Steroid Biosynthesis Lecture (Dr. Theisen) Flashcards
Progesterone
- Synthesized in the Adrenal Glands, Ovaries, and Testes
- Distributed to Uterus
- Mediates IMPLANTATION (Nidation) and maintenance of Pregnancy
Glucocorticoids (Cortisol, Cortisone, and Corticosterone)
- Synthesized in Adrenal Glands
- Distributed to a Large Number of Tissues and Organs (Ed: Muscle, Liver)
- Increases Blood Pressure and Na+ uptake in Kidneys
- Mediates response to Stress by Increasing PROTEIN CATABOLISM and GLUCONEOGENESIS and Reducing INFLAMMATION
Aldosterone
11- Deoxycorticosterone
- Synthesized in Adrenal Glands
- Distributed to Kidney Tubules, Colon, and Parotid Gland
- Increases Na+/ H2O Retention, K+ Excretion, and Blood Pressure
Estradiol
Estrone
- Synthesized in Ovaries (Major), Placenta, and Adipose Tissue
- Distributed to Primary and Secondary Reproductive Organs
- Mediates Feminization, Estrous Cycle, and Inhibits Testosterone Synthesis
Testosterone
5 alpha Dihydrotesterosterone
Dehydroepiandrosterone
- Synthesized in Adrenal Glands, Ovaries, and Testes (Major)
- Distributed to Primary and Secondary Reproductive Organs and Muscle
- Mediates SPERMATOGENESIS, Secondary Male Characteristics, Bone Maturation, and Virilization
Endocrine Signaling
“LONG DISTANCE Signaling”
- Signal —> Bloodstream —> Distant Target Cells
- Freely Distributed Signals
- Long lasting (Long Half-life in Minutes), Takes time to go through the Circulator System to find a Target Cell
Leptin Gene
- Leptin is released from FAT and Signals to the Hypothalamus that you are FULL!!!
Ligands
- Can be Proteins, Small Peptides, Amino Acid Derivatives, Hydrophobic Molecules (Steroid hormones like ESTROGEN)
- Even Gases (NO)
Main Categories:
1) Small LIPOPHILIC MOLECULES: Steroid Hormones!!!!!!!!!
2) Water Soluble Molecules- Hydrophilic (Ex GROWTH FACTORS)
Lipophilic “Lipid Loving”
- Steroid Hormones: Progesterone, Estradiol, Testosterone, Cortisol, Aldosterone, Vitamin D
- Thyroid Hormone: Thyroxine
- Retinoids: Retinol, Retinoid Acid
RECEPTOR LOCATION AND TYPE:
- Found in the Cytoplasm and Nucleus
- Family of DNA Binding Transcription Factors
Hydrophilic “Water Loving”
- Amino Acids Derived: Histamine, Serotonin, Melatonin, Dopamine, Norepinephrine, Epinephrine
- From lipid Metabolism: Acetylcholine
- Polypeptides: Insulin, Glucagon, Cytokines, Thyroid-Stimulating Hormone
Cholesterol Conversion to Steroid Hormones
- Hormone: From Greek word meaning Impetus
- Distal Signaling Molecules (Steroids or Peptides (Amino Acids))
- STEROIDS are important Signaling Molecules Synthesized from Cholesterol
- Unlike Peptide Hormones (Which to their receptors on a Cell’s Outer Surface) Steroids Target Cells and bind to RECEPTORS LOCATED IN THE CYTOPLASM that Translocate to the nucleus
a) HYDROPHILIC and HYDROPHOBIC DIFFERENCES
b) Longer lasting Signal Due to Stability and Turnover Rate
* ***This is important for ENDOCRINE Signaling, must travel through the Body
Receptors
- HIGH AFFINITY, Bind to Ligands with Great Specificity (Concentration of Ligand in Bloodstream is Low)
Two general types of Receptor:
1) INTRACELLULAR RECEPTORS:
- Steroid Receptor can have receptor in Cytosol (Ex Estrogen), alters Gene Expression in Nucleus
2) CELL SURFACE RECEPTORS:
- External Domain binds ligand, Transmembrane Domain Anchors Receptor, Cytoplasmic Domain initiates Signal by change in Conformation
Receptors Cont
1) SMALL HYDROPHOBIC:
- Signaling molecules that can diffuse across the Cytoplasmic Membrane and Bind to INTRACELLULAR RECEPTORS
2) HYDROPHILIC:
- MOST SIGNALING Molecules are Hydrophilic and require CELL SURFACE RECEPTORS
Cholesterol Conversion to Steroid Hormones
1) These Receptors are Transcription Factors:
- Bind to the Signaling Hormone and to DNA
- Most of which have a Domain that can Interact in Transcriptional Complexes to Initiate/ Repress Gene Expression
2) Steroid Hormones Regulate:
- Cell Growth and Differentiation into Specific Cell Types
- The body’s Response to STRESS
- Metabolism of Nutrients
Cholesterol Conversion to Steroid Hormones
1) Hormone: From Greek word meaning Impetus
- Distal Signaling Molecules (Steroids or Peptides (Amino Acids))
2) STEROIDS are important Signaling Molecules Synthesized from Cholesterol
3) Unlike Peptide Hormones (Which to their receptors on a Cell’s Outer Surface) Steroids Target Cells and bind to RECEPTORS LOCATED IN THE CYTOPLASM that Translocate to the nucleus
a) HYDROPHILIC and HYDROPHOBIC DIFFERENCES
b) Longer lasting Signal Due to Stability and Turnover Rate
* ***This is important for ENDOCRINE Signaling, must travel through the Body
4) These Receptors are Transcription Factors:
- Bind to the Signaling Hormone and to DNA
- Most of which have a Domain that can Interact in Transcriptional Complexes to Initiate/ Repress Gene Expression
5) Steroid Hormones Regulate:
- Cell Growth and Differentiation into Specific Cell Types
- The body’s Response to STRESS
- Metabolism of Nutrients
Steroid Hormone Synthesis
- Steroid Hormone are Synthesized from Cholesterol in the Smooth Endoplasmic Reticulum of the Adrenal Cortex, Ovaries, and Testes
- These tissues Obtain Cholesterol form CIRCULATING LDL, from DE NOVO SYNTHESIS FROM ACETYL COA, or from Cholesterol Esters stored in Cytoplasmic Lipid Droplets
Steroid Hormone Synthesis Cont
- Mechanism of Steroid Hormone Synthesis
- The Synthesis of Steroid Hormones begins with the RATE LIMITING STEP Catalyzed by DESMOLASE, an Enzyme that incorporates a Carbonyl Group (C=O) on the D Ring of Cholesterol and cleaves off a Six Carbon piece of its Side Chain (Between Carbons 20 and 22), to form PREGNENOLONE
**MUST BE REGULATED!!!!!!!
Desmolase
- Essential for production of PREGNENOLONE
- P 450 Family- MONOOXIGANSE
- It is only found in Tissues that produce Steroid Hormones (Gonads and Adrenal Cortex)
-
**EXPRESSION and ACTIVITY stimulated by PEPTIDE HORMONES:
1) Adrenocorticotropic Hormone (ACTH)
2) Luteinizing Hormone (LH)
3) Follicle- Stimulating Hormone (FSH)
Adrenocorticotropic Hormone (ACTH)
- Secreted during Stressful Conditions
- From PITUITARY Gland but tuned on by CORTICOTROPIN -RELEASING Hormone (CRH) from Hypothalamus
- Stimulates release of Cortisol from the Adrenal Cortex
- Activates Expression of DESMOLASE
Luteinizing Hormone (LH)
- From PITUITARY GLAND but turned on by GONADOTROPIN-RELEASING HORMONE (GnRH) from Hypothalamus
- INCREASES Activity of Desmolase
Follicle Stimulating Hormone (FSH)
- From Pituitary Gland but turned on by GONADOTROPIN-RELEASING HORMONE (GnRH) from Hypothalamus
- Males: Promotes SPERMATOGENESIS
- Females:
a) Affects Menstruation
b) Stimulates Estrodial Production in Ovaries, Activates the Enzyme AROMATASE!!!!!!
Pregnenolone (An Alcohol)
1) Acts as a MODULATOR of Neurotransmitter Signaling in the Brian without being converted to other Steroids
- Effects the NMDA Glutamate Receptor (Memory and Learning)
* ****Treatment thought to help Multiple Neurological Disorders
2) Must be Converted to PROGESTERONE for Synthesis of Other Progesterogens (Enzymes) = 17 ALPHA HYDROXYLASE and 3 BETA HYDROXYSTEROID DEHYDROGENASE
a) MINERALCORTICOIDS:
- Affect Sodium/ Water levels in Tissues
b) GLUCOCOIRTICOIDS:
- Affect Brain Development
- Affect Immune Function (Suppression)
- Affect Glucose Metabolism and Fight or Flight (Epinephrine)
- Have affinity for Mineralocorticoid Receptors and are 100 times more Concentrated than Mineralocorticoids
c) ESTROGENS
- Female Sex Characteristics
d) ANDROGENS
- Male Sex Characteristics
- Anabolic Steroids (Synthetic forms used as PEGs)
* ***Affecting Natural Testosterone Signaling Pathways
**17 ALPHA HYDROXYLASE = Multiple Arms of the Pathway
Progesterone specifically Converted in a Tissue Specific Manner to:
1) ALDOSTERONE:
- A Minerlcorticoid
- Adrenal Cortex (Zona Glomerulosa)
2) CORTISOL
- A Glucocorticoid
- ADRENAL CORTEX (Zona Fasciculata)
3) ESTRADIOL
- An Estrogen
- From TESTOSTERONE in Ovaries
- Minor amount in Adrenal Cortex
4) TESTOSTERONE
- An Androgen
- And more potent DIHYDROTESTOSTERONE in TESTES
- Minor amount in Adrenal Cortex
ALDOSTERONE:
- A Mineralcorticoid
- Adrenal Cortex (Zona Glomerulosa)
- Promotes the Retention of Na+ and H2O in the Kidneys, as well as Excretion of H+ and K+
- REDUCED Levels = too Much Salt
- EXCESSIVE Levels = CONN SYNDROME: Increase Blood Volume, Hypertension
CORTISOL
- A Glucocorticoid
- ADRENAL CORTEX (Zona Fasciculata)
- Also known ad HYDROCORTISONE
- Anti Inflammatory and Autoimmune properties
- Stimulates the Breakdown of Muscle. Gluconeogenesis, and Glycogen Synthesis
- Elevates leaves associated with CUSHING SYNDROME, a Condition marked by the accumulation of Fat on the Face and Trunk (Can be caused by Increased Cortisol production due to pituitary or Adrenal Tumors or Chronic Administration of Corticosteroids)
- Also important Affect on ACTH Feedback Inhibition
ESTRADIOL
- An Estrogen
- From TESTOSTERONE in Ovaries
- Minor amount in Adrenal Cortex
TESTOSTERONE
- An Androgen
- And more potent DIHYDROTESTOSTERONE in TESTES
- Minor amount in Adrenal Cortex
Cortisol
- Have affinity for Moneralcorticoid Receptors and are 100 times more Concentrated than Mineralocorticoids
- Cortisone has MUCH LOWER Affinity for Mineralocorticoids
Cortisol —- (11 Beta Hydroxysteroid Dehydrogenase) ——> Cortisone
Cortisol Cont
- CORTISOL Suppression of the Immune System Glucocorticoids such as CORTISOL cause IMMUNOSUPPRESSION by INHIBITING both Cellular and Humorla Immune Response.
- They Induce the production of i-KBa Inhibitory Protein, which helps Sequester the Transcription Factor Nuclear Factor Kappa B (NF-KB) in Inactive Cytoplasmic Complexes.
- NF-KB is NECESSARY for the Synthesis of many Cytokines, such as INTERLEUKIN (IL)-2, which are needed for T Cell Proliferation.
- Cortisol also promotes T Cell Apoptosis. Decreased IL-2 and its Receptor lead to an INHIBITION of Donal Expression of B Lymphocytes as well.
Other Enzyme Deficiences
1) Relatively Common inherited Defect (1 in 12,000 live Births) is in 21 HYDROXYLASE:
A) It leads to Salt Washing (Hyponatremia) and Hypotension due to Decreased production of ALDOSTERONE, and Hypoglycemia due to DECREASED PRODCTION OF CORTISOL
B) In Females, this Deficiency causes VIRILISM (Development of Male Secondary Characteristics) due to an INCREASED Flow of Intermediates into ADRENAL ANDROGENS
2) A Rare Deficiency of 17 ALPHA HYDROXYLASE
- Causes a loss of Cortisol as well as Sex Steroids
- However, the Decrease in Cortisol is compensated for by Increased Production of CORTICOSTERONE
3) Defects in 11 BETA HYDROXYLASE
- Cause Hypertension due to the accumulation of 11 DEOXYCORTICOSTERONE, which has Mineralocorticoid Activity
Vitamin D
- Vitamin D2 (Ergocalciferol) and Vitamin D3 (Cholecalciferol) are found in Liver, Eggs, Fish, Plants, and Vitamin D fortified foods such as Milk and Cereal
- Vitamin D3 (Cholecalficerol) is also produced in the Skin via a Mechanism that requires exposure to Sunlight
- CALCITROL, the Bioactive form of Vitamin D, is derived from Vitamins D2 and D3
Progesterone and Pregnancy
- Progesterone supports Gestation (Pregnancy) and Embryogenesis and is also involved in the maintenance of the Menstrual Cycle.
- It regulates the Voltage-Gates Ca2+ Channels on the SPERMATOZOA, prepares the Uterus for IMPLANTATION, causes Smooth Muscle Relaxation, and Decreases Meternal Immune Response.
- A Decrease in Progesterone levels precedes Menstruation, Labor, and Lactation
Glucocorticoids and Infant Respiratory Distress SYndrome
- In normal terms Infants, a Burst of Glucocorticoids during delivery alters the Lung Structure by stimulating the Production of SURFACTANT, which allows the air spaces to Expand.
- In preterm Neonates, this process is defective, leading to Infant Respiratory Distress Syndrome (IRDS).
- IRDS can be prevented by giving Glucocorticoids to expectant mothers
Metabolic Modulation of Steroid Hormone Effects
- The response of Target Tissues to a Steroid Hormone is sometimes determined by further metabolism of the Hormone. For Example, Mineralocorticoid target tissues such as the Kidneys, Colon, and Parotid Gland contain a receptor that has equal affinity for both Mineralo- and Glucocorticoids.
- These tissues avoid Na+/ H2O Retention induced by the much higher circulating levels of GLucocoritcoids by metabolizing Cortisol to Cortisone through the action of 11 BETA HYDROXYSTEROID DEHYDROGENASE.
- Cortisone has a much lower affinity for the Mineralocorticoid Receptor.
- Natural Licorice root contains Isoflavones, which are Inhibitors of 11 BETA DEHYDROGENASE. Therefore, consumption of real Licorice can lead to Hypertension due to Salt Retention
- The ANDROGENIC Potency of Testosterone is amplified by its Conversion to DIHYDROTESTOSTERONE (DHT) mediated by the Enzyme 5 ALPHA REDUCTASE.
- DHT has a much Higher Affinity than Testosterone for the Androgen Receptor.
- FINASTERIDE, an Inhibitor of 5 Alpha Reductase, prevents this potentiation. Finasteride has been used to treat benign Prostatic Hyperplasia. The Drug has also been used to treat MALE PATTERN BALDNESS, which is caused by the action of DHT in the Scalp
Steroid Hormones and Globulins
- Steroid Hormones are transported in the Blood Complexed to specific Carrier Proteins. The Human Corticosteroid Bidning Globulin (CGB) is a GLYCOSYLATED GLOBULIN that belongs to the Serine Protease Inhibitor (SERPIN) family of Proteins.
- CGB is involved in the Transport and Release of the majority (80 to 90%) of Plasma Glucocorticoid Hormones and also Progesterone.
- Sex Steroids such as Testosterone, Dihydrotestosterone, and Estradiol are transported by the Homodimeric Glycoprotein, Sex Steroid Hormone Binding Globulin (SHBG), and to a lesser extent by ALBUMIN.
- Whereas SHBG is only partially Saturated in Women, its Binding sites are mostly occupied by Testosterone in Men. Both CGB and SHBG are made mostly in the Liver
Rennin-Angiotensin- Aldosterone System (RAAS)
- The Renin- Angiotensin- Aldosterone System (RAAS) controls Blood Pressure and Fluid Balance. Kidneys release the Enzyme Renin into Circulation when a Low Blood Volume is sensed.
- Renin cleaves the Zymogen Angiotensin (Made by the Liver) into Angiotensin I, which is subsequently Proteolytically processed into the Vasoconstrictor Angiotensin II in LUNG Capillaries by Angiotensin- Converting Enzyme (ACE). Angiotensin II stimulates th release of Vasopressin from the Pituitary Gland and the Mineralo-corticosteroid hormone Aldosterone from the Adrenal Cortex.
- Aldosterone Blood Pressure and Volume, ACE Inhibitors are widely used in the treatment of Hypertension. Vasopressin acts as a Vasoconstrictor, stimulates Thirst, and Increases Water Retention in the Kidneys
Cortisol Suppression of the Immune System
- Glucocorticoids such as Cortisol cause Immunosuppression by Inhibiting both Cellular and Humoral Immune response. They Induce the production of i-KB Alpha Inhibitory Protein, which helps Sequester the Transcription Factor Nuclear Kappa B (NF-KB) in Inactive Cytoplasmic Complexes.
- NF-KB is necessary for the Synthesis of many Cytokines, such as Interleukin (IL)- 2, which are needed for T Cell Proliferation.
- Cortisol also promotes T Cell Apoptosis. Decreased IL-2 and its receptor lead to an Inhibition of Clonal Expansion of B Lymphocytes as well
Disorders associated with Vitamin D
- Normal Blood Ca2+ levels are 8.4 to 10.2 mg/dL. Deficiencies in Vitamin D occur due to (1) Inadequate Dietary Intake, (2) Conditions that disrupt the Absorption of Lipids, (3) Poor Functioning of the Liver and Kidneys, (4) Hypoparathyroidism, and (5) Lack of exposure to Sunlight (Ex Winter days in Northern latitudes or excessive use of Sunscreen).
- Vitamin D deficiency manifests as BRITTLE BONES observed as RICKETS in Children (marked by Growth Deficiency and Skeletal Deformities), OSTEOMALACIA in adults (Marked by “Pathological Fractures”), and HYPOCALCEMIC TETANY (Involuntary Muscle Contractions due to LOW BLOOD Ca2+).
- Intake of too many Vitamin D Supplements causes an Excess of Vitamin D, which results in elevated levels of Ca2+ in Blood (Hypercalcemia) and Urine (Hypercalciuria).
- Patients with this condition appear dazed, have a loss of Appetite, and may present with SARCOIDOSIS. The latter is an Inflammatory of Tissues marked by the presence of Clusters of Immune Cells (Granulomas) in various tissues, such as Lungs, Skin, and Lymph Nodes
Vitamin D Background
- Effects of Vitamin D are attributed to its active form (CALCITROL aka 1,15 DIHYDROXYCHOLECALCIFEROL)
- **Technically NOT classified as a Steroid
- Choelsterol’s Sterane is broken during the Synthesis like Steroid Hormones
- Though, Vitamin D acts through binding to a Nuclear Receptors and altering the expression of Target genes containing Vitmain D Response Element (VDRE0 sequences
VITAMIN D;
- Derived from Cholesterol
- Has signaling Properties like Steroid Hormones
Vitamin D Mechanism
1) CHOLECALICFEROL (Vitmain D3) is the INACTIVE form of Vitamin D
- It is produced in SKIN from the Photochemical Cleavage of the B Ring of 7- DEHYDROCHOLESTYEROL (Via UV IRRADTIATION IN THE SKIN)
- In Intestinal Cells from ERGOCALCIFEROL (Vit D3)
2) Subsequent steps for activation take place in the LIVER and the KIDNEYS
* ** CHOLECALCIFEROL is FIRST Hydroxylated in the liver by 25- HYDROXYLASE to Generate 25- Hydroxycholecalciferol
3) 25 Hydroxycholecalciferol is then Hydroxylated in the PROXIMAL TUBULES of the Kidneys by:
* 1 ALPHA HYDROXYLASE***
- Generates 1,25 DIHYDROXYCHOLECALCIFEROL (Calcitriol)
- The action of 1 Alpha HYDROXYLASE is stimulated by PARATHYROID HORMONE (PTH) and Low Blood Concentration of PHOSPHATE but INHIBITED by CALCITRIOL
Vitamin D Signaling
- Calcitriol stimulates Intestinal Cells to INCREASE the Absorption of Ca2+ and Phosphate from the Intestinal Lumen, INCREASE the Reabsorption of Ca2+ by the Kidneys, and promote RESORPTION of Ca2+ from Bone.
- The Resulting effect of CALCITRIOL is and ELEVATION in BLOOD Ca2+ and PHOSPHATE Levels
- PTH, Parathyroid Hormone and CALCITONIN are Peptide Signals
Deficiencies in Vitamin D
- Inadequate Dietary INTAKE
- Conditions that Disrupt the ABSORPTION of LIPIDS
- Poor Functioning of the Liver and Kidneys
- HYPOPARATYROIDISM
- Lack of Exposure to SUNLIGHT
- BRITTLE BONES and DEFORMITIES
A) RICKETTS in Children
B) OSTEOMALACIA in Adults = Fractures - HYPOCALCAMIC TETANY (Involuntary Muscle Contractions due to LOW BLOOD CALCIUM)
