Steroid Hormones Biosynthesis

Describe the molecules in which ChL is a precursor of? 

What is the core structural feature of steroid hormones?

Lipid compounds with a carbon skeleton formed by four fused rings.

Describe the unique ability of steroid hormones receptors

A specific Receptor can bind to more than one ligand due to similar structure of steroid hormoes

Describe the steps of cortisol synthesis

1. Cholesteryl esterase (cholesterol ester lipase)

   • removes ester from cholesterol ester and produces free cholesterol.

2. Steroidogenic acute regulatory protein (StAR)

   • Moves ChL from outer → inner mitochondrial membrane.

   • rate-limiting step

3. Cholesterol side-chain cleavage (P450scc) enzyme

   • Produces pregnenolone

   • From there, pregnenolone is transformed to specific steroid hormones dictated by the cell

What regulates:

• Cholesteryl esterase

• StAR

• Cholesterol side-chain cleavage (P450scc)

Cholesteryl esterase: posttranslational modification:

• cAMP → PKA → Phosphoylation of cholesteryl esterase → active state

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StAR- stimulated by:

• LH

• ACTH

• Angiotensin II

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Cholesterol side-chain cleavage (P450scc)- transcription

• Gene contains CRE (cAMP regulatory element) 

• cAMP binding → increases expression

1. What cells make testosterone?

2. What cells make DHT?

3. Describe the potentency of DHT vs Testosterone

Leydig cells:

• main site of testosterone synthesis

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Sertoli cells:

• Prduces Dihydrotestosterone (DHT) via (5α-reductase),

  • ***However, most of the conversion of testosterone to DHT occurs outside the testes.***

  • DHT= 10 times more potent than testosterone.

1. What are estrogens formed by?

2. Where is this enzyme found?

1. Estrogens are formed by aromatization of androgens

2. Aromatase = complex ER enzyme found in ovary and numerous other tissues

Block Out Later

1. What does 3-beta-hydroxysteroid Dehydrogenase Deficiency affect? Hereditary?

2. What is the consequence of 3-beta-hydroxysteroid Dehydrogenase Deficiency in males/females?

Deficiency: affects gonads/ adrenal glands; autosomal recessive

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Males:

• abnormalities of the external genitalia.

Females:

• slight abnormalities of the external genitalia at birth

1. What does 17-alpha-hydroxylase Deficiency affect? Heredity?

2. Effect on Males/Females? 

17-alpha-hydroxylase deficiency affect the gonads and the adrenal
glands; Heredity: autosomal recessive

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Effects:

• Female: internal reproductive organs are underdeveloped

• Males: Infertility

• Increased production of aldosterone

What does 21-hydroxylase Deficiency affect? Symptoms? Hereditary?

• affects the adrenal glands; autosomal recessive

• most common form of adrenal congenital hyperplasia.

• Symptoms:

  • low fertility rate.

  • hypotension

  • Females:

    • hirsutism (excessive body hair)

    • male pattern baldness

Differentiate between the two forms of vitamin D

• Vitamin D2 is largely human-made and added to foods.
  

• Vitamin D3 is produced from 7-dehydrocholesterol by exposure to ultraviolet light.

Describe the steps of Vitamin D synthesis

1. @ Epidermis:

   • UV light cleaves 7- dehydrocholesterol, → vitamin D3 (cholecalciferol).

2. Vitamin D3 binds vitamin D binding protein (DBP) → into liver

3. @ liver:

   • vitamin D3 → 25(OH)D3

4. @ Kidney:

   • 25(OH)D3 → calcitriol

1. What four things can cause Vit. D deficiency?

2. Risk Factors?

3. associated diseases?

4. Correlation?

Vit. D Deficiency:

• Inadequate sunlight exposure

• Disorders of vitamin D absorption

• Certain disorders of the liver and kidney

• Deficiency of parathyroid hormone

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Risk factors:

• Age

• Darker skin color

• Malnutrition

• Obesity:  Vitamin D is extracted from the blood by fat cells, altering its release into the circulation.

• Sunscreens and excessive clothing

• Geographic location (high latitude)

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Associated Diseases:

• Rickets; impeded growth, bone deformities

• Osteomalacia; a bone thinning disorder

• Osteoporosis; reduced bone mineral density

  • Muscle ache and weakness

• CVD: LVH, atherosclerosis, vascular calcification, and renin/angiotensin system

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Inverse correlation with incidence of certain types of cancer

What occurs to 90% of steroid hormones?

90% steroid hormones in plasma are bound to plasma proteins

• Specialized – high affinity for particular hormone

• Nonspecific - binds a variety of hydrophobic hormones (albumin)

What type of protein structure are prevalent on steroid receptors?

Zn fingers

Describe how steroid hormones affect protein transcription

Describe how steroid hormones are inactivated

• @ Liver; excreted as urine (and some as bile)

• Mechanism:

  • Reduction/Conjugation formation