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30 Cards in this Set

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Gonadotropin-releasing Hormone (GnRH)
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
Menotropins
From urine of postmenopausal women
Contain naturally-modified FSH and LH activity of low potency
Urofollitropin
Menotropin containing only FSH activity
Human Chorionic Gonadotropin (hCG)
From urine of pregnant women
Secreted by placenta
LH activity (ovulation and progesterone secretion)
Therapeutic Uses of GnRH & Analogs
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
Therapeutic Uses of Menotropins
Anovulatory Infertility due to insufficient secretion of FSH and LH
Urofollitropin until follicle development observed
hCG to induce ovulation and permit implantation
Side Effects of Menotropins
Hyperstimulation Syndrome:
Ovarian enlargement
Ascites
Hydrothorax
Hypovolemia and shock
Increased risk of spontaneous abortion?
Increased risk of multiple births (20%)
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
Conjugated Estrogens
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)
Esters of Estradiol
Esterification slows absorption from site of injection
Benefit - longer duration of action
DIPROPRIONATE ESTRADIOL
Synthetic, Steroidal Estrogens
ETHINYL ESTRADIOL
Potent agonists
Less-rapidly metabolized by liver ➙ Longer duration of action
Orally effective
Synthetic, Non-steroidal Estrogens
Diethylstilbestrol (DES)
Moderately potent agonist, slowly inactivated by liver, orally effective, common in past usage
Therapeutic Uses of Estrogens
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
Non-Steroidal Drugs for Osteoporosis
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
Clomiphene
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
Tamoxifen
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
Raloxifene
Approved as agonist for postmenopausal osteoporosis
Antagonist at uterus
Early evidence of antagonism at breast
Aromatase Inhibitors
ANTI ESTROGEN, by blocking production
Anastrozole
Competitive non-steroidal inhibitors of aromatase responsible for conversion of androgens to estrogens
Derivatives of Progesterone
Medroxyprogesterone acetate
21 carbon steroids
Can stimulate endometrial secretions and support pregnancy in test animals
Variable androgenic and estrogenic side effects
Derivatives of Nortestosterone
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
Anti-Progestins
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
Finasteride
Blocks conversion of testosterone to DHT
Transdermal Contraception
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
Contraceptive Ring
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
Intradermal Contraception
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
Combined Oral Contraceptives (COCs)
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®)
Contraceptive Mild SEs
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
Contraceptive Serious Side Effects
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.
Side Effects of Estrogen Replacement Therapy (ERT)
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.
Post-Coital Birth Control
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