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30 Cards in this Set
- Front
- Back
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Gonadotropin-releasing Hormone (GnRH)
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Decapeptide secreted by the hypothalamus
Serum half-life = 4 min Secretion occurs in pulses Pulsitile IV or subcutaneous administration @ 60 - 120 min ➙ FSH and LH secretion Continuous administration ➙ gonadotropin suppression |
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Menotropins
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From urine of postmenopausal women
Contain naturally-modified FSH and LH activity of low potency |
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Urofollitropin
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Menotropin containing only FSH activity
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Human Chorionic Gonadotropin (hCG)
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From urine of pregnant women
Secreted by placenta LH activity (ovulation and progesterone secretion) |
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Therapeutic Uses of GnRH & Analogs
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Induction of ovulation in amenorrheic women
In vitro fertilization -Continuous leuprolide to suppress LH & FSH Controlled gonadotropin doses ➙ follicle development and ovulation Delayed puberty - pulsitile (Gonadorelin) Precocious purberty - continuous (Leuprolide) Endometriosis - Leuprolide Prostate cancer - Leuprolide, Histrelin, Goserelin |
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Therapeutic Uses of Menotropins
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Anovulatory Infertility due to insufficient secretion of FSH and LH
Urofollitropin until follicle development observed hCG to induce ovulation and permit implantation |
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Side Effects of Menotropins
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Hyperstimulation Syndrome:
Ovarian enlargement Ascites Hydrothorax Hypovolemia and shock Increased risk of spontaneous abortion? Increased risk of multiple births (20%) |
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Natural Estrogens
How are they administered? How are they eliminated? |
Estradiol, Estrone, Estriol
Structurally similar compounds with similar potencies Quickly inactivated by liver by conjugation (sulfation and glucoronation). Rapid elimination by kidneys Not orally effective. Administration ➙ transdermal or intramuscular |
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Conjugated Estrogens
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Obtained from pregnant mare’s urine or stallion
Circa 60% sulfated estrone Orally effective at high concentrations Common drug: Premarin® (Wyeth) Premarin + progestin = Prempro® (Wyeth) |
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Esters of Estradiol
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Esterification slows absorption from site of injection
Benefit - longer duration of action DIPROPRIONATE ESTRADIOL |
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Synthetic, Steroidal Estrogens
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ETHINYL ESTRADIOL
Potent agonists Less-rapidly metabolized by liver ➙ Longer duration of action Orally effective |
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Synthetic, Non-steroidal Estrogens
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Diethylstilbestrol (DES)
Moderately potent agonist, slowly inactivated by liver, orally effective, common in past usage |
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Therapeutic Uses of Estrogens
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Dysmenorrhea
Difficult or painful menstruation Caused by overstimulation of uterus by prostaglandins Usual therapy: NSAIDs For intractable dysmenorrhea: Inhibit ovulatory cycle by chronic administration of estrogens and progestins Post-partum breast engorgement Therapy: estrogens at high doses for 8 - 10 days post-partum to inhibit lactation Hirsutism Masculinization due to excess androgen production by ovary or adrenals Contraception Menopause Caused by cessation of ovulatory cycle Symptoms attributable to lack of estrogen stimulation Hot flashes, sweating, atrophic vaginitis Treatment with estrogens (ERT), usually in conjunction with progestin Postmenopausal Osteoporosis Loss of bone matrix due to estrogen deficiency Greatest bone loss within five years of menopause Therapy: chronic or cyclic administration of estrogen + progestin immediately after menopause or at onset of bone loss Withdrawal of therapy may result in accelerated bone loss |
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Non-Steroidal Drugs for Osteoporosis
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Bisphosphonates
Alendronate Pharmacodynamics: 1-10% oral dose is absorbed 50% accumulates in bone 50% excreted in urine Retard dissolution of hydroxyapatite crystals Used in Paget’s disease Recently approved for treating hypercalcemia: Malignancy Osteoporosis Alendronate: Now commonly used for post-menopausal osteoporosis Also shown useful in preventing male vertebral fractures |
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Clomiphene
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Used in the treatment of anovulatory infertility
Acts by inhibiting estrogen-mediated repression of GnRH release by hypothalamus Not effective in patients with pituitary or ovarian disfunction Dosing regimen causes rise in plasma LH and FSH levels by 5th day Single dosing regimen results in single ovulation Repeated dosing required for subsequent ovulations Normal ovulatory cycle not usually resumed Effectiveness 80% of patients ovulate 40 to 50% of these become pregnant |
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Tamoxifen
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Orally effective
Used to treat steroid-dependent breast cancer Inhibits estrogen stimulation of cancer growth Can be used on pre- and post-menopausal women with ER-positive tumors As effective as cytotoxic anti-neoplastics Many fewer serious or unpleasant side effects Becoming drug of choice Side effects: Hypercalcemia Bone pain Increased risk of endometrial cancer |
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Raloxifene
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Approved as agonist for postmenopausal osteoporosis
Antagonist at uterus Early evidence of antagonism at breast |
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Aromatase Inhibitors
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ANTI ESTROGEN, by blocking production
Anastrozole Competitive non-steroidal inhibitors of aromatase responsible for conversion of androgens to estrogens |
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Derivatives of Progesterone
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Medroxyprogesterone acetate
21 carbon steroids Can stimulate endometrial secretions and support pregnancy in test animals Variable androgenic and estrogenic side effects |
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Derivatives of Nortestosterone
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Norethindrone
L-norgestrel 19 carbon steroids Can stimulate cellular changes in endometrium but cannot support pregnancy in test animals More effective inhibitors of gonadotropin secretion. Majority of oral contraceptives now employ a nortestosterone derivative Late generation analogs have reduced androgenic and estrogenic side effects |
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Anti-Progestins
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RU486 (Mifepristone)
Controversial abortifacient Binds both progesterone and glucocorticoid receptors - preventing gene transcription Other potential therapeutic uses: Inhibition of progesterone- and glucocorticoid-dependent tumors Effective in treatment of fibroid tumors Cushing’s disease Post-coital birth control |
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Finasteride
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Blocks conversion of testosterone to DHT
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Transdermal Contraception
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ORTHO EVRA® – The “Patch”
Transdermal administration of norelgestromin and ethinyl estradiol Norelgestromin = active metabolite of norgestimate Patch applied weekly Advantages: Bypasses hepatic metabolism Lower peak plasma concentrations of drug than COCs Presumed lower rates of side effects Better compliance Comparable failure rates to COCs in typical usage Disadvantages: Skin allergies Higher steady state concentrations of drug than COCs |
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Contraceptive Ring
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NuvaRing®
Flexible ring, inserted in vagina Removed after 3 weeks to allow for menstruation Delivers etonorgestrel and ethinyl estradiol at lower steady state concentrations than COCs Etonorgestrel = active metabolite of norgestrel Advantages: Purported lower side effects Very high compliance Efficacy about equal to COCs |
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Intradermal Contraception
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Norplant II® (Jadelle®)
Two flexible capsules containing norgestrel Inserted under skin on upper arm or thigh Insertion and removal require minor surgery with local anesthetic Effective for up to 5 years Approved in 1990 in USA Many millions of users worldwide Serum steroid levels are 1/5 to 1/3 of oral contraceptives Fewer side effects Effectiveness: After One Year: 0.2 failures per 100 women years After Five Years: 0.8 failures per 100 women years |
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Combined Oral Contraceptives (COCs)
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Monophasic
Constant low dose of estrogen + constant higher dose of progestin Diphasic and triphasic Constant low dose of estrogen + variable dose of progestin Progestin dose increased in two or three phases Most common: Progestin increased each week of 21 day dosing regimen Progestin-Only (“Mini-Pill”) Low dose of progestin Taken every day Most commonly used drugs: Estrogen: Ethinyl estradiol (Estinyl®) Progestin: Norethindrone (Norlutin®), L-norgestrel (Ovrette®) |
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Contraceptive Mild SEs
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Mild Side Effects
Nausea Breast discomfort Fluid retention (decrease E dose) Weight gain Depression Hair growth (Decrease progestin or switch to 3rd generation drug (e.g. norgestrel)) Headache Common but transient For recurrent migraines - stop therapy due to risk of stroke Amenorrhea Short to prolonged period of non-ovulation after cessation of treatment |
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Contraceptive Serious Side Effects
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Thromboembolism and thrombophlebitis (first serious side effect discovered)
Pulmonary embolism Thrombotic and hemorrhagic strokes Risk of thromboembolism: Non-users - 1 per 1000 women years Users - 3 per 1000 women years Risk rises within first month; remains constant Risk returns to normal within one month of discontinuance Underlying physiological cause: Decrease in Anti-thrombin III (major inhibitor of blot clotting) Cardiovascular Disorders Myocardial Infarction Risk of MI increased slightly for all COC users Risk much greater in women with predisposing conditions Diabetes or smokers Underlying physiological cause: Decreased levels of HDL and increased levels of LDL cholesterols Hypertension 3-6 fold increase in the incidence of overt hypertension Contributing factor to increased thrombolic and coronary risk Cancer Complicated and Controversial Liver Cell Adenoma Prolonged use (>3 years) leads to increase risk of benign hepatic adenomas Usually not life-threatening - unless adenoma ruptures Cervical and Vaginal Cancer Clear risk due to use of diethylstilbestrol (DES) Risk only for daughters of women who used DES during 1st trimester of pregnancy Breast Cancer Controversial. Most studies show increased risk. |
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Side Effects of Estrogen Replacement Therapy (ERT)
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Recent results of the NIH Women’s Health Initiative study:
16,000 healthy women 50 to 79 years old Estrogen plus progestin (Prempro® - Wyeth) compared to placebo group Small decrease in bone fractures Small decrease in colorectal cancer 26% increase in breast cancer 29% increase in heart attacks 41% increase in strokes 22% overall increase in cardiovascular disease Bottom Line? ERT only for moderate to severe symptoms of menopause (hot flashes and night sweats) and as second-line drug for prevention of osteoporosis. |
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Post-Coital Birth Control
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Estrogens or progestins taken at high doses for 5-6 days following intercourse
99% effective when begun by 72 hours post-coitum Estrogens typically used: conjugated estrogens, ethinyl estradiol New studies suggest that 3rd generation progestins are more effective. “Plan B” drug (L-norgestrel) recently approved by FDA. Mechanism – Disruption of implantation by altering endometrium Strong side effects Nausea Vomiting Severe cramps |
