question

CASE STUDY A 25-year-old woman with menarche at 13 years and menstrual periods until about 1 year ago complains of hot flushes, skin and vaginal dryness, weakness, poor sleep, and scanty and infrequent menstrual periods of a year's duration. She visits her gynecologist, who obtains plasma levels of follicle-stimulating hormone and luteinizing hormone, both of which are moderately elevated. She is diagnosed with premature ovarian failure and recommended estrogen and progesterone replacement therapy. A dual-energy absorptiometry scan (DEXA) reveals a bone density t-score of ;2.5 SD, ie, frank osteoporosis. How should the ovarian hormones she lacks be replaced? What extra measures should she take for her osteoporosis while receiving treatment?

answer

The patient should be advised to start daily transdermal estradiol therapy (100 mcg/d) along with oral natural pro-gesterone (200 mg/d) for the last 12 days of each 28-day cycle. On this regimen, her symptoms should disappear and normal monthly uterine bleeding resume. She should also be advised to get adequate exercise and increase her calcium and vitamin D intake as treatment for her osteoporosis.

question

HPG Axis

answer

The hypothalamus, pituitary, and gonads (HPG axis) work together through an integrated feedback mechanism to control the reproductive systems in men and women. The cascade begins in the arcuate nucleus of the hypothalamus, which pulses gonadotropin-releasing hormone (GnRH) and is released into the hypothalamic-pituitary portal vasculature. Pulsatile release of GnRH is associated with an increase in the synthesis and release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The levels of sex steroids, negatively feed back to the hypothalamus to regulate the frequency of GnRH release and the amplitude of gonadotropin secretion

question

In men, _____ acts on testicular Leydig cells to stimulate the synthesis of testosterone and _____ acts on Sertoli cells to stimulate the production of proteins required for sperm maturation.

answer

LH FSH

question

In woman, ___ and ___ stimulate the growth of developing ovarian follicles and steroidogenesis. .

answer

LH and FSH

question

Give the 3 gonadal activity stages

answer

o Quiescent time: rapid body growth; maturation o Puberty: initiation of ovarian cyclic function {menstrual cycle} lasting 30 to 40 years o Menopause: failure of ovary to respond to gonadotropins --> end of cyclic bleeding

question

What is thought to trigger puberty?

answer

neuronal maturation - allows for proper frequency and pulse of GnRH to allow for FSH and LH release

question

At the onset of puberty, FSH and LH are released in small amounts inducing small amounts of estrogen to be released in the female... what secondary characteristics develop from this

answer

1) breast development 2) alteration of fat distribution 3) growth spurt

question

Following a year after production of estrogens, what is the next major change a female experiences?

answer

increases estrogen triggers endometrial changes and periodic bleeding there may be a few anovulatory cycles following by normal cyclic function

question

The menstrual cycle Ovarian follicles enlarge initially in response to what hormone? This hormone triggers the release of which hormone and what does this induce? what occurs 5-6 days following the initial hormone response? What are granulosa cells? what do they secrete? What stimulates ovulation? What happens once the secondary oocyte is launched from the follicle? what happens to the residual follicle if pregnancy occurs? what happens if no pregnancy occurs?

answer

o Ovarian follicles enlarge in response to FSH, increased estrogen levels stimulate the growth of ~ 4-5 follicles o 5-6 days later: one follicle begins to mature more rapidly and secretes estrogen while others become atretic Granulosa cells surrounding the ovum produce estrogen which peaks at mid cycle, the cells then begin to secrete progesterone. Surge in LH and FSH --> ovulation/ release of the ovum Granulosa and theca cells of the ruptured follicle becomes the corpus luteum which continues to produce estrogens and progesterone for the remainder of the cycle, or longer if pregnancy occurs (require chorionic gonadotropin from embryo) No pregnancy --> corpus luteum degrades and the endometrium (which proliferated during follicular phase) is shed during menstruation

question

Menopause what causes it? what happens with plasma gonadotropin concentration? typically age of occurrence? what happens to estrogen levels? can estrogen be maintained?

answer

Occurs due to ovarian follicle exhaustion Consequently negative feedback loss on hypothalamic-pituitary centers resulting in increase in plasma gonadotropins mean age: 52 years (U.S.) reduction in estradiol/other hormone production Estrogen levels may persist due to: adipose and other non-endocrine tissues convert androstenedione to estrone and estradiol

question

What are some causes for ovarian malfunction?

answer

temporary emotional or environmental stress associated with amenorrhea inflammatory/neoplasms that destroy ovaries, uterus or pituitary pituitary prolactinomas( amenorrhea and infertility - they inhibit LH)

question

Estrogens: Are all estrogens steroids?

answer

No, many substances exhibit estrogenic activity. Steroidal estrogens have been derived from animal sources and nonsteroidal estrogens can be found such as phenols, flavonoids (soybean), bisphenols (manufactured plastics)

question

Estrogens: Give the 3 major forms of estrogen What cells synthesize estrogen? During pregnancy, where are significant amounts of estrogen's produced?

answer

E2 = 17-B-Estradiol Present throughout the entire female RT, MOST POTENT E1 = estrone Androstenedione --> Estrone via aromatase least abundant during reproductive years, increases in menopause E3 = estriol Hepatic formed from estradiol only produced in significant amounts during pregnancy from placenta Estrogen synthesis occurs in the theca and granulosa cells of the ovarian follicles During pregnancy, a significant amount of estrogen is produced from the fetal-placental unit

question

Where can we derive natural estrogens for human use?

answer

Equine estrogens collected from the urine of a stallion(male) commonly used - conjugated equine estrogens - PREMARIN

question

What are the advantages of synthetic estrogens

answer

chemical mods. enhance oral effectiveness

question

List the 4 commonly used synthetic estrogens GIRLS love MEEE!

answer

ethinyl estradiol micronized estradiol esterified estrogens estradiol transdermal

question

does estradiol flow freely in plasma?

answer

no, mainly bound to A2-Globulin - SHBG low affinity to albumin ONLY FREE ESTROGEN CAN CAUSE PHYSIOLOGICAL CHANGES

question

Give the conversion steps for estradiol following its production in granulosa cells

answer

Estradiol converted to (by the liver/other tissues): estrone, estriol (low estrogen receptor affinity) 2-hydroxylated derivatives and conjugated metabolites are lipid insoluble and cannot cross the membrane --> excreted in bile. They can subsequently be hydrolyzed in the intestine to active forms which are reabsorbed. This is referred to as enterohepatic cycling which leads to significant hepatic: peripheral ratio of estrogens. The significance is that high levels of hepatic estrogens may be responsible for synthesis of increased clotting factors and plasma renin substrate. To minimize enterohepatic effects use routes of administration that avoid first pass effects (vaginal, transdermal, injection).

question

Pharmacodynamics: Estrogens give the steps from plasma to translation

answer

1) binds SHBG - A2 2) dissociates and diffused into cell 3) binds nuclear receptor ERa or ERb - causes dissociation of HSP90 4) complex then forms homodimer - this binds to EREs triggered transcription and eventually translation

question

How can estrogen cause different genomic and thus protein products in different cells?

answer

The specific genes that are transcribed depends on: Receptor activated Transcription factors(presence, concentration) Chromatin organization this forms the basis of SELECTIVE ESTROGEN RECEPTOR MODULATORS

question

What are some common non-genomic effects of estrogen?

answer

Membrane Estrogen Receptors can induce rapid effects independent of transcription. Examples include: rapid, granulosa cell calcium uptake, increased uterine blood flow, activation of nitric oxide

question

What are the female maturative effects of estrogen?

answer

females require estrogen for normal maturation they stimulate the development of the vagina, uterus, uterine tubes,and secondary sex characters such as: stromal development ductal growth in breast growth spurt/stopping axillary/pubic hair growth fat redistribution skin pigments(areola, genitals)

question

What are the endometrial effects of estrogen?

answer

promotes endometral lining development (continuous exposure = hyperplasia) coordinates with progesterone during normal menstrual cycle

question

What are the female metabolic effects of estrogen?

answer

1) maintains normal skin and vessel structure 2) decrease bone loss - PTH antagonist 3) stimulates leptin from adipocytes 4) hepatic effects - increases: CBG, TBG, SHBG, renin substrate, transferrin, fibrinogen - IMPORTANT: RESULTS IN HIGHER CIRCULATING LEVELS OF CORTISOL, T3/T4, ESTROGENS, IRON, COPPER, TEST, ETC... 5) Increase HDL, slight decrease to LDL, reduce NET cholesterol, increase plasma triglycerides

question

What are the coagulative effects of estrogen?

answer

also decreases platelet adhesion

question

What are some other effects of estrogen?

answer

induces synthesis of progesterone receptor influences on behavior and libido promotes a sense of well-being in women who are estrogen-deficient loss of intravascular fluid into extracellular space --> edema. Compensatory retention of sodium and water by the kidneys.

question

Estrogens: Clinical Uses Primary Hypogonadism: Causes: When to initiate drug therapy: Drugs used: After first menses:

answer

Castration, primary failure of ovarian development(genetic - turners), menopause, other Initiated at 11-13 years of age to stimulate secondary sex characteristics, optimal growth, menses as well as avoiding psychological effects of the delayed puberty Agents used: conjugated estrogens ethinyl estradiol After first menses, transition to combination therapy (estrogen + progestins) on days 1- 21 of each month

question

Estrogens: Clinical Uses Postmenopausal Hormonal Treatment women with what should be generally treated with HRT? in addition to the signs and symptoms of post-menopause (loss of period, vasomotor issues, insomnia, genital atrophy), what are some long lasting effects seen to occur following menopause?

answer

AKA - HRT always weigh the benefits to risks Generally, women with premature menopause should receive hormone therapy 1) acceleration of bone loss, which in susceptible women may lead to vertebral, hip, and wrist fractures 2) lipid changes, which may contribute to the acceleration of atherosclerotic cardiovascular disease

question

Situation - Postmenopausal or oophorectomy Give the possible cardiovascular changes Estrogen replacement- positive effects? what happens to LDL, HDL and cholesterol? what happens to MI and CVA frequency? Whats wrong with this information? How should we measure cardiovascular issues with use of HRT? WHO SHOULD DEFINITELY RECEIVE HORMONE THERAPY REGARDLESS? why are transdermal/vaginal HRT possible favorable?

answer

Reduction in estrogen levels results in increase plasma cholesterol and LDL LDL receptors drop No effects on HDL Conclusion - increase atheroma risk Following estrogen replacement: decrease in total cholesterol: decrease in LDL increase in HDL 50% reduction in myocardial infarction frequency and as much as 40% reduction in fatal stroke frequency - findings have been disputed ! More recent evidence: the benefit of HRT for cardiovascular parameters depends largely on the amount of atherosclerosis at the onset of therapy, breast cancer risk is not increase if given right after menopause and for period of 7 years women with premature menopause transdermal or vaginal administration may be associated w/ decrease CV risk because it bypasses the liver circulation.

question

Postmenopausal or oophorectomy how should we treat hot flushes, insomnia and atrophic vaginitis

answer

symptomatic relief -- use lowest estrogen does possible for a limited period of time. Improved sense of well-being is often seen.

question

Postmenopausal or oophorectomy What are some predisposing factors to osteoporosis besides lowered estrogen? who are at highest risk for bone loss following menopause the affects on bone following estrogen replacement, drugs used, and what else is important for maintain bone levels?

answer

Factors influencing osteoporosis development: amount of initial bone present, calcium and vitamin D intake, physical activity Highest risk: smokers, thin, Caucasian, inactive, with low calcium intake + strong family history Estrogen replacement: Conjugated Estrogen or ethinyl estradiol effective in preventing decrease in bone density recurring menopause. Insuring adequate daily calcium intake is also important. 1500 mg

question

Estrogen mono therapy associated with increased risk of... unless the woman had a ..... the addition of what with estrogen prints endometrial hyperplasia and reduces cancer risk? what is the combination protocol? what is the continuous combination therapy? -what does it help to eliminate (which is caused by non-cont.) what are the positive and adverse effect what are the advantages of vaginal or transdermal estrogen therapy use? other uses:

answer

Estrogen monotherapy is associated with an increased risk of endometrial carcinoma., this is not a concern for women who have had a hysterectomy. The addition of progestational agent (+ estrogen) prevents endometrial hyperplasia and markedly reduces cancer risk. Combination Protocol : Estrogen (Premarin), first 25 days of the month Progestin (medroxyprogesterone) added during last 10-14 days of month cyclic bleeding may occur as well as menopausal symptoms or migraines on estrogen-free days. Continuous combination therapy: cyclic bleeding eliminated with continuous combination therapy (0.625mg conjugated equine estrogens + 2.5 mg medroxyprogesterone {Prempro} ) control of vasomotor symptoms, prevents genital atrophy, maintains bone density, promotes favorable lipid profiles Adverse effects with continuous therapy: endometrial atrophy, breakthrough bleeding (biopsy required if bleeding occurs after first few months) Vaginal or transdermal use: bypasses the first-pass effect, they are almost completely absorbed into the circulation, ratio of liver: peripheral effects is reduced. o Other Uses: Estrogen + progestins: -ovulation suppression for treating intractable dysmenorrhea -ovarian suppression used to manage hirsuitism and amenorrhea due to excessive ovarian androgen secretion

question

Estrogens: Clinical Uses Adverse Effects General rule: use smallest dose possible to minimize AEs

answer

uterine bleeding (may also be endometrial carcinoma) endometrial hyperplasia (add progestin) nausea, breast tenderness, hyper pigmentation = common increase frequency of: gall disease HTN cholestasis migraines Cancer: only in prolonged therapy - breast tumor risk and endometrial carcinomas

question

Endometrial cancer higher risk of... what reduces the risk?

answer

Via chronic estrogen mono therapy 15 times higher for women on high doses of estrogen for five or more years. Addition of progestin decreases risk to that lower than the general population

question

Breast cancer what increases risk what reduces risk

answer

Women on Estrogen + progesterone HRT show increase breast epithelial cell proliferation and density. Following unilateral breast cancer surgery, tamoxifen (an estrogen partial agonist) treatment reduces by 35% breast cancer risk on contralateral. The drug is well tolerated and has positive, estrogen-like changes in plasma lipids and stabilizes bone loss

question

Estrogens: Clinical Uses Contraindications

answer

estrogen-dependent neoplasm (endometrium or breast) undiagnosed genital bleeding liver disease history of thromboembolic disease heavy smokers

question

Progesterone What is the most important human progestin? what is it a precursor to? What are the sites of biosynthesis? What are the synthetic progestins? what are the difference between these and the 3rd generation type?

answer

progesterone Ovaries(corpus luteum), testis, adrenals, placenta 21 carbon compounds h-progesterone m-progesterone megestrol(Megace) dimethisterone never 19 nortestosterone - lower androgenic activity than older synthetics - gestdone - norgestimate - desogestrel - norethindrone - drospirenone

question

which of the 3rd generation progestins yields a 6-7 x increase in thromboembolism and is a spironolactone derivative causing hyperkalemia

answer

drospirenone

question

Drugs

answer

h-progesterone m-progesterone megestrol dimethisterone

question

Pharmacokinetics of Progesterone Absorption rate T 1/2 First pass/Hepatic metab.

answer

rapidly absorbed 5 minute high first pass effect - oral route is ineffective pregnanediol conjugated with glucoronide is then excreted in urine an can be measured diagnostically other metabolites are found in smaller concentrations

question

Pharmacodynamics of Progesterone from cell to nucleus

answer

progestin enters cell binds to either A or B isoforms of progestin receptor (alternative spliced gene product) dimerization, diffusion to nucleus, initiate transcription - binds to response elements similar to that of CREs response specificity depends on presence of receptors and transcription factors

question

Physiologic Effects of Progesterone Hormonal functions:

answer

development of the breast secretory apparatus causes endometrium to go from a proliferative to a secretory phase maintains the endometrium during pregnancy

question

Physiologic Effects of Progesterone Metabolism

answer

stimulates lipoprotein lipase promoting fat deposition significant effect on carbohydrate metabolism --> increases basal insulin levels and insulin response to glucose promotes glycogen storage (liver) promotes ketogenesis

question

Physiologic Effects of Progesterone Other Effects: renal tubules body temp ventilation CNS

answer

competes with aldosterone at renal tubule: decreasing sodium reabsorption. This in turn leads to an increase in adrenocortical aldosterone secretion. increases body temperature increases ventilatory response to CO2 depressant/hypnotic CNS effects

question

What are the clinical uses of progesterones? when is long term ovarian suppression indicated? what is a significant problem with long term ovarian suppression? what is the diagnostic value of progesterone?

answer

hormone replacement treatment hormonal contraception Long-term ovarian suppression causes prolonged anovulation and amenorrhea {large, parenteral does -- e.g. IM medroxyprogesterone (depot Provera) acetate/ 90 days} o Indicated for: dysmenorrheal, endometriosis, hirsutism, bleeding disorders (where estrogens are contraindicated), precocious puberty to prevent menstruation o significant problem: substantial delay before normal ovulatory function is regained Diagnostic Uses: used to assay estrogen secretion: - If administration of progesterone or medroxyprogesterone (for 5-7 days) is followed by withdrawal bleeding in amenorrheic patients, this indicates that the endometrium has been stimulated by estrogen

question

Adverse Effects: Progesterone

answer

Increased blood pressure (oral contraceptives) reduces plasma HDL (more androgenic progestins)

question

Androgens: list them: List their importance List the pathology associated with them

answer

Testosterone, DHEA, Androstenedione small amounts are produced - important for hair growth, libido and metabolic effects pathology - hirsutism, amenorrhea, polycystic ovary syndrome

question

Inhibin and Activin: function: molecule and difference in subunit function

answer

modulares response to LH and FSH Peptides composed of multi dimeric forms AB = inhibin - inhibit FSH BB = activin - promote FSH

question

Relaxin Similar to what compounds Site of Action Synthesized by Physiological effects

answer

GH and insulin ovary, blood, uterus, placenta granulosa cells of corpus luteum o Physiological effects: decrease uterine contractility increase glycogen synthesis/water uptake by myometrium changes mechanical characteristics of pubic ligaments/cervix, promoting delivery (facilitates dilatation and shortens labor)

question

Hormonal Contraception What are the two preparations

answer

Estrogen/Progestin combinations: Monophasic: constant dosage of both steroids during the cycle Biphasic,Triphasic, tetra phasic: dosage of one or both components changed once, twice, or three times during the cycle Continuous progestin treatment (no concurrent estrogen administration)

question

What are the functions of estrogen and progesterone in contraception?

answer

Estrogen: inhibits ovulation steady doses are taken over 21 days Drugs - ethinyl estradiol, mestranol (prodrug to ethinyl estradiol, monophasic) and estradiol valerate Progesterone inhibits endometrial implantation and thickens cervical mucus

question

Give the monophasic preparation for OCs

answer

small steady doses taken over 21 days Estrogen: ethinyl estradiol Progesterone: Drospirenone Desogestrel Norgestimate Norgestrel Norelgestromin : patch, apply 1/week Norethindrone Norethindrone acetate Levonorgestrel Levonorgestrel [extended cycle]: 84 active pills/ 7 inactive "reminder" pills Levonorgestrel: 365 active pills, no withdrawal bleeding Etonogestrel (NuvaRing): vaginal insert

question

Give the biphasic preparations

answer

increasing doses over 11-21 days Norethindrone - Necon

question

Give the triphasic preparations

answer

Estrogen: Ethinyl estradiol Progesterone(increasing dose over 3 consecutive intervals): Noregestimate Norethidrone + acetate Levenorgestrel -dose of ethinyl estradiol increase 3X over 84 days, reduces incidence of breakthrough bleeding w/ monophasic extended cycle Desogestrel

question

Give the four-phasic preparations

answer

Estradiol valerate/Dienogest (Natazia) reduces incidence of menorrhagia

question

Estrogens are always combined with _____ to limit endometrial growth

answer

progestin

question

What are the preferred estrogens for combination OCs?

answer

ethinyl estradiol mestranol (prodrug of EE)

question

Give the different intervals of combination contraceptives

answer

21 days on, 7 days placebo for withdrawal bleeding 84 days on, 7 days placebo, 4 cycles a years 365 days - continuous

question

How long do Otrho Evra transdermal patches last?

answer

3 weeks

question

How long to NuvaRing (vaginal rings) last?

answer

3 weeks

question

Advantages of multiphase OCs?

answer

by altering the dosage within a cycle, one can achieve near physiological levels of estrogen:progesterone ratios as seen during menstrual cycles it also decreases the total amount of hormone taken during a cycle

question

Progestin mono therapy Contraceptive when is it indicated what is a common side effect? What is the drug and what is the oral form of the drug commonly referred to as? high or low dose? How often does it prevent ovulation? how effective in preventing pregnancy?

answer

those who cannot risk using estrogen due to HTN, History of thromboembolism, nursing mother high incidence of bleeding initially, decreases with time, amenorrhea is common mini pill: Norethindrone given in low doses continually (mono phase) 70-80 % effective 98 % effective

question

Whats the drug name of the progestin implant? is it effective? DOA? Given as a what? How much less steroid release relative to oral type? what effect does this have? what are the disadvantages?

answer

Etonogestrel - Implanon very effective (99.8%) 2-4 year duration subcutaneous capsule releases 20-30 % as much as oral steroid --> low levels cause little changes to lipoprotein and carb metabolism and limited effects on BP Disad: surgical removal/insertion of implant, irregular bleeding

question

What is the drug name of the progestin injectable? Dosing interval and route? How long can ovulation suppression last?

answer

Medroxyprogesterone (Depo-Provera) IM every 3 months can suppress ovulation for years

question

What is the drug name of the progestin intrauterine device? how long does it release progestin for?

answer

Lenonorgrestrel (mirena, skyla) progestin released gradually over 5 years

question

Postcoital Contraceptives: What is the more common name? what are the different formulations? treatment should optimally occur within how many days? use often concurrently with what kind of drug?

answer

the morning after pill high does estrogen alone progestin alone combination 72 hours = 99 % effective antiemetic - 40 % = nausea and vomiting

question

Give the different postcoital contraceptive drugs and combinations as well as dosing interval

answer

estrogen alone: conjugated estrogens (Premarin), ethinyl estradiol, diethylstilbestrol (5 consecutive days) progestin alone: levonorgestrel (Plan B, Next Choice, Fallback Solo) one large dose or two smaller doses combination: norgestrel + ethinyl estradiol (Ovral, Preven) Mifepristone (Mifeprex): progesterone antagonist

question

Contraceptives: Estrogen and Progestin MOA:

answer

estrogen/progestins: suppresses GnRH, FSH & LH to suppress follicular development & inhibit ovulation progestin: inhibits endometrial implantation, makes cervical mucus impassable to sperm reducing chances of fertilization

question

Contraceptives: Physiologic Effects of oral Contraceptives: UTERI BLEED onto SKIN BREAST increase CARDIO and CNS activity OVARIES are ENDOCRINE HEPATOCYTES METABOLIZE LIPIDS and CARBS

answer

ovarian: depressed, following discontinuation, 75 % ovulate 1st post treatment, 90 % by 3rd cycle, 2 % remain amenorrheic for up to several years uterine: possible hypertrophy and polyp formations, cervical mucus changes - post ovulation type - thick, less breast: some enlargement, estrogen alone or in combo --> lactation suppression CNS: reduction in gonadotropins, estrogen increases, progestin decrease, progestins = thermogenic Endocrine: changes adrenal structure and function, estrogens increase CBG, TBG, SHBG(increase in plasma hormones!), increases plasma renin -->increase aldosterone, androgen suppression blood: inconsistent alteration in coagulation time, increase factors II, VII, IX, and X, decrease anti-thrombin III, increased fibrinogen, increase serum iron/total iron binding capacity (transferrin) Hepatic: increase fibrinogen and factor production, changes in hepatic drug excretion and metabolism, reduce bile flow, cholelithiasis, Lipid metabolism: estrogens = increases triglycerides, phospholipids, cholesterol and HDL, lowered LDL, 19-nortestosterone(progestin derivatives) antagonize these effects carbohydrate metabolism: decreased GI absorption, progesterone increases basal insulin and sensitivity to insulin release in response to glucose, reduced carb tolerance with long term - norgestrel - can be reversed cardiovascular: slightly higher BP and HR, monitor skin: chloasma(pigments), enhanced by UV and in darker woman, decreases sebum production and acne via androgen suppression

question

Contraceptives: Risk of conception Factor contributing to contraceptive failure

answer

oral contraception Small risk of conception (when these agents are used as directed) Pregnancy rate (combination agents): 0.5-1 per 100 women years at risk Factors contributing to contraceptive failure: phenytoin administration antibiotic administration(disruption of enterohepatic circulation) missing doses

question

Contraceptives: Other Clinical uses:

answer

o Primary hypogonadism: prevent estrogen deficiency in young females after attaining growth o Acne and hirsutism(sebum reduction, androgen suppression) o Endometriosis o Decreased chance of ovarian cyst o Severe dysmenorrhea -- major symptom long-term progestin dose or long-term progestin/estrogen doses prevents endometrial tissue periodic breakdown

question

Adverse Effects: Contraceptives There is low incidence of serious known toxicities associated with oral contraceptives. Adverse effects are reversible and can usually be remedied by a change in formulation. Mild Adverse Effects:

answer

Nausea, mastalgia, edema, breakthrough bleeding o Remedy: change preparation to one containing less estrogen change preparation to one containing progestins with greater androgenic action Headache o typically mild/transient o migraine: often worsened by treatment (discontinue use)

question

Adverse Effects: Contraceptives There is low incidence of serious known toxicities associated with oral contraceptives. Adverse effects are reversible and can usually be remedied by a change in formulation. Moderate Adverse Effects

answer

may require discontinuation of oral contraceptive use Breakthrough bleeding: o most common problem using progestational agent alone for contraception—(25%) o more often seen in patients using low-dose agents compared to combination drugs with higher progestin/estrogen levels Weight gain: o more likely with combination drugs containing androgen-like progestins o Remedy: dieting/changing medication to one containing less progestin effect Increase Skin Pigmentation: o more common in dark-skinned women o incidence increases with time: o 5% -- end of first-year; 40% -- after eight years Acne: o worsened by androgen-like progestin containing contraceptives o improved by contraceptives containing large estrogen content

question

Adverse Effects: Contraceptives There is low incidence of serious known toxicities associated with oral contraceptives. Adverse effects are reversible and can usually be remedied by a change in formulation. Severe Adverse Effects:

answer

Venous Thromboembolic Disease (related to estrogen not progestin component) o Risk increases 3 fold compared to women not taking oral contraceptives o unrelated to: age, mild obesity, cigarette smoking o Contributing factors: reduced venous blood flow arterial/venous endothelial proliferation enhanced coagulation (reduced antithrombin III levels) Myocardial Infarction: o Slightly increased risk in patients using contraceptives if the following risk factors are also present: o Obesity, hypertension/preeclampsia,hyperlipoproteinemia, diabetes o Significantly increased risk for smokers: (risks increase 45X) Depression: o Incidence: 6% with some contraceptive formulations; may be necessary to discontinue treatment. Cancer: Risk Reduction: endometrial/ovarian cancer Lifetime risk of breast cancer not be affected by oral contraceptive use. Some studies have indicate a possible increased risk of breast cancer in younger women Cervical cancer risk: uncertain

question

Contraindications: Contraceptives:

answer

Thrombophlebitis, thromboembolic phenomena, CV disorders, heart failure Tumors of the breast or estrogen-dependent neoplasms, fibroids Adolescents in whom epiphysial closure has not been completed Pregnancy Patients > 35 who smoke Used with caution in patients with liver disease, asthma, eczema, migraine, diabetes, hypertension, optic neuritis, or convulsive disorders

question

Drug interactions:

answer

Antibiotics - reduced enterohepatic circulation CYP induction in liver - reduced efficacy - phenytoin

question

Beneficial Effects: Oral Contraceptives

answer

Reduction is ovarian cancer and cysts, endometrial cancer, benign breast disease decreased PID, ectopic pregnancy, iron deficiency, duodenal ulcers, rheumatoid arthritis improvement in premenstrual symptoms, endometriosis, acne and hirsuitism

question

Estrogen/Progesterone Inhibitors & Antagonists: Selective Estrogen Receptor Modulators (SERMs): whats the idea behind these drugs and what benefits can they offer?

answer

ER-induced transcription slightly in differs in organs, SERMs can activate gene expression in certain organs. The advantage is specificity. A SERM that blocks estrogen effects in one tissue will not impact estrogen binding in another tissue. Can help in slowing metastasis of cancer or to treat osteoporosis.

question

What are the major SERM drugs?

answer

Tamoxifen Raloxifene Clomiphehe

question

Tamoxifen (Nolvadex) type of drug Full or partial agonist? Steroid or non-steroid? Route Adverse effects clinical indications

answer

Competitive partial agonist, inhibitor of estradiol at estrogen receptors nonsteroidal orally active Adverse/Side effects: hot flushes, nausea/vomiting (frequency = 25%) Clinical indications: adjuvant therapy for breast cancer:(35% decrease in contralateral breast cancer frequency), chemoprevention of breast cancer in high-risk women No improvement in outcome associated with treatment > 5 years Tamoxifen (due to agonist properties) stimulates the endometrium; increasing endometrial cancer risk

question

Raloxifene (Evista) partial or full agonist whats the difference between this drug and tamoxifen? indication prophylaxis for? Vd and T1/2

answer

SERM partial estrogen agonist-antagonist --> same effect as tamoxifen in lipids and bone, BUT DOES NOT appear to stimulate the endometrium or breast o Indicated for use prevention of postmenopausal osteoporosis o Prophylaxis of breast cancer in women with risk factor o High Vd, long T 1?2 (> 24hrs)

question

Mifepristone (RU-486, Mifeprex) has affinity for which type of receptors? agonist or antagonist? half life- long or short what does it do to the corpus luteum? Indications and Clinical uses? What the major use? What is it commonly marketed with? Whats the other drugs function? Dosing protocol? What the significance of this combination? adverse effects?

answer

"19-nor steroid" with high affinity for progesterone receptors. competitively inhibits progesterone action at the receptor, long half-life luteolytic properties when administered in mid-luteal time frame effective emergency postcoital contraceptive Possible Clinical Uses: endometriosis, breast cancer, other neoplasms (with glucocorticoid/progesterone receptors) Present major use: early pregnancy termination (effective approximately 85% of the time) Commonly marketed along with Misoprostil: synthetic PGE1 analogue that stimulates uterine contraction. RU486 given as a single oral dose followed by misoprostal ~48hrs later. Combination terminates 1st trimester pregnancy ~ 95%. o Major Adverse Effect: prolonged bleeding

question

Danazol (Danocrine) overall activity of drug effect on ovarian function T 1/2 MOA What receptors does is bind to? Which enzymes does it inhibit? Clinical use adverse effects contraindications

answer

weak progestational, androgenic, and glucocorticoid activity. Suppresses ovarian function. slowly metabolize; half-life > or 15 hours o Mechanism of Action: inhibits midcycle LH/FSH surge but no effect on basal LH/FSH levels o Binds to many receptor types/proteins including: Androgen, progesterone, glucocorticoid, SHBG, CBG, but not estrogen receptor o Inhibit several cytochrome P450 systems, including: P450scc -- cholesterol side chain-cleaving form, P450c11 -- 11-beta-hydroxylase, P450C17 -- 17-alpha-hydroxylase, P450c21 -- 21-hydroxylase o Clinical Uses: Primary use: treating endometriosis marked improvement after 3 months Other uses: o breast fibrocystic disease o hematologic diseases: Christmas disease(Hemophilia B), idiopathic thrombocytopenic purpura o Adverse Effects: weight gain, edema, reduced breast size, acne, voice deepening, headache, hot flushes, libido changes, muscle cramps, increased hair growth Contraindication: urogenital anomalies in the newborn o pregnancy o breast feeding

question

Anastrozole (Arimidex): MOA indication

answer

o inhibits aromatase -- required for estrogen synthesis o effective in tamoxifen-resistant breast cancer

question

Letrozole (Femara) MOA Clinical use

answer

o nonsteroidal aromatase inhibitors o comparably effective as tamoxifen o Clinical uses: tamoxifen-resistant breast cancer, adjuvant treatment of precocious puberty (combo w/ androgen antagonist), excessive aromatase syndrome

question

Fulvestrant (Faslodex) MOA Indication

answer

pure estrogen receptor antagonist o Inhibits dimerization of the bound estrogen receptor and eventually leads to receptor downregulation o Used for the treatment metastatic breast cancer resistant to tamoxifen

question

Clomiphene (Clomid) MOA and SOA Stimulates what in amenorrhea or ovulatory abnormalities such as polycystic kidney disease? T1/2 high or low protein binding? clinical use adverse effects Multiple pregnancy frequency Contraindications/Cautions

answer

SERM, partial agonist at estrogen receptors - antagonist in the hypothalamus has been shown to increase gonadotropin & estrogen secretion (loss of feedback inhibition). It stimulates ovulation in patients with amenorrhea or other ovulatory abnormalities (polycystic ovarian disease PCOS; 7% of population) The drug is slowly excreted; T 1?2 = 5-7 days with significant protein binding ClinicalUses: -promote ovulation patients wishing to become pregnant -not useful if abnormality is due to underlying ovarian or pituitary failure -80% of patients with amenorrhea/anovulatory abnormalities will initiate ovulatory cycling: 50% of these patients are likely to become pregnant Adverse Effects: o Most common: hot flushes o a variety of other symptoms probably secondary to hormonal changes (due to ovulatory menstrual cycle); headache Multiple pregnancy: frequency = 10% Contraindications/Cautions o consider dosage reduction in patients with enlarged ovaries o treatment > one-year: possible increase risk for low-grade ovarian cancer

question

Side note - endometriosis

answer

Endometriosis is the presence of benign endometrial glands and stroma outside the uterus. It afflicts 5% to 10% of women of reproductive age and regresses after natural or artificial menopause. Sites most frequently involved are the ovaries (> 60%), other uterine adnexa (uterine ligaments, rectovaginal septum, pouch of Douglas) and the pelvic peritoneum covering the uterus, fallopian tubes, rectosigmoid colon and bladder. Endometriosis can be even more widespread and occasionally affects the cervix, vagina, perineum, bladder and umbilicus. the signs and symptoms of endometriosis depend on the location of the implants. The most common complaint is dysmenorrhea, owing to implants on the uterosacral ligaments. These lesions swell immediately before or during menstruation, producing pelvic pain. In fact, half of all women with dysmenorrhea have endometriosis. Infertility is the primary complaint in one third of women with endometriosis

Estrogens and Progestins – Flashcards

Unlock all answers in this set

Haven't found what you were looking for?

Search for samples, answers to your questions and flashcards