Biochemistry - Steroid hormones
Progesterone
(synthesized in corpus luteum in response to stimulation by luteinizing hormone) - prepares the uterine endometrium for implantation of a fertilized egg - inhibits contraction of the uterus - inhibits development of a new follicle - acts as a differentiation factor in mammary gland development - maintains pregnancy
Estrogen in females
- Guide formation of the female reproductive tract (vagina, uterus, ovaries - and external genitals) - At puberty - guide the appearance of secondary sex characteristics, such as breast and body hair growth, and fat distribution.
Common step of steroid synthesis
Common Step 1st step: conversion of cholesterol to pregnenolone enzyme: 20α,22 desmolase
Role of StAR in steroid synthesis
Synthesis begins in the mitochondria of steroidogenic tissues - occurs in the inner mitochondrial membrane - Cholesterol transported into the mitochondria - moved from the outer mitochondrial membrane to the inner mitochondrial membrane via Steroidogenic Acute Regulatory Protein (StAR)
Location of androgen synthesis
Testosterone - primarily produced in the testes - synthesis also occurs in the zona reticulosum of adrenal cortex
Corticosteroid binding globulin
cortisol
Sex steroid binding globulin
testosterone and estradiol
Testosterone synthesis - delta4 pathway
∆4 pathway: Pregnenolone is converted to progesterone by 3-β-hydroxy steroid dehydrogenase Progesterone is then converted to 17-α-hydroxyprogesterone by 17-α-hydroxylase (CYP17), which is hydroxylated by 17-α- hydroxylase (CYP17) to form androstenedione 17-β-hydroxy steroid dehydrogenase then converts androstenedione to testosterone
Testosterone synthesis - delta5 pathway
∆5 pathway (the main pathway in the testes): Pregnenolone is hydroxylated by 17-α-hydroxylase (CYP17) to form 17-α-hydroxy pregnenolone, which in turn is also acted on by 17-α-hydroxylase (CYP17) to form dehydroepiandrosterone (DHEA). DHEA is then converted to androstenedione by 3-β-hydroxy steroid dehydrogenase. 17-β-hydroxy steroid dehydrogenase then converts androstenedione to testosterone.
Aldosterone synthase
CPY11B2
20 alpha, 22 desmolase
CYP11A
11-beta-hydroxylase
CYP11B1
17-alpha-hydroxylase
CYP17
Aromatase
CYP19
21-alpha-hydroxylase
CYP21
Mechanism behind steroid hormone signaling
- On exiting the blood stream steroid hormones dissociate form the binding globulins and can enter the target cell by diffusion - Steroid hormone receptors can also be cytoplasmic (e.g. for estrogen) or nuclear - steroid hormone-receptor complex binds to the DNA and can activate or repress the expression of one or more genes
Sources of cholesterol
- Receptor mediated uptake of Low Density Lipoprotein (LDL) by the LDL-receptor - synthesized in a multistep process from acetyl CoA
Role of estrogen in females and males
- The adolescent bone-growth spurt is fueled, and then halted, by estrogens (regulate fertility)
Role of steroids in transcription of genes
- activate or inhibit transcription of certain genes through binding to specific nuclear receptors - nuclear receptors bind DNA at hormone response elements (HSE) - Transactivation domain: binds coactivator proteins that interact with the basel transcription machinery; recruits other proteins that positively affect receptor-ligand complex - DNA binding domain - Ligand binding domain (where hormone binds) - Nuclear localization signal
Addison's Disease
- autoimmunity against the adrenal cortex, inherited glucocorticoid synthesis dysfunction or pituitary disease - results in a failure to make cortisol and aldosterone
How estrogen acts as transcription factors
- estrogen receptor is located in the cytoplasm, - masked by the heat shock protein, HSP90. - estradiol (E2) enters cell -> displaces HSP90 and binds to the estrogen receptor - hormone-receptor complex translocates into the nucleus, dimerizes and binds to the estrogen response element (ERE) as a homodimer - enhances gene transcription by recruitment of coactivator proteins. *In the absence of ligand, the estrogen receptor cannot bind to the DNA
Androgens contribute to __; location of synthesis
- growth and development of the male reproductive system (penis, testes, prostate and sperm) - synthesized in the Leydig cells of testes and secreted in response to luteinizing hormone from anterior pituitary
Glucocorticoids
- guide fundamental processes associated with converting sugar, fat, and protein stores to useable energy including by: 1. enhancing the expression of enzymes involved in gluconeogenesis 2. mobilizing amino acids from extrahepatic tissues, which then serve as substrates for gluconeogenesis; 3. inhibiting glucose uptake in muscle and adipose tissue (a mechanism to conserve glucose); 4. stimulating fat breakdown in adipose tissue - play a role in inhibiting swelling and inflammation, and in suppressing immune responses
Characteristics of steroid hormones
- lipid solubility allows passing out of the cell through cell membrane after synthesis - hydrophobic & travel in the aqueous blood stream - must be complexed to specific binding globulins
Synthesis of estrogen (pathway)
- made from androgens - involve the conversion of androstenedione or testosterone by aromoatase (CYP19) - produced in the ovary, as well as the skeletal muscle and adipose tissue - Estradiol is the most potent ovarian estrogen whereas estrone is mostly produced in extra ovarian tissues
Mineralocorticoids
- regulate inorganic molecules such as sodium, potassium, and hydrogen to maintain water balance in and around cells ex. aldosterone
Cushing syndrome
- sustained and pronounced hypersecretion of the glucocorticoid cortisol - excess production by one or both adrenal glands, or overproduction of the adrenocorticotropic hormone (ACTH - produced in the pituitary, regulates cortisol production) - result of pituitary adenomas or ectopic, ACTH-producing tumors, or primary adrenal gland disease - can also be caused by high doses of corticosteroid medications over an extended period of time e.g. prednisone for inflammatory diseases, such as rheumatoid arthritis, lupus and asthma, or to prevent rejection of a transplanted organ - most cases are sporadic although there are some genetic causes that have pituitary adenomas as a feature, including multiple endocrine neoplasia type 1 (MEN1) and familial isolated pituitary adenoma (FIPA).
Testosterone in males
- type of androgen - switches the development of somatic tissues to the male phenotype and suppresses female development - later triggers male puberty, influencing vocals, facial hair, muscle mass, and behaviors such as sex drive and aggressiveness - converted to the more active form dihydrotestosterone (DHT) within target tissues (in males)
Activity of 17-alpha-hydroxylase
1. Hydroxylation activity: It catalyzes the hydroxylation of carbon 17 (C17) of progesterone or pregnenolone. 2. C17-C20 lyase activity: It can catalyze the cleavage of the 2-carbon side chain of progesterone or pregnenolone at C17. - activities allow the biosynthesis of steroid hormones to occur via two separate pathways - allows 17 hydroxylated steroids (precursors of cortisol; C21)chains and one where the side chain is cleaved (precursors of sex hormones; C19)
Aldosterone synthesis (pathway)
1. cholesterol is converted in 2 steps to progesterone 2. Progesterone converted to aldosterone through a hydroxylation and an oxidation step catalyzed by the CYP11B system 3. CYP11B goes through hydroxylation and oxidation to produce aldosterone
Cortisol synthesis (pathway & step location)
1. conversion of cholesterol to pregnenolone occurs in the inner mitochondrial membrane by 20α,22 desmolase (CYP11A) 2. Pregnenolone moves to cytoplasm -> forms progesterone (catalyzed by 3-β-hydroxy steroid dehydrogenase). 3. 17-α-hydroxylase (CYP17) in the ER catalyzes the conversion of progesterone to 17-α-hydroxy progesterone 4. 17-α-hydroxy progesterone hydroxylated by 21-α-hydroxylase (CYP21) to form 11-deoxycortisol 5. 11-deoxycortisol transported back into the inner mitochondrial membrane -> hydroxylated by 11-β-hydroxylase to form cortisol 6. Cortisol then exits the cell Note: 17-α-hydroxylase (CYP17) an important enzyme with two activities 17-α-hydroxylase (CYP17) - this enzyme has two activities: 1. Hydroxylation activity: It catalyzes the hydroxylation of carbon 17 (C17) of progesterone or pregnenolone. 2. C17-C20 lyase activity: It can catalyze the cleavage of the 2-carbon side chain of progesterone or pregnenolone at C17. - activities allow the biosynthesis of steroid hormones to occur via two separate pathways - allows 17 hydroxylated steroids (precursors of cortisol; C21)chains and one where the side chain is cleaved (precursors of sex hormones; C19)
Describe the five classes of steroid hormones
- corticosteroids: Glucocorticoids and mineralcorticoids (adrenal cortex) - sex steroid hormones: Testosterone (testes), estrogens (ovaries), progesterone (ovaries) Note: sex hormones are also produced in lesser amounts in the adipose tissue and adrenal glands in males and females, and by the placenta during pregnancy
