Steroid Hormones Flashcards
Androgens and estrogens are synthesized where?
In the testes and ovaries via androstenedione and tesosterone
Androgens and estrogens serve as important drug targets.
Some drugs bind to receptors - tamoxifen
Some drugs inhibit biosynthetic enzymes - finasteride
Androstenedione is synthesized via 2 different pathways
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).
DHT is synthesized in peripheral tissues
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.
DHT is formed from testosterone through the action of what enzyme?
5a-reductase
Estrogens are a family of ovarian-derived steroid hormones.
17beta-estradiol is the most abundant estrogen.
Estrone is found in many tissues.
Estriol is more common in the placenta during pregnancy.
Estrogens derive from the androgens via the action of an aromatase complex
The aromatase complex involves three hydroxylations via NADPH and 02. These groups are eliminated to afford double bonds and an aromatic A ring.
How is estrone formed?
Formed via aromatization of androstenedione.
17beta estradiol is formed via aromatization of testosterone.
Ovarian steroidogenesis involves several cell types
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.
Aromatase activity in kidney, liver, etc, is important for?
Important drug target because it can cause disease
Hyperactive aromatase causes….
gynecomastia in males
Vitamin D is structurally derived from steroids.
It has a similar mechanism of action.
Vitamin D is a precursor to 1,25(OH)2-D3 (calcitriol), which is important for..?
Absorption of calcium - can be supplemented from the diet
Most vitamin D is produced via…
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
Vitamin D3 is hydroxylated in the liver and kidneys.
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.
Androgen signaling is implicated in..
prostate cancer, prostatic hyperplasia, and male pattern baldness
Estrogen signaling is implicated in..
Breast cancer and ovarian cancers
Testoserone is synthesized via..
17-hydroxylation in the leydig cells
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.
- Testosterone stimulated by HCG (produced by placenta.
- testosterone reaches a peak of 250ng/dL, then falls off.
- testosterone stimulated by maternal LH
- Testosterone falls to a minimum
- Testosterone reaches 500ng/dL to 700 in men (30-50 in women during same time)
Testosterone is metabolized to..
DHT and estradiol
DHT binds to androgen receptor more efficiently than testosterone.
TRUE
Mechanisms for androgen receptor signaling:
- DHT binds with a higher affinity for the receptor than testosterone.
- 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
Effects of androgens:
In utero - HCG stimulates test. production and Wolffian differentiation.
DHT develops external genitalia.
What is senescence? (androgens)
serum testosterone decreases by up to 80%
Deficiencies of androgens are due to what?
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)
Estrogen receptors exist as what?
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.
Domains of Estrogen Receptors:
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
Do ER alpha and ER beta do the same thing?
No, they have differing and sometimes opposing actions on certain genes.
In many cases, ER beta inhibits ER alpha mediated transcriptional activation.
Genomic Pathway of ER
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.
Non-genomic Estrogen signaling
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.
Estradiol binding affinity?
100% binding in sex organs and non sex organ tissues.
Agonist binding to ER
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
Antagonist binding to ER
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.
Gonadotrophins increase…
cholesterol side-chain cleavage and aromatase
Ovary produces…
estrogen and progesterone
