Steroid Hormone Synthesis

Question 1

Steroid

Answer 1

Derivatives of cholesterol

Question 2

Androgens

Answer 2

Male sexual function

Male sexual development/behavior

Question 3

Estrogens

Answer 3

Female sexual development/behavior

Question 4

Progestins

Answer 4

Regulation of menstrual cycle and pregnancy

Question 5

Mineralocorticoids

Answer 5

Regulate mineral balance (Na+, K+) related to blood volume and pressure

Question 6

Glucocorticoids

Answer 6

Regulate metabolism

Effects essentially oppose insulin

Stress hormones

Question 7

Intracrinology

Answer 7

Cell generated signal that acts on the cell where prohormone is converted to active hormone at site of action

Question 8

Where are hormones produced?

Answer 8

Adrenal glands (corticosteroids, mineralocorticoids, trace estrogen/androgens)

Ovaries

Testes

Question 9

What enzymes are responsible for synthesizing hormones?

Where are these enzymes located?

Answer 9

Dehydrogenases or P450 oxidases

Oxidases (ER), some in mitochondria

Question 10

What is the first step in steroid hormone synthesis and where does it occur?

Answer 10

Side chain cleavage, mitochondria

Question 11

What is unique about progesterone compared to the other hormones?

Answer 11

It is an intermediate in the synthesis of other steroids but it can serve as a sex hormone independently also

Question 12

Defects in which 2 enzymes of steroid hormone synthesis are most important to know right now?

Answer 12

21 hydroxylase

11Beta hydroxylase

Question 13

What would defects in 21 hydroxylase or 11 beta hydroxylase result in?

Answer 13

1) block synthesis of steroids glucocorticoids and mineralocorticoids
2) divert precurosrs toward synthesis of androgens

Question 14

Congenital Adrenal Hyperplasia

• Occurs due to defects in which enzymes?
• What is the impact on steroid synthesis?
• What impact would this have on sex determination?

Answer 14

• 21 Hydroxylase and 11 Beta hydroxylase
• The individual cannot produce mineralocorticoids so there is no feedback inhibition of ACTH secretion in the pituitary so ACTH is constantly secreted resulting in enlarged adrenal glands.
• The steroid percursors are pushed toward production of androgens leading to virilization of females (development of male sexual characteristics)

Question 15

• 5alpha reductase is an enzyme that converts ____ to ____
• Which tissues have this enzyme?
• Why is knowledge of this enzyme clincially important?
• What drugs inhibit this enzyme?

Answer 15

• Testosterone to dihydrotestosterone
• prostate, external genetalia, areas of dermis (results in loss of hair)
• inhibition of this enzyme spares testosterone activity in other tissues
• Finasteride and dutasteride

Question 16

Estrogens are made from _____ by what enzyme and at what location?

Answer 16

Androgens

Aromatase

At sites distanct from the site of synthesis due to expression of aromatase

Question 17

What structure is present in esterone (estrogen precursor) that is important for its action?

Answer 17

Esterone has an aromatic ring that is important for binding to the estrogen receptor

Question 18

• The mineralocorticoid receptor can also bind cortisol.
• Why is this a challenge and how is it overcome?

Answer 18

• Receptor has >>> affinity for mineralocorticoids but cortisol is produced in >>> higher quantities so the cells with MR need a way to inactivate cortisol in these cells.
• Cortisol is converted to the inactive form cortisone in cells that express MR by 11Beta-HSD2

Question 19

Where are steroid hormone receptors located?

What happens when they bind to their ligand?

Answer 19

Intracellularly in the cytoplasm

When they bind to their ligand they move to the nucleus

Question 20

What does it mean to say that steroid hormone receptors are modular?

Answer 20

The areas where they bind to different things are segregated - activation site (ligand binding domain), DNA binding domain and transcriptional activation domains

Question 21

What is the role of chaperones in steroid hormone receptor action?

Answer 21

They bind to the receptor in the absence of hormone and hold the receptor in the cytoplasm

Question 22

What happens to the chaperones (hsp70 and hsp90) on the steroid hormone receptor when the ligand binds?

Answer 22

The chaperones dissociate and the receptors dimerizes and moves to the nucleus

Question 23

Where do steroid hormones bind in the nucleus?

Answer 23

Due to the dimerization, each monomer has a DNA binding domain that binds the same sequence. Thus, the receptor will bind at a site in the DNA where the sequence will be repeated in some way (palendromic DNA binding sites)

Question 24

Mineralocorticoid receptor

• What is its name?
• Where is this located?
• What does it do?

Answer 24

• Epithelia Na+ Channel (ENaC)
• Apical surface of membrane
• Pumps sodium out of lumen and into tissues

Question 25

Glucocorticoid receptor

• What enzymes does it affect?
• What does it do?

Answer 25

• Phosphoenolpyruvate carboxykinase and glucose 6 phosphatase
• Stimulates gluconeogenesis and glucose release from liver

Question 26

There are 2 types of nuclear receptors. What are they?

Answer 26

Type 1 - steroid hormone receptors

Type 2 - localized in the nucleus, bind to other lipophilic ligands (VitA, VitD, Thyroid hormone)

Question 27

What happens when ligand binds to type 2 nuclear receptor?

Answer 27

Complex switches from repressive action to activating complex

Question 28

Type 2 nuclear receptors bind DNA as a _____

Answer 28

heterodimer

Question 29

Unlike steroid hormone receptors, type 2 receptors bind to _______ on DNA

Answer 29

Direct repeats

Question 31

Are all type 2 nuclear receptors permeable to the plasma membrane?

Answer 31

No - example thyroid hormone requires plasma membrane transporter

Question 32

The discovery of type 2 nuclear receptors prompted the concept of thinking of nuclear receptors as a family of _______

Answer 32

Transcription factors

Question 33

Finasteride and Dutasteride are ________ inhibitors that are prescribed to treat _______. They also treat ______ off label.

Answer 33

5-alpha reductase (converts testosterone to DHT)

Benign prostatic hyperplasia

Male pattern baldness