Flashcards in 5α pharmacology Control of reproductive hormones Leuprolide Estrogens (ethinyl estradiol, DES, mestranol) Selective estrogen receptor modulators Hormone replacement therapy Anastrozole/exemestane Progestins Mifepristone (RU-486) Deck (42):
What hormone is synthesized and released from the hypothalamus to stimulate release of LH and FSH from the pituitary?
You prescribe a patient clomiphene. Do LH and FSH levels increase or decrease?
Increase (clomiphene prevents normal feedback inhibition on GnRH in hypothalamus, thereby increasing GnRH production [and thus LH/FSH])
Explain how GnRH agonists can demonstrate both agonistic and antagonistic properties.
Pulsatile GnRH is required for normal function, & GnRH agonists therefore can be agonistic (pulsatile use) or antagonistic (continuous use)
Oral contraceptives and danazol work at the level of the ____ (hypothalamus/anterior pituitary/ovaries) to prevent release of LH and FSH.
Leydig cells in the testis are stimulated by which hormone to produce testosterone?
A patient with PCOS has increased testosterone levels, resulting in hirsutism. Name two drugs that block testosterone synthesis.
Ketoconazole and spironolactone
Which hormone, found in the adrenal cortex, is important for synthesis of androgens like testosterone and androstenedione from progesterone?
P-450c17 (can be inhibited by ketoconazole and danazol)
A postmenopausal woman presents with breast cancer. Name a drug that you could prescribe to lower her estrogen levels by blocking aromatase.
Anastrozole, which is an aromatase inhibitor; blocks conversion of testosterone to estradiol, as well as androstenedione to estrone
How do selective estrogen receptor modulators (SERMs) like tamoxifen and raloxifene downregulate the effects of estrogen?
They are estrogen receptor antagonists, but they can have agonist (estrogenic) effects depending on the site of action
A patient presents with benign prostatic hyperplasia (BPH). What drug is useful for treating BPH by decreasing dihydrotestosterone levels?
Finasteride, which is a 5α-reductase inhibitor that converts testosterone to the more potent dihydrotestosterone
Name three antiandrogenic drugs that function by preventing steroid hormones (testosterone, DHT) from binding to their specific receptors.
Flutamide, cyproterone, and spironolactone
A woman receiving treatment for her uterine fibroids takes a GnRH analog dosed in a continuous manner. What side effects might she have?
Side effects=antiandrogenic actions and nausea/vomiting (this is leuprolide, dosed continuously to inhibit GnRH [and thus FSH and estrogen])
How do the clinical uses of leuprolide differ depending on the way in which it is administered?
Leuprolide is a gonadotropin-releasing hormone (GnRH) agonist when dosed in a pulsatile manner and a GnRH antagonist when dosed continuously
Name four common clinical uses for leuprolide.
Infertility (pulsatile), prostate cancer (continuous, used with flutamide), precocious puberty (continuous), & uterine fibroids (continuous)
A man with prostate cancer is prescribed a GnRH analog with agonist properties. Should it be dosed in a pulsatile or continuous manner?
Dose continuously to inhibit GnRH, which decreases circulating androgens that can stimulate prostate adenocarcinoma (this is leuprolide)
When used continuously, leuprolide ____ (upregulates/downregulates) pituitary GnRH receptors, leading to ____ (increased/decreased) FSH/LH.
Downregulates, decreased (leuprolide can be used in lieu of GnRH)
What are the mechanisms of action of ethinyl estradiol, diethylstilbestrol, and mestranol?
They bind to estrogen receptors and act as agonists
Name four conditions in women that are treated with estrogens. Estrogens also can be used to treat which condition in elderly men?
Hypogonadism, ovarian failure, menstrual abnormalities, and postmenopausal hormone replacement therapy; androgen-dependent prostate cancer
What are the adverse effects of treatment with exogenous estrogens?
Increased endometrial cancer risk, abnormal uterine bleeding in postmenopausal women, vaginal clear cell adenocarcinoma, hypercoagulability
You diagnose a woman with clear cell adenocarcinoma of the vagina. What should you ask about in her history?
In utero exposure to diethylstilbestrol
Name three contraindications to estrogen therapy.
Estrogen receptor–positive breast cancer, a history of deep vein thrombosis, and smoking while >35 years old
A female patient with a history of deep vein thrombosis (DVT) desires birth control. What options would you recommend for her?
Estrogen therapy can precipitate future DVTs, thus you would recommend to her nonestrogen birth control methods (progesterone only methods)
A woman comes to you desiring birth control. What is an important question to ask her while history-taking?
Whether she is a smoker or not; if she is, any contraceptive option containing estrogen would be contraindicated
A 40-year-old woman is trying to get pregnant. How does the interaction of clomiphene at the hypothalamus increase ovulation?
Elevated FSH and LH increase ovulation (clomiphene is a selective estrogen receptor modulator that blocks negative feedback on LH and FSH)
What are two primary clinical uses for clomiphene? What are four adverse effects associated with its use?
Infertility and polycystic ovarian syndrome; hot flashes, ovarian enlargement, multiple simultaneous pregnancies, and visual disturbances
You prescribe a patient tamoxifen for treatment of breast cancer. How does it work?
Because it acts as an estrogen antagonist in the breast, it treats and prevents recurrence of ER/PR-positive breast cancer
You order tamoxifen for a patient with breast cancer. What events may occur due to estrogenic effects of tamoxifen at other locations?
Tamoxifen is associated with endometrial cancer and thromboembolic events (acts as an estrogen receptor agonist at the uterus and bone)
Which selective estrogen receptor modulator reduces the resorption of bone and is used to treat osteoporosis?
Raloxifene, which acts as an estrogen receptor agonist in bone and reduces bone resorption (note that it still has risk of thromboembolism)
What is the main difference between tamoxifen and raloxifene?
Raloxifene does not increase risk of endometrial cancer (antagonist at uterine tissue), whereas tamoxifen does (agonist at uterine tissue
What are the indications for hormone replacement therapy?
Relief/prevention of menopausal symptoms (e.g., hot flashes, vaginal atrophy) and osteoporosis that is caused by decreased estrogen levels
Progesterone is added to a patient's hormone replacement therapy regimen. This is because unopposed estrogen increases the risk of what?
Endometrial cancer (however, this combination may increase the risk of cardiovascular events)
• You prescribe hormone replacement therapy for an elderly woman. What secondary benefit does this have on her bones and what's the mechanism?
It increases estrogen, which decreases osteoclast activity, thus helping to prevent osteoporosis
What is the mechanism of action of anastrozole and exemestane?
Anastrozole and exemestane function by inhibiting aromatase, the enzyme that converts androgens to estrogens
A postmenopausal woman has a hard, immobile breast lump. What investigation should you conduct and how does that guide treatment options?
If found to be estrogen receptor–positive, anastrozole and exemestane would work well (this is likely breast cancer)
What effect do progestins have on the endometrium?
On binding the progesterone receptor, they reduce the growth of the endometrial lining while increasing its vascularization
Name three clinical uses of progestins
In oral contraceptive pills, to treat endometrial cancer, and to treat abnormal uterine bleeding
A woman with abnormal uterine bleeding starts taking progestins. What result would you expect?
Progestins bind to endometrial progesterone receptors, leading to reduced growth and increased vascularization, thus improving the bleeding
• What is the mechanism of action of mifepristone (RU-486)?
It competitively inhibits progestins at progesterone receptors
• What is the primary clinical use of mifepristone? What is it administered with?
Termination of pregnancy in conjunction with the administration of misoprostol (PGE1)
• What are the known toxicities of mifepristone?
Heavy bleeding, gastrointestinal effects (nausea, vomiting, anorexia), abdominal pain
• A woman who bleeds excessively when injured wants to terminate an unwanted pregnancy. What treatment option should be avoided in her case?
Mifepristone (RU-486) can be associated with heavy bleeding and should be avoided in this particular patient