Today’s USMLE® Step 1 question of the day focuses on a 35-year-old woman presents to her primary care provider for evaluation of endometriosis. What medication side effects is this patient at risk of developing? Let’s find out!
A 35-year-old woman presents to her primary care provider for evaluation of endometriosis. The patient was diagnosed nine months ago, and she has taken combined oral contraceptives and ibuprofen. The patient continues to experience significant pain with menstruation and sexual intercourse. Temperature is 37.6°C (99.7°F), blood pressure is 120/75 mmHg, and pulse is 64/min. Pelvic examination is notable for rectovaginal tenderness and nodularity of the uterosacral ligament. The patient is initiated on a new medication that binds directly to GnRH receptors. When this medication is administered continuously, it can lead to the downregulation of GnRH receptors.
Which of the following side effects is this patient at risk of developing after starting this new medication?
A. Deep vein thrombosis
B. Endometrial malignancy
C. Pelvic inflammatory disease
D. Reduced bone density
E. Ovarian hyperstimulation syndrome
Scroll down for the correct answer!
The correct answer to today’s USMLE® Step 1 Question is…
D. Reduced bone density
Correct: See Main Explanation.
Incorrect Answer Explanations
A. Deep vein thrombosis
Incorrect: Patients taking estrogen-containing contraceptives are at risk for developing deep vein thrombosis (DVT). This patient was initiated on a GnRH analog (e.g. leuprolide). GnRH analogs can predispose patients to develop menopause-like symptoms like nausea, hot flashes, and osteoporosis.
B. Endometrial malignancy
Incorrect: Exogenous estrogen use and specific selective estrogen receptor modulators (e.g. tamoxifen) can increase the risk of developing endometrial cancer. These medications do not directly bind to GnRH receptors.
C. Pelvic inflammatory disease
Incorrect: This patient was most likely started on a GnRH agonist to treat endometriosis. However, GnRH agonists are not known to increase the risk of developing pelvic inflammatory disease. GnRH agonists can cause menopause-like and andropause-like symptoms, including hot flashes, osteoporosis, reduced libido, impotence, and gynecomastia (in men). Furthermore, patients may experience nausea, lightheadedness, and injection site irritation.
E. Ovarian hyperstimulation syndrome
Incorrect: Clomiphene acts as an estrogen receptor antagonist in the hypothalamus, reducing estrogenic negative feedback inhibition. These changes ultimately result in increased LH and FSH secretion from the pituitary gland. Clomiphene can lead to ovarian hyperstimulation syndrome, manifest with abdominal distention/pain, rapid weight gain, dyspnea, and respiratory distress. GnRH agonists (e.g. leuprolide) are not associated with ovarian hyperstimulation syndrome.
Main Explanation
This patient presented with endometriosis and was started on a GnRH agonist, which can cause reduced bone density and osteoporosis.
GnRH agonists (e.g., leuprolide, nafarelin, triptorelin) bind to GnRH receptors in the pituitary gland. These medications can be given in either a pulsatile or continuous fashion. When administered in a pulsatile pattern, they mimic the physiological secretion of GnRH from the hypothalamus. GnRH agonists bind and activate GnRH receptors, thereby increasing the downstream synthesis of LH, FSH, and sex hormones. This method of administration was historically used to treat infertility but is rarely used nowadays due to the availability of better alternatives.
In contrast, continuous administration of GnRH agonists caused an initial, transient stimulation of GnRH receptors and increased sex hormone synthesis. Over time this results in a downregulation in the number of GnRH receptors, and the body becomes less sensitive to the hormone. These changes decrease the downstream synthesis of LH, FSH, and sex hormones. Continuous administration can treat endometriosis, uterine fibroids, prostate cancer, and precocious puberty.
When given continuously, the medication can cause menopause-like and andropause-like side effects. These symptoms include hot flashes, reduced bone density, decreased libido, as well as impotence and gynecomastia in men. Furthermore, patients may experience nausea/vomiting, lightheadedness, and injection site irritation.
Major Takeaway
GnRH agonists can be given in a pulsatile pattern to treat infertility or a continuous pattern to treat conditions such as endometriosis, uterine fibroids, and prostate cancer. If given continuously, GnRH agonists can cause menopause-like and andropause-like side effects, including hot flashes, reduced bone density, and decreased libido.
Want to learn more about this topic?
Watch this Osmosis video: Endometriosis: Clinical sciences
References
- Swayzer, D.V., Gerriets, V. (2020) “Leuprolide”. StatPearls [Internet]. Web Address: https://www.ncbi.nlm.nih.gov/books/NBK551662/.
- Wilson, A.C., Meethal, S.V., BOwen, R.L., Atwood, C.S. (2007) Leuprolide acetate: A drug of diverse clinical applications. Expert Opinion on Investigational Drugs. 16(11), 1851-1863. Doi: 10.1517/13543784.16.11.1851.
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