Pharmacology of Female and Male Gonadal Medications Flashcards
Give three ways to increase bioavailability of a hormone agent?
- Alter structure (usually 17C position) to avoid first pass metabolism
- Use an alternate route of administration to avoid first pass metabolism
- Micronize the hormone molecules -> suspend in oil so they are protected from first pass metabolism
What portion of the estrogen is required for receptor binding? Other than saving from first pass metabolism, what other function does 17C modification have?
Phenolic A ring -> phenyl + alcohol
Also inhibits oral estrogens from binding sex hormone binding globulin, so they are more orally bioavailable
Who are the only women who can use estrogen alone? If you are starting estrogen therapy, what is the latest it can be started for postmenopausal symptoms?
Women without a uterus -> otherwise you need to give progesterone as well to prevent endometrial hyperplasia
Must start estrogen therapy within 10 years of menopause
What are the contraindications to estrogen therapy?
- Estrogen dependent neoplasma
- Undiagnosed genital bleeding
- Hepatic disease (decrease the metabolism)
- Pregnancy
- History of thromboembolic disorder (increased cardiovascular risk)
What is progesterone vs progestins?
Progesterone - natural
Progestins - synthetic
Umbrella term: Progestogens
What are the two primary indications for postmenopausal hormone replacement therapy (HRT)?
- High risk of osteoporosis - especially thin, white smokers with a family history (start before bone loss)
- Atrophic vaginitis
Is estrogen first line in osteoporosis? Does it restore bone loss?
No, not first line. Calcium / vitamin D / bisphosphonates are.
Does not restore bone loss -> must be started early (i.e. within 10 years of menopause). Can only prevent further progession.
How does estrogen affect your warfarin levels?
It decreases your warfarin levels (probably by CYP induction to some extent, idk)
What is the mechanism of oral contraceptives in the treatment of hirsutism and acne in androgen excess?
- Estrogens feedback negatively on LH, reducing ovarian androgen production
- Estrogens increase hepatic SHBG production, which reduces free androgen levels
What is the mechanism of action of spironolactone? What is it used for?
Competitive antagonist for androgen receptor (as well as aldosterone receptor), and inhibits androgen biosynthesis (like ketoconazole, 17,20 desmolase / 17a hydroxylase))
-> used for treatment of female hirsutism, i.e. as in PCOS
What vitamin / mineral combination has been used effectively in the treatment of hirsutism in PCOS?
Magnesium-zinc-calcium-vitamin D
Zinc inhibits 5a reductase
Others interfere with steroidogenesis or some shit
What drug is an antiandrogen by blocking 5alpha-reductase?
Finasteride
What are the three main synthetic progestins?
- Medroxyprogesterone
- Norethindrone
- Norgesterel
- >look for a “-gest” and its probaly gucci
How should chronic anovulation with continuous estrogen stimulation of uterus be handled in PCOS?
Give oral contraceptives, especially containing synthetic progestins
-> Daily dose and then withdrawal to induce withdrawal bleeding
What are the benefits of metformin therapy in PCOS?
- Improve hepatic insulin senstivitiy
- Reduce androgen production in ovarian theca cells
- Induction of ovulation (like clomiphene)
What is clomiphene used for and why?
Treatment of infertility
- > tends to block estrogen receptor in hypothalamus, which makes hypothalamus see low estrogen -> increasing GnRH release
- > leads to increased FSH levels, and subsequent follicle stimulation
Who is clomiphene only effective in and when should it be administered?
Only effective in infertile women with adequate estrogen levels (just not getting enough LH surge)
Should be administred for 5 days in early follicular phase -> before follicle dominance occurs to increase chance of multiple follicle recruitment (however, associated witih risk of multiple gestation)
What other class of medications can induce ovulation by reducing circulating estrogen levels?
Aromatase inhibitors - i.e. Anastrozole, Letrozole, exemestane
- > similar mechanism to clomiphene, increase FSH levels by causing hypoestrogen environment.
- > Use at same time in follicular phase
How can FSH / LH be directly used to induce ovulation? Describe the regimen.
FSH - give once daily during follicular phase
LH - normal surge will be inhibited due to negative feedback from FSH inducing estrogen. Thus, give hCG (mimics LH) roughly 36 hours before you want to ovulation.
What is ovarian hyperstimulation syndrome?
An adverse effect occuring in women given ovulation induction / superovulation drugs. Results in increased vasoactive substances like VEGF being secreted during follicle luteinization.
VEGF causes ascites, hypovolemia, and hemoconcentration
What are the three primary androgen drugs? Adverse effect of concern and how can it be avoided
- Testosterone salts - long IM release
- Methyltestosterone
- Fluoxymesterone
Adverse effect: hepatotoxicity if given orally -> recommend using patch, gel, on buccal mucosa, or subcutaneous pellet
What is the clinical use of testosterone agonists?
- Treat hypogonadism + promote puberty (secondary sexual characteristics)
- Stimulate anabolism to promote recovery after a burn or injury
- Male hypogonadism in adulthood
What are some symptoms and signs of male hypogonadism?
Decreased libido, erectile dysfunction, infertility, depression
Decreased body hair, decreased musscle mass, gynecomastia, osteoporosis, anemia
What is one clear indication to discontinue testosterone therapy? What is one clear contraindication to starting?
If hematocrit is >54%.
-> Testosterone acts like erythropoietin to some extent.
Do not start if PSA > 4 ng/mL (causes prostate hyperplasia)
What are likely side effects of testosterone therapy in children?
- Initial growth spurt followed by premature closure of the epiphyseal plates
- Gynecomastia -> children have more extraglandular aromatase activity
What happens to females and males of all ages with testosterone therapy?
Females - virilization, male pattern baldness, hirsutism
Males - Decreased testicular size (decreased FSH / LH leads to gonadal atrophy)
What is Danazol and what is it used for?
An ethinyl derivative of testosterone -> Weak androgen agonist and inhibitor of midcycle surge of FSH / LH.
Used in treatment of ENDOMETRIOSIS
What are possible side effects of danazol?
- Pseudotumor cerebri
2. Excessive virilization / hepatotoxicity -> same effects as rest of testosterone treatments
How does longterm use of anabolic steroids affect your cardiovascular risk?
Increases risk of MI and stroke
Lowers HDL, increases LDL and triglycerides
Give a GnRH agonist and antagonist. Why might one be preferred over the other for treatment of prostate cancer?
GnRH agonist - Leuprolide
GnRH antagonist - Cetrorelix
Cetrorelix might be preferred because there is no initial LH spike which GnRH agonists give.
Give two non-steroidal androgen receptor antagonists used in the treatment of prostate cancer. Which one has the better side effect profile? What are they given in combination with?
Flutamide
Bicalutamide (less hepatotoxic than flutamide)
Give in combination with GnRH agonist (i.e. leuprolide)
What is the mechanism of action of abiraterone and what is it used for? What should it be given in combination with?
Inhibits testosterone synthesis by inhibiting CYP17A1 (17alpha hydroxylase), an enzyme needed to make androgens from progestins
Used for treatment of castration-resistant prostate cancer
Give in combination with prednisone
What is the mechanism of action of finasteride and what are the indications?
5alpha reductase inhibitors (ur gonna have an ass to ride)
- Benign prostatic hyperplasia
- Androgenic alopecia
- Adjunctive therapy for prostate cancer
What is the most common treatment for uterine fibroids?
GnRH agonist - Leuprolide. Since they are estrogen sensitive.
What drug can be used in combination with replacement doses of hydrocortisone as an anti-androgen?
Ketoconazole
- > very strong 17,20 desmolase blockade
- > replacement of glucocorticoids is necessary
