Steroid Hormone Synthesis Flashcards
Steroid
Derivatives of cholesterol
Androgens
Male sexual function
Male sexual development/behavior
Estrogens
Female sexual development/behavior
Progestins
Regulation of menstrual cycle and pregnancy
Mineralocorticoids
Regulate mineral balance (Na+, K+) related to blood volume and pressure
Glucocorticoids
Regulate metabolism
Effects essentially oppose insulin
Stress hormones
Intracrinology
Cell generated signal that acts on the cell where prohormone is converted to active hormone at site of action
Where are hormones produced?
Adrenal glands (corticosteroids, mineralocorticoids, trace estrogen/androgens)
Ovaries
Testes
What enzymes are responsible for synthesizing hormones?
Where are these enzymes located?
Dehydrogenases or P450 oxidases
Oxidases (ER), some in mitochondria
What is the first step in steroid hormone synthesis and where does it occur?
Side chain cleavage, mitochondria
What is unique about progesterone compared to the other hormones?
It is an intermediate in the synthesis of other steroids but it can serve as a sex hormone independently also
Defects in which 2 enzymes of steroid hormone synthesis are most important to know right now?
21 hydroxylase
11Beta hydroxylase
What would defects in 21 hydroxylase or 11 beta hydroxylase result in?
1) block synthesis of steroids glucocorticoids and mineralocorticoids
2) divert precurosrs toward synthesis of androgens
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?
- 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)
- 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?
- 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
Estrogens are made from _____ by what enzyme and at what location?
Androgens
Aromatase
At sites distanct from the site of synthesis due to expression of aromatase
What structure is present in esterone (estrogen precursor) that is important for its action?
Esterone has an aromatic ring that is important for binding to the estrogen receptor
- The mineralocorticoid receptor can also bind cortisol.
- Why is this a challenge and how is it overcome?
- 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
Where are steroid hormone receptors located?
What happens when they bind to their ligand?
Intracellularly in the cytoplasm
When they bind to their ligand they move to the nucleus
What does it mean to say that steroid hormone receptors are modular?
The areas where they bind to different things are segregated - activation site (ligand binding domain), DNA binding domain and transcriptional activation domains
What is the role of chaperones in steroid hormone receptor action?
They bind to the receptor in the absence of hormone and hold the receptor in the cytoplasm
What happens to the chaperones (hsp70 and hsp90) on the steroid hormone receptor when the ligand binds?
The chaperones dissociate and the receptors dimerizes and moves to the nucleus
Where do steroid hormones bind in the nucleus?
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)
Mineralocorticoid receptor
- What is its name?
- Where is this located?
- What does it do?
- Epithelia Na+ Channel (ENaC)
- Apical surface of membrane
- Pumps sodium out of lumen and into tissues
Glucocorticoid receptor
- What enzymes does it affect?
- What does it do?
- Phosphoenolpyruvate carboxykinase and glucose 6 phosphatase
- Stimulates gluconeogenesis and glucose release from liver
There are 2 types of nuclear receptors. What are they?
Type 1 - steroid hormone receptors
Type 2 - localized in the nucleus, bind to other lipophilic ligands (VitA, VitD, Thyroid hormone)
What happens when ligand binds to type 2 nuclear receptor?
Complex switches from repressive action to activating complex
Type 2 nuclear receptors bind DNA as a _____
heterodimer
Unlike steroid hormone receptors, type 2 receptors bind to _______ on DNA
Direct repeats
Are all type 2 nuclear receptors permeable to the plasma membrane?
No - example thyroid hormone requires plasma membrane transporter
The discovery of type 2 nuclear receptors prompted the concept of thinking of nuclear receptors as a family of _______
Transcription factors
Finasteride and Dutasteride are ________ inhibitors that are prescribed to treat _______. They also treat ______ off label.
5-alpha reductase (converts testosterone to DHT)
Benign prostatic hyperplasia
Male pattern baldness
