Steroid Hormones

Question 1

Androgens and estrogens are synthesized where?

Answer 1

In the testes and ovaries via androstenedione and tesosterone

Question 2

Androgens and estrogens serve as important drug targets.

Answer 2

Some drugs bind to receptors - tamoxifen

Some drugs inhibit biosynthetic enzymes - finasteride

Question 3

Androstenedione is synthesized via 2 different pathways

Answer 3

In the adrenal glands, pregnenolone undergoes CYP450c17 catalyzed 17-hydroxylation and then C17,20 side chain scission.
This leads to dehydroepiandosterone. This is the most common pathway in the testes (the delta-5 pathway).

Question 4

DHT is synthesized in peripheral tissues

Answer 4

Testosterone is metabolized via 17-hydroxylation and 5a- reduction
17-ketosteroids are produced in many peripheral tissues and are less active testosterone
DHT is produced via 5a-reduction of the double bond and its the most potent hormone derived from test.

Question 5

DHT is formed from testosterone through the action of what enzyme?

Answer 5

5a-reductase

Question 6

Estrogens are a family of ovarian-derived steroid hormones.

Answer 6

17beta-estradiol is the most abundant estrogen.
Estrone is found in many tissues.
Estriol is more common in the placenta during pregnancy.

Question 7

Estrogens derive from the androgens via the action of an aromatase complex

Answer 7

The aromatase complex involves three hydroxylations via NADPH and 02. These groups are eliminated to afford double bonds and an aromatic A ring.

Question 8

How is estrone formed?

Answer 8

Formed via aromatization of androstenedione.

17beta estradiol is formed via aromatization of testosterone.

Question 9

Ovarian steroidogenesis involves several cell types

Answer 9

Progesterone is manufactures in the corpus luteum and is then secreted.
Progesterone is taken up by theca cells to produce androstenedione and testosterone.
Testosterones are secreted and picked up by granulosa cells, which express aromatase, to make estriol and estrone.

Question 10

Aromatase activity in kidney, liver, etc, is important for?

Answer 10

Important drug target because it can cause disease

Question 11

Hyperactive aromatase causes….

Answer 11

gynecomastia in males

Question 12

Vitamin D is structurally derived from steroids.

Answer 12

It has a similar mechanism of action.

Question 13

Vitamin D is a precursor to 1,25(OH)2-D3 (calcitriol), which is important for..?

Answer 13

Absorption of calcium - can be supplemented from the diet

Question 14

Most vitamin D is produced via…

Answer 14

Photolysis reaction in the skin via UV light from the sun.

The B ring of 7-dehydrocholesterol is cleaved via photolysis to afford vitamin D3

Question 15

Vitamin D3 is hydroxylated in the liver and kidneys.

Answer 15

Transported into the liver via vitamin D-binding protein where it undergoes 25-hydroxylation.
The liver 25-hydroxylase is a CYP450 reductase complex that catalyzes the oxygenation in an NADPH-dependent fashion.

Question 16

Androgen signaling is implicated in..

Answer 16

prostate cancer, prostatic hyperplasia, and male pattern baldness

Question 17

Estrogen signaling is implicated in..

Answer 17

Breast cancer and ovarian cancers

Question 18

Testoserone is synthesized via..

Answer 18

17-hydroxylation in the leydig cells

Question 19

Testosterone:
1. First trimester in utero--->
2. Second trimester in utero--->
3. Birth----->
4. Adolescence---->
5. Puberty----->
Luteinizing hormone is the main stimulus for testosterone secretion after birth.

Answer 19

1. Testosterone stimulated by HCG (produced by placenta.
2. testosterone reaches a peak of 250ng/dL, then falls off.
3. testosterone stimulated by maternal LH
4. Testosterone falls to a minimum
5. Testosterone reaches 500ng/dL to 700 in men (30-50 in women during same time)

Question 20

Testosterone is metabolized to..

Answer 20

DHT and estradiol

Question 21

DHT binds to androgen receptor more efficiently than testosterone.

Answer 21

TRUE

Question 22

Mechanisms for androgen receptor signaling:

Answer 22

1. DHT binds with a higher affinity for the receptor than testosterone.
2. Co-regulators that bind to the AR are cell specific
   - This allows cell-specific gene regulation due to androgen binding
   - Effects hair follicles vs. testicular differentiation

Question 23

Effects of androgens:

Answer 23

In utero - HCG stimulates test. production and Wolffian differentiation.
DHT develops external genitalia.

Question 24

What is senescence? (androgens)

Answer 24

serum testosterone decreases by up to 80%

Question 25

Deficiencies of androgens are due to what?

Answer 25

Commonly due to deficiencies of CYP17 hydroxylase
-Entirely female genitalia, lack of internal organ development.

Deficiency in 5a reductase
-failure of external genitalia to develop (due to lack of DHT)

Question 26

Estrogen receptors exist as what?

Answer 26

Two isoforms. ER alpha and ER beta.
These form heterodimers.

ER alpha found primarily in endometrium, ovary, mammary gland, hypothalamus

ER beta found in kidney, intestinal mucosa, lung, bone, brain, prostate, and vasculature.

Question 27

Domains of Estrogen Receptors:

Answer 27

A/B: NH-2 terminal domain contains activation function-1
(A/F-1) segment-can activate transcription independent of ligand binding
ER beta - does not have AF-1 domain

C - DNA binding domain - highly conserved, interacts with ERE (estrogen response element)

D - “hinge region” nuclear localization signal
E and F - ligand binding domain, receptor dimerization and ligand dependent transactivation mediated by AF-2

Question 28

Do ER alpha and ER beta do the same thing?

Answer 28

No, they have differing and sometimes opposing actions on certain genes.

In many cases, ER beta inhibits ER alpha mediated transcriptional activation.

Question 29

Genomic Pathway of ER

Answer 29

Binding of estrogen to ER induces phosphorylation of the receptor and conformational changes in the receptor.

Activating functions, AF1 and AF2, are available for binding with co-activators and or co-repressors.

Receptor dimerization occurs and binding to the promoter regions of DNA leads to stimulation of activity of RNA polymerase II.

Question 30

Non-genomic Estrogen signaling

Answer 30

ER receptors also interact in the cytoplasm with secondary cell messengers.

ER binds to growth factors and activate various tyrosine kinase receptors … IGF-IR, EGFR and HER2

Estradiol especially activates these downstream pathways…Akt, RAS, mTOR, Raf

They promote cell proliferation and survival. These pathways are up-regulated in various cancers.

Question 31

Estradiol binding affinity?

Answer 31

100% binding in sex organs and non sex organ tissues.

Question 32

Agonist binding to ER

Answer 32

Helix 12 seals steroid in hydrophobic pocket
In the presence of agonist, helix 12 folds across the ligand binding pocket, stabilizing ligand receptor interaction and promoting a conformation conducive for co-activator association

Question 33

Antagonist binding to ER

Answer 33

In the presence of an antagonist, steric hindrance precludes folding of helix 12 across the ligand binding pocket. Instead, it positions itself in the region typically occupied by the co-activator, thereby blocking the activation function of the receptor.

Question 34

Gonadotrophins increase…

Answer 34

cholesterol side-chain cleavage and aromatase

Question 35

Ovary produces…

Answer 35

estrogen and progesterone