Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
45 Cards in this Set
- Front
- Back
|
"Natural" estrogens
|
Very weak oral activity
Esters of fatty acids Micronized p.o. tabs Pellets for s.c. implantation Oil vehicle for i.m. injection Transdermal patches, vaginal creams |
|
|
"Conjugated" estrogens
|
Extract of pregnant horse urine
-Includes some unique equine estrogens -Mixture of sulfate and glucuronide esters -Very low potency: 1.25, 0.625, 0.3 mg/day Post-menopausal/replacement therapy only Must add progestin if pt. has a uterus Recent data on lack of efficacy, and possible untoward outcomes, have diminished use substantially Premarin®, PremPro® |
|
|
Synthetic estrogens
|
Natural estrogens made orally active
Other “non-estrogenic” structures -Diethylstilbestrol, Dienestrol (creams only) Used in oral contraceptives, and never for post-menopause replacement Much more potent: -30 ug ethinyl estradiol = 1.25 mg conjugated estrogens |
|
|
Postmenopausal Hormone Therapy: to do or not to do
|
Based on a variety of trend analyses from a large number of studies, HRT is probably sort of helpful in some ways to certain demographic and age groups of women, and should probably be avoided by other groups because of enhanced risks of problematic side effects.
|
|
|
Estrogens "antagonists": indicated uses, SERMS mechanism
|
First generation are very weak agonists
Indicated uses: -Estrogen-dependent malignancy -Stimulate LH-FSH and ovulation -Post-menopause replacement SERMs: selective estrogen receptor modulator -Produce different ER conformations -Recruit different coactivators than estrogen -α versus β receptors: may result in different transcription products in different tissues |
|
|
Clomiphene
|
- Weak estrogen antagonist
- Used for many years in treatment of infertility, esp. when follicular phase FSH-LH is low - Clomiphene for 5-7 days p.o. raises FSH-LH by blocking estrogen negative feedback - Elevated FSH-LH stimulates ovarian follicular development and raises estrogen secretion to prime adequate LH surge. - Clomid®, Serophene® |
|
|
Tamoxifen
|
- Weak competitive inhibitor at estrogen receptor
- Is an estrogen agonist at very high doses - But, is proving very useful as an antagonist therapy in estrogen-responsive breast malignancy. - Has now been proven to reduce recurrence of disease in contralateral site. - Improves serum lipids: Chol & LDL but no effect on HDL - Nolvadex® |
|
|
Raloxifene
|
- A big step up from older SERMs
- Somewhat different structure than older SERM’s, but retains basic receptor-binding core. - Very high affinity for ERalpha and beta - Estrogen agonist effect on bone but antagonist on breast and uterus - FDA approved for treatment of post-menopausal osteoporosis - LDL-C decreased but HDL-C not increased (LDL2-C is increased) - Evista®, 60 mg tabs - Generic product now available |
|
|
Bazedoxifene
|
SERM formulated in combination with conjugated estrogens;
Has high affinity for ER No stimulation of breast Anti-osteoporotic Favorable lipid profiles |
|
|
Fulvestrant
|
- Pure estrogen antagonist
- Binds to receptor but has no trace of agonist action in animal models, even at extreme doses. - ER assumes a different conformation than when bound with estradiol. - Biggest potential for treatment of estrogen-dependent malignancy - Faslodex® |
|
|
Summary of SERM effects
|
Estradiol
-Stimulates bone, decreases cholesterol -Increases TG, BC, endometrium Tamoxifen -Stimulates bone, decreases cholesterol, decreases BC, decreases endometrium -Increases TG Raloxifene -Increases bone, decreases cholesterol, BC, endometrium -Increases TG Acolbifene -Stimulates bone, decreases cholesterol, TG, BC, endometrium |
|
|
Adverse reactions to estrogens
|
Endometrial Cancer
-ever used estrogen alone (29 studies) -meta-analysis: rel. risk = 2.3 (95% = 2.1-2.5) -risk disappears if progestin added Breast Cancer -studies of 10-20 yrs estrogen alone -89 prospective: rr = 1.3 (1.2-1.5) -239 case-control: rr = 1.2 (1.0-1.4) Thromboembolic disorders -most frequently familial, congenital -black box warning Breakthrough bleeding -concomitant progestin prevents Reduction of lactation |
|
|
Type I and II aromatase inhibitors
|
Type I
Steroids: irreversibly bind and inactivate enzyme -Formestane (Lentaron), Exemestane (Aromasin) Type II Not steroids: act as competitive inhibitors of enzyme -Letrozole (Femara), Anastrazole (Arimidex) Main use is metastatic hormone dependent cancers |
|
|
Estrogen synthesis inhibitors: mechanisms, use
|
Typically inhibitors of aromatase (CYP-19)
-Some are steroids (Formestane, Exemestane) -Some not steroidal (Anastrozole, Letrozole, Fadrozole) -Affects only estrogen synthesis Part of multi-drug regimen to diminish estrogen burden in malignancy Clinical trials showing better outcomes than older SERMs alone in breast cancer therapy. |
|
|
Progestins: indications for therapy
|
Contraception (oral or parenteral)
Dysmenorrhea and PMS Post-menopause replacement Threatened or habitual miscarriage Chemotherapy (palliative) |
|
|
Natural progestins
|
Progesterone or 17alpha-OH-Progesterone
Esters of fatty acids Very weak activity, no oral administration Oil vehicle for i.m. injection Very limited market - pregnancy Occasionally in IUD for contraception |
|
|
C-21 compounds (progesterone)
|
relatively weak - 5-10 mg/day p.o.
also in oil for i.m. injection used for replacement or palliative therapy for contraception, injected i.m. q3mo generic name: medroxyprogesterone acetate Provera®, Megace® |
|
|
19-Nor compounds (androgen)
|
more potent – 0.1-3 mg/day p.o.
very widespread use for contraception alone or in combination with estrogen p.o. also silastic implants and oil i.m. injection potent hemostatic effect in uterus several compounds - all closely related |
|
|
Progestin adverse effects
|
Fewer, less severe than with estrogens
Uncertain cancer risk (?) Possible thromboembolic complications with 19-nor types May lower HDL and raise LDL cholesterol Amenorrhea with long-acting injectables Raises basal body temperature |
|
|
Mifepristone
|
- Inactive progesterone receptor antagonist (RBA = 530%)
- No intrinsic activity at all - Used to induce abortion, along with prostaglandin agonist - Restricted to 50 days since LMP - Blocks PgR in uterus, endo-metrium is shed - Routinely used in Europe - Recently entered US market - Also antagonizes Type II glucocorticoid receptor - Mifeprex® |
|
|
Traditional oral contraceptives: components, effects
|
Combinations of estrogen & 19-nor progestin
Principal effect: FSH-LH surge suppression Also: progestin transforms endometrium to a secretory state right away (too long) Also: progestin diminishes zygote transport in Fallopian tube. Also: progestin thickens cervical mucus In addition, estrogen serves as replacement. |
|
|
Hormonal contraceptives "Newer models"
|
Essentially combinations of estrogen & 19-nor progestin
“Multiphasic”: Week or more of increasing progestin at 2 or 3 levels. More than 20 brands -Some change estrogen level as well Seasonale®: 30 µg EE + 150 µg l-norgestrel for 84 days, then 7 days placebo. Other versions starting to appear. -Lybrel®: 20 µg EE + 90 µg l-norgestrel daily for whole year Still more concepts: Injectable in oil, sc implanted capsules, transdermal patches, IUDs containing hormone, vaginal rings |
|
|
Contraceptive patch
|
5 cm2 skin patch (transdermal)
Holds 6 mg norelgestromin (150 µg/day) + 750 µg ethinyl estradiol (20 µg/day) 3 patches/pk, wear each patch for 7 days Many markets world-wide since 2001 Evra® (Ortho) |
|
|
Progestin only contraception
|
All norethindrone, 350 µg/day p.o.
Ovulation inhibition: somewhat < 100% -but overall failure rate same as combination OC’s Other possible actions hostile to conception: -decidualize endometrium -thicken cervical mucus About 7 product names Also used in implants or injections Also: injectable MPA @ 150 mg |
|
|
Contraceptive gel
|
- Potent progestin
- Combined with estrogen - Individual capsules - Apply one daily anywhere on skin - Still under development Nesterone |
|
|
"Emergency" contraceptive
|
Pack contains two 0.75 mg tabs of l-norgestrel
Take each 12 hr apart ASAP after intercourse, preferably within 72 hrs Usual mechanisms, 98.9% success rate Plan B®, sold over-the-counter in pharmacies Also: Taking 4-6 combo OC tabs at once is showing effectiveness. |
|
|
Ulipristal acetate
|
Emergency oral contraceptive
Works for up to 5 days post-fertilization Not taken with prostaglandin On US market for a year. Compound is a potent PgR antagonist and a weak agonist Also antagonizes the Type II glucocorticoid receptor |
|
|
Gestrinone
|
Weak progestin, potent PgR and AR agonist
Not estrogenic but has potency as anabolic androgen Can be effective as an oral contraceptive Will also suppress hypothamamic-pituitary hornones, to starve endometrium of pituitary – ovarian support in treatment of endometriosis |
|
|
Adverse effects of oral contraceptives
|
Discomfort, breakthrough bleeding
Unintended pregnancy Post-pill amenorrhea & infertility Cardiovascular complications - interaction between age and smoking to greatly increase risk of coronary disease with o.c. use |
|
|
Adrogens: indications for therapy
|
Males
-Eunichoidism, hypopituitarism, impotence -Delayed puberty, if at least 16 yo -Hemopoesis Females -Palliative therapy of malignancy -Post-partum breast engorgement -Post-menopause, added to estrogen for anabolic effects |
|
|
Natural androgens
|
Testosterone, DHEA, Androstenedione
Esters of fatty acids Aqueous suspension or oil for i.m. Subcu. pellet, buccal tab, dermal patch Both anabolic and androgenic Some weaker versions can be used in women and children with very little adverse effect. |
|
|
Synthetic androgens
|
Orally active: 17-methyl, 9-fluoro-
Much more potent; only for adult men Possible adverse reactions: -virilization, etc. -gynecomastia, oligospermia -liver disease, prostatic hyperplasia |
|
|
"Anti-androgens": use
|
Men:
-prostate hypertrophy and malignancy -baldness Women: -hirsutism |
|
|
Finasteride
|
- Competetive antagonist of 5alpha-reductase
- Blocks conversion of testosterone to DHT - Reduces burden of hypertrophied or malignant prostate - Also administered for male baldness, one-quarter tab/day p.o. - Proscar®, Propecia® |
|
|
Androgen receptor modulators (SARMs)
|
Not steroids but are competetive inhibitors of the androgen receptor.
No intrinsic activity Flutamide has significant problems of hepatotoxicity Principally used for malignant prostate Lower doses being tested for hirsutism |
|
|
Minoxidil
|
- Effective vasodilator and anti-hypertensive, when
taken orally - Opens K+ channels in vascular smooth muscle - Does not interact with hormones or receptors - Used as topical medication on scalp to retard baldness - Promotes local vasodilation to increase blood flow - Rogaine® - liquid |
|
|
Anabolic steroids
|
All derivatives of androgens
Less androgenic but more anabolic potency Appropriate uses to stimulate hemopoesis and other anabolic responses in feeble or malignant conditions Most side effects result from massive dosing that is hepatotoxic. ALL ANDROGENS AND ANABOLIC STEROIDS ARE SCHEDULE III DRUGS |
|
|
Tetrahydrogestrinone (THG)
|
aka “The Clear” – very hard to detect
Very potent – similar affinity for androgen receptor as DHT Also binds to progesterone and glucocorticoid receptors Synthesized from gestrinone, a useful PgR agonist Easily conjugated and excreted |
|
|
Follitropin alpha
|
Pure human FSH made in Chinese hamster oocytes by recombinant DNA technology
FSH has 2 subunits plus carbohydrate residues Injected s.c. for 9-12 days Patient must present daily for i.m. injection Measure estradiol every day; ultrasound too Ovarian follicular stimulation |
|
|
Chorionic gonadotropin
|
To stimulate ovulation
Extract of pregnancy urine hCG is biologically identical to pituitary LH After several days of FSH, give 1 massive injection of hCG s.c. Stimulates ovulation; harvest ova in males, hCG stimulates testosterone from Leydig cells, esp. in neonatal cryptorchidism |
|
|
GnRH
|
decapeptide, from a much larger precursor
secreted into hypothalamic portal blood stimulates release of both LH and FSH secreted in circhoral pulses synthetic agonists are peptides with 1 or more changes of sequence (e.g., d-Ala6) |
|
|
THE PHOSPHATIDYLINOSITOL/PHOSPHOINOSITIDE CYCLE
|
GnRH binds to outside of cell
G protein coupled reaction involving intracellular calcium which promotes movement of granules to cell surface LH is excreted from pituitary A mechanism leading to tachyphylaxis The rapid decline (loss) of response to a drug following the initial response ….because the G-protein receptor subunits need to reassemble before responding again, but this is possible only after the receptor ligand is gone -Why brain give pulsatile GnRH release |
|
|
GnRH stimulation of ovulation
|
Superactive analog administered in pulsatile fashion continuously for 2 weeks
Pulses necessary to avoid tachyphylaxis Need functional pituitary FSH-LH levels rise to stimulate follicles May need to add estrogen or hCG to complete ovulatory process. |
|
|
GnRH suppression of FSH-LH release
|
Same compounds - often potent agonists
Principle: G-coupled receptors must dissociate from ligand and reassemble in order to respond to another ligand Superactive agonist with high affinity dissociates slowly from receptor, so ….. FSH-LH secretion stops |
|
|
GnRH agonist use
|
Intermittent application
-stimulates ovulation Constant application of huge dose -arrest of FSH-LH secretion -stop precocious puberty -stop pituitary support of gonadal steroid-driven malignancy (breast, prostate) -Also used to treat endometriosis -Pure GnRH antagonists also in works |
