WBR0510

Author	[[PageAuthor::Gonzalo A. Romero, M.D. [1] (Reviewed by Will Gibson)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pharmacology, MainCategory::Physiology
Sub Category	SubCategory::Endocrine, SubCategory::Reproductive
Prompt	[[Prompt::A pharmacist is planning a study with mice in order to determine the effects of a novel drug called “Compound A572”. He knows that the drug is supposed to work in the hypothalamus, to regulate the release of different pituitary hormones. He measures serum concentration of hypothalamic hormones and determines that the drug causes different changes in FSH and LH if dosed continuously or in a pulsatile fashion. Which of the following drugs has a similar mechanism of action as “Compound A572”?]]
Answer A	AnswerA::Flutamide
Answer A Explanation	[[AnswerAExp::Flutamide is a nonsteroidal competitive inhibitor of androgens at the androgen receptor. It is used to treat prostate cancer and hyperandrogenism in polycystic ovarian syndrome.]]
Answer B	AnswerB::Finasteride
Answer B Explanation	[[AnswerBExp::Finasteride is a 5 alpha-reductase inhibitor used to treat benign prostatic hyperplasia and male-pattern baldness.]]
Answer C	AnswerC::Mifepristone
Answer C Explanation	[[AnswerCExp::Mifepristone is a competitive inhibitor of progestins at the progesterone receptors. It is used to terminate pregnancy in combination with misoprostol (PGE1 analogue).]]
Answer D	AnswerD::Ketoconazole
Answer D Explanation	[[AnswerDExp::Ketoconazole is a steroid synthesis inhibitor that inhibits desmolase, the enzyme responsible for transforming cholesterol into pregnenolone.]]
Answer E	AnswerE::Leuprolide
Answer E Explanation	[[AnswerEExp::Leuprolide is a GnRH analogue. When dosed continuously, it inhibits the production of FSH and LH, thereby leading to hypogonadism. When dosed in a pulsatile manner, it increases the production of FSH and LH. In turn, FSH and LH stimulate the production of sex hormones.]]
Right Answer	RightAnswer::E
Explanation	[[Explanation:: Leuprolide is a GnRH analogue. GnRH is normally secreted in a pulsatile fashion to stimulate the HPA axis. GnRH secretion is negatively regulated by prolactin secreted in the pituitary. GnRH is thought to be positively regulated by kisspeptin, but the precise circuitry underlying the GnRH pulse generator is still unclear. Leuprolide acts similarly to endogenous GnRH; when used in pulsatile fashion, it acts as an agonist, while if used continuously, it acts as an antagonist. Continuous dosing of the drug causes the pituitary to downregulate GnRH receptors due to negative feedback. The anterior pituitary thereby decreases the production of Follice Stimulating Hormone (FSH) and Leutenizing Hormone (LH). Recall that FSH and LH are responsible for stimulating the release of sex hormones in both men and women. Leuprolide therefore causes hypogonadism and has important therapeutic roles in diseases associated with the activity of sex hormones. Leuprolide is often used continuously with flutamide to treat prostatic cancer or uterine fibroids. Leuprolide is administered in pulsatile dosing in cases of infertility. Educational Objective: Leuprolide is a GnRH analogue, which acts on the pituitary. If used continously it decreases FSH and LH. If used in a pulsatile fashion it increases FSH and LH levels. References: Okamura H, Tsukamura H, Ohkura S, Uenoyama Y, Wakabayashi Y, Maeda K. Kisspeptin and GnRH pulse generation. Adv Exp Med Biol. 2013;784:297-323. Friedman, A. J., Barbieri, R. L., Doubilet, P. M., Fine, C. A. L. L. I. O. P. E., & Schiff, I. S. A. A. C. (1988). A randomized, double-blind trial of a gonadotropin releasing-hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uteri. Fertility and sterility, 49(3), 404-409. Crawford, E. D., Eisenberger, M. A., McLeod, D. G., Spaulding, J. T., Benson, R., Dorr, F. A., ... & Goodman, P. J. (1989). A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. New England Journal of Medicine, 321(7), 419-424. First Aid 2014 page 590]]
Approved	Approved::Yes
Keyword	WBRKeyword::Pituitary hormones, WBRKeyword::Pituitary, WBRKeyword::Hypothalamus, WBRKeyword::GnRH, WBRKeyword::Gonadotropins, WBRKeyword::Gonadotropin releasing hormone, WBRKeyword::Gonadotropin, WBRKeyword::Leuprolide, WBRKeyword::Hormone
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