Endocrine 2 Exam 1: Lapinsky (p1-19)

All steroid hormones share the same basic ___-ring structure that contains 17 carbons (called the steroid nucleus)

four

5α-____ is a key structural backbone related to many steroids.

cholestane

Seen on 5α-cholestane, position __ is important for ER

3

Seen on 5α-cholestane, position __ is important for AR

5

Seen on 5α-cholestane, position __ is important for PR

6

Seen on 5α-cholestane, position 17 is important as well as position ___ (which is removed by aromatase)

19

A dashed substituent (below the plane) = ____

alpha

A wedged substituent (above the plane) = ____

beta

Key point: Steroid nucleus ___ count can serve as a predictor of steroid hormone receptor binding

carbon

The carbon count of the steroid nucleus is a key structural feature that helps determine which steroid hormone receptor ___ a molecule can bind to

family

Note that carbons that are NOT part of the traditional 5α-Cholestane nucleus are ___ considered in counting

not

Note that carbons that are NOT part of the traditional 5α-Cholestane nucleus are not considered in counting, but rather are designated as ___ ___

functional groups

example of carbons that are NOT part of the traditional 5α-Cholestane nucleus

-Both 17β-estradiol and 17α-ethinyl estradiol are ____ estranes (regardless of added carbons at the 17 position)

C18

Functional groups can fine-tune steroid receptor _____ as a means of removing ___ ___

selectivity, side effects

What are the 5 main steroid hormone receptors?

ER, PR, AR, GCR, MCR

_____ is derived from the parent hydrocarbon 5α-cholestane (C27)

cholesterol

_____, ___, and ___ are derived from the parent hydrocarbon 5α-pregnane (C21)

progesterone, hydrocortisone, aldosterone

_____ and ___ are derived from the parent hydrocarbon 5α-androstane (C19)

testosterone, 5α-DHT

5α-DHT is 5x more ___ than testosterone

potent

_____ and ___ are derived from the parent hydrocarbon estrane (C18)

estradiol, estrone

Estradiol is 10x more ___ than estrone

potent

What are the prototype AR agonists?

testosterone, 5α-DHT

What are the prototype ER agonists?

estradiol, estrone

What enzyme converts testosterone to 5α-DHT?

5α-reductase

What enzyme converts testosterone to estradiol?

aromatase

What enzyme converts estradiol to estrone?

17β-HSD

The steroid nucleus of Estrane has how many carbons?

18

What is the prototype endogenous agonist with Estrane?

17β-estradiol

Key Structural Features of Estrane

-loss of C19 angular methyl

-____ ___ ring

-most ___ steroid nucleus

aromatic A, compact

What is the primary steroid hormone receptor with Estrane?

estrogen receptor (ER)

Why does the C18 steroid nucleus of Estrane fit the ER receptor?

-small, planer estrane nucleus fits ____ ER pocket

-aromatic A ring stabilizes ___-___ agonist conformation

compact, helix-12

Remember estrane = ___

estrogen

The steroid nucleus of Androstane has how many carbons?

19

What is the prototype endogenous agonist with Androstane?

testosterone

Key Structural Features of Androstane

-angular C19 methyl is ____

-____-aromatic A ring

-no ___ side chain

retained, non, c17

What is the primary steroid hormone receptor with Androstane?

androgen receptor (AR)

Why does the C19 steroid nucleus of Androstane fit the AR receptor?

-androstane nucleus is slightly ___ than estrane, which provides the optimal __ fit for AR but is too small for PR, GCR, MCR

larger, steric

Remember adding one carbon to estrane = ____

androstane

The steroid nucleus of Pregnane has how many carbons?

21

What are the prototype endogenous agonists with Pregnane?

progesterone, cortisol

Key Structural Features of Pregnane

-2 carbon side chain at C17

-increased ___ and ___

polarity, flexibility

What are the primary steroid hormone receptors with Pregnane?

progesterone receptor (PR), glucocorticoid receptor (GCR)

Why does the C21 steroid nucleus of Pregnane fit the PR/GCR receptors?

-pregnane nucleus with a C17 side chain is required for PR/GCR ___; explains __-___

recognition, cross-reactivity

Remember pregnane = ____ and stress hormones

pregnancy

The steroid nucleus of MCR-biased Pregnane also has 21 carbons, and has what prototype endogenous agonist?

aldosterone

Key Structural Features of MCR-biased Pregnane

-pregnane core

-____/___ functionalization

aldehyde/hydroxyl

Why does the C21 steroid nucleus of Pregnane fit the MCR receptor?

-the functional group ___ biases pregnane scaffold toward MCR over GCR

pattern

Remember MCR ligands are "____" pregnanes

decorated

The steroid nucleus of Cholestane has how many carbons?

27

What is the prototype endogenous agonist with Cholestane?

cholesterol

Key Structural Features of Cholestane

-long ___ side chain

-____ cholestane nucleus

aliphatic, bulky

the C27 steroid nucleus of Cholestane fits ___ traditional steroid receptors

no

Why does the C27 steroid nucleus of Cholestane fit no traditional receptors?

-too ___ for traditional steroid hormone receptor "ligand-binding pockets"

large

Remember Cholestane is in cell membranes and is the ___ to all other steroids

precursor

Endogenous agonist of Estrogen Receptor (ER)?

estradiol

Estrogen Receptor (ER) Primary Physiological Role

-___ sex development

-reproductive cycling

-___ maintenance

female, bone

ER Target Tissues

-___

-___

-___

-CNS

breast, uterus, bone

ER Common Adverse Effects

-endometrial ___

-breast ____

-_____

hyperplasia, stimulation, thromboembolism

Remember that Estrane has only 18 carbons (smallest steroid), and therefore causes ___ ___ effects

broad proliferative

Endogenous agonists of Androgen Receptor (AR)?

testosterone, DHT

Androgen Receptor (AR) Primary Physiological Role

-____ sexual development

-____ signaling

male, anabolic

AR Target Tissues

-_____

-muscle

-skin

-CNS

prostate

AR Common Adverse Effects

-virilization

-acne

-prostate ___

-dyslipidemia

growth

Endogenous agonist of Progesterone Receptor (PR)?

progesterone

Progesterone Receptor (PR) Primary Physiological Role

-____ maintenance

-____ differentiation

pregnancy, endometrial

PR Target Tissues

-____

-breast

-CNS

uterus

PR Adverse Effects

-weight gain

-mood changes

-sedation

-possible ___ spillover

glucocorticoid

Endogenous agonist of Glucocorticoid Receptor (GCR)?

cortisol

Glucocorticoid Receptor (GCR) Primary Physiological Role

-stress response

-glucose metabolism

-____ suppression (anti-_____)

immune, inflammatory

GCR Target Tissues

-liver

-___ cells

-muscle

-adipose

immune

GCR Adverse Effects

-hyperglycemia

-muscle ___

-osteoporosis

-_____

wasting, immunosuppression

GCR has the same scaffold as PR, but different substitutions, ---> leading to the GCR driving ___

catabolism

Endogenous agonist of Mineralocorticoid receptor (MCR)?

aldosterone

Mineralocorticoid receptor (MCR) Primary Physiological Role

-____ and __ retention

-____ excretion

-volume control

sodium, water, potassium

MCR Target Tissues

-____ (distal nephron)

-heart

kidney

MCR Adverse Effects

-____

-____

-____

hypertension, edema, hypokalemia

Remember that MCR toxicity is ___ and ___ driven

volume, electrolyte

Remember enzyme inhibition ___ levels of everything downstream

decreases

Remember enzyme inhibition ___ levels of everything upstream

increases

The drug _____ inhibits the conversion of cholesterol to pregnenolone, therefore shutting down the entire steroid hormone system!!

aminoglutethimide

Aminoglutethimide is mechanistically valid but clinically ____ (bc shuts down the entire steroid hormone system)

awful

The drug _____ is a dual inhibitor of 7α-hydroxylase and 17,20-lyase, blocking conversion of pregnenolone and progesterone into androgen precursors

abiraterone

Abiraterone is used together with a corticosteroid for treatment of ___ ___

prostate cancer

Abiraterone causes ___ excess because there is increased pregnenolone, which gets converted into aldosterone

mineralocorticoid

The drug _____ blocks 5α-reductase (blocks conversion of testosterone to more potent dihydrotestosterone)

finasteride

Finasteride is used for treatment of ___

BPH

The drug _____ blocks aromatase (converts androgens to estrogens) and is used to treat breast cancer

anastrazole

The drug ___ is an investigational compound studied as a 17β-hydroxysteroid dehydrogenase inhibitor (blocks conversion of estrone into more potent estradiol)

PBRM

Remember that E1 = ____ and E2= __-___ (based on the number of alcohols they contain)

estrone, 17β-estradiol

E1 (1 alcohol): estrone: has a ____ at position 17

E2 (2 alcohol): 17β-estradiol: has an ____ at position 17

ketone, alcohol

% circulating estrogen in blood

(E1) estrone: __-__% (storage reservoir)

(E2) 17β-estradiol: 10-20%

60-80

relative ER agonist potency

(E1) estrone: 0.1

(E2) 17β-estradiol: __ (signal)

1

(E1) estrone is more _____ (ie higher % in blood), but is 10x less potent as an ER compared to estradiol

prominent

(E2) 17β-estradiol is most potent, but is quickly ___ in the liver to a less potent __

oxidized, E1

What enzyme converts E1 (estrone) → E2 (estradiol) (more potent)?

17β-HSD1

What enzyme converts E2 (estradiol) → E1 (estrone) (less potent)?

17β-HSD2

17β-HSD1 carries out ____ reactions (gain H)

reduction

17β-HSD2 carries out ____ reactions (lose H)

oxidation

The ___ between 17β-HSD1 and 17β-HSD2 is a "local tissue potency switch"

balance

C3-OH interaction

(E1) estrone: and (E2) 17β-estradiol have ____ H bonding with the ER

strong