negative feedback; therefore, GnRH, FSH, and estrogen levels may normalize by day 60.
Educational objective:
Continuously administered GnRH receptor agonists (eg, leuprolide) initially stimulate pituitary FSH and ovarian estrogen secretion. However, prolonged use eventually inhibits endogenous GnRH release and downregulates pituitary GnRH receptors, causing decreased GnRH, FSH, and estrogen levels. The resulting hypogonadotropic, hypogonadal state induces amenorrhea, thereby improving dysmenorrhea associated with endometriosis.