Female Pharmacology Flashcards by Meghan May

converts the androgens (Testosterone, Androstenedione and Hydroxyandrostenedione) to the respective estrogens, Estradiol, Estrone and Estriol)

the aromatase enzyme

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What are the three natural estrogens and which is the most potent?

Estradiol>Estrone>Estriol

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67% of circulating estrogens are bound to:

Where is estrogen metabolized?

sex steriod binding globulin and albumin

in the liver

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There are two nuclear estrogen receptors: _______and_____.They are ligand-activated transcription factors that increase or decrease the transcription of target genes. They have different tissue distributions and transcriptional regulatory effects on a wide number of target genes

ER-alpha and ER-beta.

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Both ERs exist as multiple mRNA isoforms due to differential promoter use and alternative splicing. This concept of _________in ER conformation is central to understanding the mechanism of action of estrogen agonists and antagonists.

There is evidence of a cell membrane receptor for estrogen that signals non-transcription estrogenic effects.

ligand- mediated changes

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enhances skeletal maturation and epiphyseal growth plate closure to limit linear growth and a role in feedback regulation of gonadotropin release

Estrogen

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Estrogen has positive effects on bone mass mainly by decreasing the number and activity of

osteoclasts

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Estrogens alter a number of pathways affecting the clotting cascade. Estrogens slightly____ a number of coagulation factors II, VII, IX, X, and XII, and________ the anticoagulation factors protein C, protein S, and antithrombin III. Fibrinolytic pathways also are affected, with decreased levels of plasminogen-activator inhibitor 1 (PAI-1) protein with a concomitant increase in fibrinolysis. Thus, estrogens______ both coagulation and fibrinolytic pathways – an imbalance in these opposing activities could cause adverse effects.

increase

decrease

increase

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Estrogens role in cervical mucus and endometrium

increases amount of cervical mucus and its water content to facilitate sperm penetration as well as promoting endometrial proliferation

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The naturally occurring hormone,______ is secreted by the ovary, mainly from the corpus luteum during the second half of the menstrual cycle. It’s synthesis is a component of corticosteroid biosynthesis cascade.

progesterone

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Progesterone acts on the progesterone receptor (a steroid receptor). It is a single gene that encodes two isoforms, PR-A and PR-B. How are they distributed?

ratios of each depend on tissue type and actvity depends on target tissue. MOstly results in stimulatory effect but sometimes inhibitory

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In plasma progesterone binds to _______ and ______ while some progestins bind to SHBG

Progesterone has a RAPID first pass effect

corticosteroid binding globulin and albumin

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Effect progesterone on GnRH pulses

Decreases frequency of GnRH

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Effect of progesterone on estrogen driven endometrial proliferation

decreases estrogen-driven endometrial proliferation and leads to development of a secreatory endometrium.

*abrupt decline in progesterone at end of cycle is main determinant of the onset of menstration

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AFfect of progesterone on cervical mucous and pregnancy

makes mucous viscid and maintains pregnancy

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Effect of estrogen and progestin on endometrium

estrogen: proliferation

Progestin: secreatory to limit proliferation

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Affect of estorgen and progestin on cervical mucous

Estrogen decreases viscosity and increases amount of cervical mucous

Progestin **increases **and decreases amount

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Effect of estrogen and progestin on uterine contractions

Estrogen will favor rhythmic contractions and the progestin will decrease contractions

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collected from mare’s urine and contains sulfate esters of estrone, equilin, and other naturally occuring compounds

Conjugated equine estrogens

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is the most potent of the natural estrogens in humans.
Preparations: Oral (micronized prep, because of first pass effect) patches, creams. The transdermal route minimizes hepatic effects of estrogens.

17B-estradiol

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(PREMARIN) contain sulfate esters of estrone, equilin and other equine compounds - **oral, esters are cleaved in the body. **

Conjugated equine estrogens

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(estradiol valerate or estradiol cypionate) are available and are dissolved in oil and injected I.M. resulting in slow release.

Estrogen esters

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(a semisynthetic steroid) is the most potent estrogen available. (Oral) – C17

ethinyl inhibits first pass metabolism (t 1⁄2 = 13 to 27 hours).

Ethinyl estradiol

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Therapeutic uses of estrogens

* Combination oral contraceptives

* Postmenopausal hormone replacement therapy

Failure of pituitary function/ovarian development

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Toxic side effects of estrogen therapy

Gall Bladder disease (2-3 fold increase) Oral estrogen increases risk of thromboembolic disease nausea and vomiting breast swelling migraine headaches

When is estrogen therapy contraindicated?

pregnancy, estrogen-dependent cancers, undiagnosed uterine bleeding, thromboembolic disorders

orally active with two isomers: a weak estrogen agonist and a potent estrogen antagonist \*\*\*works as a partial agonist at estrogen receptors.

induces ovulation by inhibiting the action of stronger estrogens thus inhibiting feedback and increasing pulsatile gonadotropin release

Clomiphene

MOA of Clomiphene

Clomiphene increases gonadotropin secretion and stimulates ovulation. It increases the amplitude of LH and FSH pulses without changing pulse frequency.

Side effects of Clomiphene

ovarian hyperstimulaiton, multiple births, hot flashes

Mixed estrognic and anti-estrogenic effects which are tissue specific (more anti-estrogenic in breast) Used to treat and prevent breast cancer

Tamoxifen

Estrogenic properties of SERMS such as Tamoxifen

hot flashes, sitms endometrial proliferation (more risk of endometrial cancer), increase TE events and is antiresorptive on bone

By altering the conformation of the different ERs and changing interactions with co-activators and co-repressors in a cell-specific and promoter-specific contexts, ER ligands may have a broad spectrum of activities from *purely anti-estrogenic in all tissues*, to *partially estrogenic in some tissues* with a*nti-estrogenic or no activities in others*, to purely estrogenic activities in all tissues.

SERMS – Selective Estrogen Receptor Modulators

Treatment of breast cancer in women with ER-positive tumors, and it is now indicated as the hormonal treatment of choice for both early and advanced breast cancer in women of all ages. reduces the risk of developing contralateral breast cancer and is approved for primary prevention of breast cancer in women at high risk.

Tamoxifen

MOA of Tamoxifen

exhibits anti-estrogenic, estrogenic, or mixed activity depending on the tissue. Competitive ER antagonist in breast tissue

Treatment and prophylaxis of osteoporosis in postmenopausal women and breast cancer. Reduces rate of bone loss and reduces risk for invasive breast cancer

Raloxifene

MOA of Raloxifene

SERM that is an estrogen agonist in bone

Estrogen properties of Raloxifene

reduction of cholesterol hot flashes, increased thrombosis, leg cramps no endometrial thickening

Letrozole, Anastrozole, and Exemestane are all examples of:

Aromatase inhibitors

Which aromatase inhibitors are steroidal? non steroidal?

Exemestane non: Letrozole and Anastrozole

type I agents that are substrate analogs that act as suicide inhibitors to irreversibly inactivate aromatase.

Exemestane

reversible inhibitors of aromatase

Nonsteroidal: Letrozole and Anastrozole

Use of aromatase inhibitors

tx of breast cancer by reducing local and circulating estrogen levels

major side effect of aromatase inhibitors

Hot flashes

Three progesterone preperations 1. low oral bioavailability 2. progesterone analog 3. ethinyl substituet at C17 to slow hepatic metabolism

Progesterone = low bioavailability Medroxyprogesterone = progesteorne analogue that mostly progestational Morethindrone = ethinyl substitute at C17

racemic mixture of an inactive isomer and active isomer. Substituent results in a more potent progestin with less androgenic activity

Norgestrel

testosterone derivatives, have primarily progestational rather than androgenic activity. Some synthetic progestins (especially the 19-nor compounds) have limited binding to glucocorticoid, androgen, and mineralocorticoid receptors, a property that accounts for some nonprogestational activities.

Progesterone Methydorxyprogesterone

spironolactone analogue with anti-mineralocorticoid and progestin activity.

Drospirenone

What do we need to monitor when we give women Drospirenone?

Because it antagonizes the mineralocorticoid receptor, serum K+ should be monitored in **women at risk for hyperkalemia. **

Key uses of progestins

Pregnancy prevention, emtional/physical symptoms of prementral dysphoric disorder, moderat acen vulgaris, hormonal contraceptives, post menopausal hormone replacement

progestin is used to diagnose which diseases?

secondary amenorrhea and endometrial hyperplasia

What are the three negative effects of progesterones?

Headaches, breakthrough bleeding, Adnrogenic actiosn like acne and hirsutism

MOA of Mifepristone

competitive receptor antagonist for both progesterone receptors, although it may have some agonist activity.

in combination with misoprostol or other prostaglandins, it is used for the termination of early pregnancy.

Mifepristone

Mifepristone competitively blocks the \_\_\_\_\_receptor causing _____ breakdown and placental detachment and exuplsion of embryonic pregnancy. also sensitizes _____ to contractile actions of proglandins.

Progesterone decidual myometrium

What do you need to take along with mifepristone?

misoprostal to cause contractiosn to rid of blastocyst

selective progesterone receptor modulator that acts as partial agonist at progesterone receptors

Ulipristal

MOA of Ulipristal

inhibits ovulation: inhibits LH release thus blocks LH induced follicular rupture in ovary. Should be taken up to five days after intercourse

It inhibits LH release through interaction with the hypothalamus and pituitary, and inhibition of LH-induced follicular rupture in the ovary.

Ulipristal

Side effects of Ulipristal

headache and abdominal pain

Mainstay for hormonal contraception

Estrogen and progesterone and progesterone only

Options for post-coital contraception

Combined levonorgesterel and ethinyl estradiol-- 2 doses Levonorgestreal alone (2 doses) Ulipristal

pill or high-dose estrogen-progestin combination pill is used for postcoital emergency contraception.

levonorgestrel

(non-steroidal SERM) acts as an estrogen agonist in bone. It is used for the treatment and prevention of postmenopausal osteoporosis.

Raloxifene

Therapeutic approach to postmenopausal hormone replacement therapy

need to to risk vs benefit analysis a. estrogen/progestin combo therapy for INTACT uterus b. Estrogen only (post hysterectomy)

Mestranol is converted by the body to

ethinyl estradiol.

(termed an antiestrogen) is a weak agonist of estrogen receptors in some tissues. It is used to treat infertility. It enhances gonadotropin secretion by antagonizing feedback suppression of GnRH. Can cause ovarian hyperstimulation.

Clomiphene

is the most potent natural estrogen. It is in equilibrium with estrone

17B estradiol