Steroid Hormones

Glucocorticoid

21 Cortisol, Corticosterone Adrenal cortex Glucocoticoid receptor (GR)

Progestin

21 Progesterone Ovary, placenta Progesterone receptor (PR)

Adrenal cortex

Cortisol, aldosterone, androgens, testosterone

Placenta

Estrogens, progesterone

Steroid Hormone Synthesis

Derived from cholesterol Cells synthesising steroid hormones are termed steroidogenic cells Cholesterol common precursor for all steroid hormones o All steroidogenic cells synthesize some cholesterol o Most comes from low-density lipoproteins (LDL) internalised into cell, degraded by lysosomal enzymes (free cholesterol) o Regulated so cholesterol available in times of need Unused cholesterol chemically modified and stored as lipid droplets o Conversion of this back to cholesterol is also controlled so close coordination with overall need is possible

Corpus luteum

Estrogens, progesterone

Ovaries

Estrogens, progesterone

functions of steroid hormone transport

Facilitates transport of lipophilic hormones (steroids) Prolongs circulating half life Acts as buffer to sudden changes in hormone secretion (reservoir)

Testes

Testosterone

steroid hormone secretion

Unlike peptide hormones steroids are lipophilic and can easily cross membranes o Will readily diffuse out of cell o Are not stored after synthesis Thus rate of steroid hormone secretion is controlled entirely by rate of synthesis o Via uptake, storage and mobilisation of cholesterol o Via control of steroidogenic enzyme gene experession and activity CYP11A1 (cholesterol side chain cleavage enzyme) is often rate limiting enzyme and thus a target for control

transport of steroid hromones

While steroid can easily diffuse and cross lipid membranes their lipid nature also results in low solubility o Thus transported in blood bound to transport proteins such as abundant albumin protein o Bound and free hormones are in equilibrium

transcription

o After steroid hormone binding, loss of Hsp90 binging, translocation into the nucleus and dimerization 1. Receptors bind to hormone response elements (HRE) 2. HREs are found in the promoters or enhancer of target genes 3. Interact with other factors (co-activators or co-repressors) and the RNA polymerase II complex 4. Can either turn gene expression (transcription) on and off

enzymatic modifications of cholesterol

o Hydroxylation (addition of -OH) o Dehydrogenation or reduction (removal or addition of H) o Lyase Reactions (cleavage of C-C bonds) Most of the enzymes belong to the same family the Cytochrome p450s (CYP) containing a haeme cofactor (Fe3+/4+)

steroid binding

o Steroid receptor is in cytoplasm complexed to heat shock proteins (HSP) • Blocks DNA binding domain • Prevents receptor pairing • Prevents translocation to nucleus o Upon steroid binding get a conformation change causing HSP to dissociate, freeing receptor o Different receptors interact different with different proteins and/or differently with the same factor

DNA speceficity

o xRE: hormone-x response element o The problem of specificity • Ligand receptor specificity, Receptor-DNA specificity • Context of half sites may yield preference of binding for one type of hormone receptor • Receptor specific interaction of with other classes of transcription factors binding nearby: interaction only occurs if those factors are present in cells

Signal transduction of steroid hormones

• As steroids can easily diffuse and cross lipid membranes that do not require a cell surface (membrane) receptor • Steroid receptors are transcription factors o AF1 and AF2 required for activation of transcription o CTE in class1 nuclear receptors, the CTE is required for interaction with co-regulatory proteins (HMGBs) o DNA binding site o Ligand required for ligand (hormone) binding and receptor-receptor binding (dimerization)

eliciting different trancriptional responses

• Response elements (RE) modulate steroid receptor conformation and affect cofactor recruitment • Following activation by its ligands the steroid receptor binds to RE thus adopting different conformations • Binding to different REs leads to the recruitment of common and element specific cofactors • Binding to adjacent Res may lead to the recruitment of a bridging cofactor • Binding to negative RE is followed by recruitment of co-repressors

Steroid Hormone Summary

• Steroid hormones are derived from cholesterol • Cholesterol (modified) can be stored but steroids not, hence control of steroid production is at level of synthesis • 5 classes of steroids (progestins, andogens, estrogens, corticosteroids and mineralcorticoids), vitamin D derivative is also a (seco-) steroid • Steroids diffuse easily across membranes but are of limited solubility for transported in blood via carrier proteins • Main effect via nuclear receptors • Hormone binding causes inhibitory Hsp90 dissociation, nuclear translocation, dimersation and DNA binding • Receptors bind to palindromic response elements found in regulatory region of target genes • Binding results in transcriptional control of target genes and thus new protein production

termination of steroid signal

• Tend to have long-term effects so continuously secreted at varying rates • Lipophilic nature allows them to diffuse freely, concentrated in target cells via receptors • Circulating steroids mainly inactivated/eliminated in liver but also in kidney o Converted to more hydrophilic derivative then excreted by kidney

Kidney

1,25-dihyroxycholecalciferol (Vit D derivative)

estrogen

18 Estradiol-17β, estriol Ovary, placenta Estrogen receptor (ER)

androgen

19 Testosterone, dihydrotestosterone Testis Androgen receptor (AR)

Mineralocorticoid

21 Aldosterone, 11-deoxycorticosterone Adrenal Cortex Mineralocorticoid receptor (MR)

Main Steroidogenic organs

Adrenal Cortex o Corticosteroids o Glucocorticoids o Mineralocorticoids Testes o Testosterone o Androgens Ovaries/placenta o Estrogens o Progestins