Endocrine 2 Exam 1: Estrogens, Progestins (p10-27)

What are the 3 types of GnRH-based drugs?

Pulsatile GnRH, Continuous GnRH agonists

GnRH antagonists

GnRH is normally released in a _____ manner from the hypothalamus and it has a very ____ half-life

pulsatile, short

Pulsatile GnRH (Factrel, Gonadorelin acetate, and Lutrepulse) are drugs that mimic natural GnRH, which could be used to induce ___, but these drugs are not used clinically

ovulation

Pulsatile GnRH is given in the form of ___ ____ to mimic the quick rise and fall of concentrations of this hormone within the body

IV pump

Continuous GnRH analogs (Leuprolide acetate, Triptorelin, Goserelin)

-are resistant to _____, resulting in a ____ half-life and binding with greater affinity to the GnRH receptor

proteolysis, longer

Continuous GnRH analogs (Leuprolide acetate, Triptorelin, Goserelin)

Due to the longer half-life, GnRH agonists that are resistant to proteolysis give a "_____" stimulation of the GnRH receptor

continuous

Continuous GnRH analogs (Leuprolide acetate, Triptorelin, Goserelin)

Continuous stimulation of the GnRH receptor causes ____, which causes loss of ____ over time

desensitization, function

Continuous GnRH analogs (Leuprolide acetate, Triptorelin, Goserelin)

Loss of GnRH receptor function over time leads to ____ release of FSH and LH, and therefore ____ release of estrogen and progesterone/testosterone

no, no

Continuous GnRH analogs (Leuprolide acetate, Triptorelin, Goserelin)

-clinically, these drugs are used to treat ____ and ___-___ ___ ___

infertility, androgen-dependent prostate cancer

Continuous GnRH analogs (Leuprolide acetate, Triptorelin, Goserelin)

-for IVF, used to prevent premature rises in ____

LH

Continuous GnRH analogs (Leuprolide acetate, Triptorelin, Goserelin)

-for androgen-dependent prostate cancer, used to lower ____ (testosterone) levels in males

androgen

GnRH antagonists (Ganirelix, Cetrorelix)

-block the GnRH ____

-are used in assisted fertility techniques (___) to prevent LH surges

receptor, IVF

For a GnRH agonist, effects take time (weeks) for the receptor to desensitize. For a GnRH antagonist, the effects are ____ !

quick

The gonadotropins (FSH, LH, chorionic gonadotropin (CG)) can be used for ____ purposes or for ____ use to treat infertility

diagnostic, therapeutic

Diagnostic Use of FSH- or LH- Based Drugs

-we can measure LH and FSH concentrations to ascertain the ____ of specific disease states

etiologies

Diagnostic Use of FSH- or LH- Based Drugs

-_____ may be due to low LH levels

-hypogonadotropic-hypogonadism may be due to low levels of FSH and/or LH from tumor/trauma

amennorhea

Diagnostic Use of FSH- or LH- Based Drugs

FSH and LH levels are also measured to predict the time of ____

ovulation

There is a surge in both FSH and LH levels at day ___ of the menstrual cycle

13

Ovulation is day ___ of the menstrual cycle

14

Days ___-___ is the fertile period of the women's menstrual cycle

14-28

Diagnostic Use of FSH- or LH- Based Drugs

Human CG (hCG) is the basis for ___ tests.

pregnancy

Pregnant females secrete hCG into the ___ ____

blood stream

hCG is secreted by the ___ initially and then by the synctio-trophoblastic cells of the ___

blastocyst, placenta

hCG is involved with maintaining the pregnant state by preventing endometrial smooth muscle ___

contraction

hCG prevents endometrial smooth muscle contraction (by mimicking ___ and ___)

LH, progesterone

Pregnancy tests are immobilized ___ directed into hCG. Because hCG is secreted in the urine, the female can urinate onto the strips and if hCG is present, the antibody will bind to it and color the strip.

antibodies

Therapeutic Use of FSH- or LH- Based Drugs

-for individuals (male and female) suffering from infertility, the gonadotropins can be given in the form of ____ therapy

replacement

FSH- or LH- Based Drugs used to treat infertility include:

-________

-________

-recombinant _____

-chorionic _______

-______

menotropins, urofollitropin, FSH, gonadotropins, metformin

Menotropins contain equal amounts of ___ and ___ and are given IM due to lack of purity

FSH, LH

Urofollitropin is a purified ____ preparation

FSH

Menotropins and Urofollitropin are extracted from the urine of ____-menopausal women

post

Menotropins and Urofollitropin are extracted from the urine of post-menopausal women because these women have ___ levels of E2 and P4, which means they have ____ levels of GnRH

decreased, increased

Menotropins and Urofollitropin are extracted from the urine of post-menopausal women because they have ↓E2 and P4 and ↑GnRH. So therefore, levels of FSH and LH in the urine of these women is ____

increased

Recombinant FSH (rFSH) is expressed in ___ cells. There is Follitropin α and Follitropin β.

mammalian

Chorionic Gonadotropins can be given because they mimic the actions of ___, and therefore lead to increased progesterone and therefore increased testosterone

LH

Chorionic Gonadotropins have ___ potential for building muscle due to the ability to increase testosterone

abuse

Metformin is used to treat infertility due to ___ (polycystic ovarian syndrome) and insulin ____

PCOS, resistance

PCOS causes infertility because hyperglycemia leads to high insulin, and therefore high androgens, which _____ feedback inhibition on the GnRH/FSH axis

increases

In PCOS, increased feedback inhibition on the GnHRH/FSH axis can cause the patient to be ___ due to low FSH/LH (resulting in infertility)

anovulatory

Metformin has an ____ effect (stimulates AMPK to inhibit gluconeogenesis)

antihyperglycemic

Metformin decreases glucose→decreases insulin→decreases___ → decreasing ____

LH, testosterone

Metformin decreases glucose→decreases insulin→decreases LH → decreasing testosterone →decreasing/attenuating ___ ____

feedback inhibition

Metformin decreases glucose→decreases insulin→decreases LH → decreasing testosterone →decreasing feedback inhibition→ _____ FSH/LH, egg development, ovulation

increasing

Metformin also→ increases ____

SHBG

Metformin also→ increases SHBG→ decreases androstenedione and testosterone from theca cells→ therefore decreasing "___" testosterone

free

Metformin also→ increases SHBG→ decreases androstenedione and testosterone from theca cells→ therefore decreasing "free" testosterone→ therefore ____ the GnRH/FSH/LH axis

increasing

Estrogens and Progesterone are the hormones responsible for sexual maturity. ___ are the principal source of circulating estrogens and progesterone in the pre-menopausal female

ovaries

What is the principal drug responsible for "estrogenic" activity?

17-β-estradiol

Estradiol itself is not used orally due to its extensive ___-___ hepatic metabolism (ie cleared from the blood quickly)

first-pass

The administration of estrogen and progesterone could be oral, parental, transdermal, or topical due to their ____ nature

lipophilic

Many estrogen/progesterone-based therapies aim to:

1) resist ____

2) promote ____

3) ___ effect

metabolism, absorption, local

The advantage of using an oral micronized formulation (eg estrace, MPA, activella) is to increase ___ ___ and increase ___ into the body

surface area, absorption

Estrogen/progesterone therapies that are formulated as vaginal tablets (eg vagifem) aim to have a ___ effect on the vagina

local

The advantage to using oral conjugated formulations (eg premarin, duavee) is to prevent __-___ effect in the liver

first-pass

Note that there are oral plant-derived conjugated formulations of estrogens (herbals) that have ___ been shown to have estrogen activity in the body

not

The advantage to using transdermal formulations (eg minivelle, femring) is to increase ____ and bypass the ___

absorption, liver

There are many different transdermal ____ (spray, ring, cream, patch, etc

formulations

The advantage to using intramuscular (IM) formulations is for ___ action in the body (P4 based) (3 months)

extended

The advantage to using intrauterine device (IUD) is for ___ action in the body (3-5 years) and is inserted into the ___

extended, cervix

Hormone Therapy (HT) has 2 main indications: ___ and ___

menopause, contraception

Hormone Therapy (HT) is indicated for contraception in ___-___ women

Hormone Therapy (HT) is indicated for menopause in ___-___ women

pre-menopausal, post-menopausal

Hormone Therapy (HT) is commonly used to alleviate the ___ symptoms of menopause (hot flashed, chills, sweating, paresthesias)

vasomotor

Contraceptives: the mechanism by which estrogen prevents ___ is via their actions on the negative feedback loop on the hypothalamus and pituitary gland

ovulation

Adverse Effects of Hormone Therapy

-normal effect on breast is ___ during puberty

maturation

Adverse Effects of Hormone Therapy

-effect on breast during pregnancy is to stimulate ___

lactation

Adverse Effects of Hormone Therapy

-adverse effect on breast when used for contraception or menopause is increased risk for breast _____

cancer

HT can cause breast cancer because these hormones are mitogenic (increase cell ___)

proliferation

Adverse Effects of Hormone Therapy

-the normal effect on uterus is maintaining the ___ ___ (estrogen regenerates, progesterone maintains)

menstrual cycle

Adverse Effects of Hormone Therapy

-effect on uterus during pregnancy is _____/maintenance of endometrial lining and prevention of myometrial ____ (premature delivery)

vascularization, contraction

Adverse Effects of Hormone Therapy

-effect on uterus when used for contraception is therapeutic: regulates ___, decreases ___, decreases ___

cycles, dysmenorrhea, bleeding

Adverse Effects of Hormone Therapy

-adverse effect on uterus when used for menopause is increased risk of ___ cancer (contraindicated for those at risk for uterine cancer)

endometrial

Adverse Effects of Hormone Therapy

-the normal effect on ovary is egg ___ and ___

development, ovulation

Adverse Effects of Hormone Therapy

-effect on ovary during pregnancy is to ___ ovulation (bc high E2, P4 means increased feedback inhibition)

decrease

Adverse Effects of Hormone Therapy

-effect on ovary when used for contraception or menopause is protection of ovary and ____ ovulation

decreased

Adverse Effects of Hormone Therapy

-the normal effect on liver is maintaining HDL/LDL ___ (E2→favorable, P4→unfavorable) and forming ___ proteins

ratios, clotting

The liver is the main organ that ___ estrogens and progestins

metabolizes

Adverse Effects of Hormone Therapy

-adverse effect on liver when used for contraception or menopause is ______ with CAD, TIA, DVT, VTE, PE, or liver disease

-bc increases clotting proteins!!

contraindicated

Adverse Effects of Hormone Therapy

-normal effect on the gall bladder is bile salt/fat ___ and ___

solubilization, absorption

Adverse Effects of Hormone Therapy

-effect on the gall bladder during pregnancy is increased risk for ___ and ___ ___

cholecystitis, gall stones

Adverse Effects of Hormone Therapy

-due to effects on the gallbladder, HT is contraindicated in patients with ___ and ___ __

cholecystitis, gall stones

Adverse Effects of Hormone Therapy

-normal effect on the brain is cerebral __ flow, body ___ regulation, and feedback ___

blood, temp, inhibition

Adverse Effects of Hormone Therapy

-therapeutic effect on brain when used for contraception is ___ without aura and ___ of pregnancy by decreasing ovulation

migraines, prevention

Adverse Effects of Hormone Therapy

-therapeutic effect on brain when used for menopause is control of ___ symptoms

vasomotor

___ ____: drugs that opposethe actions of estrogen by either decreasing E2 levels or antagonizing the ER receptor

anti-estrogens

Anti-estrogenic therapy could be used to treat ___ and estrogen-dependent __ ___

infertility, breast cancer

Approach 1: Inhibit Synthesis of Estrogen

-can occur by decreasing levels of ___ or by inhibiting ___ expressed in various tissues

FSH, aromatases

There is particular interest in inhibiting estrogen production locally in postmenopausal breast tissue, as this may reduce systemic ___ ___ of therapy

side effects

The aromatases convert androgens (androstenedione or testosterone) → _____

estrogens

Aromatase inhibitors can be used to treat ____ (in premenopausal women) or estrogen-dependent ___ ___ (in postmenopausal women)

infertility, breast cancer

To treat infertility, aromatase inhibitors work in the ovary by inhibiting the conversion of FSH/LH to ___

E2

To treat infertility, aromatase inhibitors work in the ovary by inhibiting the conversion of FSH/LH to E2

-low E2 causes an ___ in the amount of GnRH, FSH, and LH, therefore ___ egg development/ovulation

increase, increasing

To treat E2-dependent breast cancer, aromatase inhibitors work in the breast by inhibiting the conversion of ____ in the blood to E2

androgens

2 types of aromatase inhibitors

Type 1 (_____) : exemestane

Type 2 (___-____) : anastrozole, letrozole

steroidal, non-steroidal

Approach 2: Competitively antagonize the actions of estrogen at the receptor

-accomplished by estrogen receptor ___ (SERDs) or ___

-used to treat breast cancer or infertility

antagonists, SERMs

SERDs are estrogen receptor antagonists and include ____ (Faslodex)

fulvestrant

SERD: selective estrogen receptor ____

downregulator

SERD: Fulvestrant (Faslodex)

-does not possess any agonist activity

-used to treat E2-dependent ___ breast cancer in ___-menopausal women with disease progression on tamoxifen/other antiestrogens

metastatic, post

SERD: Fulvestrant (Faslodex)

-binds to ER with 100x higher ___ than tamoxifen

affinity

SERD: Fulvestrant (Faslodex)

-inhibits the ___ of ERs and increases their ____

dimerization, degradation

SERMs

-display properties of agonists and antagonists

-Hence, they are classified as ___ agonists

partial