Week 5

• Steroid hormones are derived from cholesterol through enzymatic modification and their two-dimensional structures look similar.
• Glucocorticoid and mineralocorticoid activity is associated with specific structural features and specificity in steroid hormone actions is essential for their distinct functions in target cells
• Glucocorticoids require a hydroxyl group at C-11, while mineralocorticoids need a hydroxyl group at C-21.
• Androgenic effects are generated by C-19 compounds with a 17β-hydroxyl group, and the presence of 17-keto reduces activity.
• Specificity in steroid hormone actions can be achieved through the evolution of receptors with a higher affinity for active hormones compared to metabolites or similar steroids.
• Estradiol and 1,25-dihydroxyvitamin D have distinct structures and high receptor affinities, while glucocorticoids, mineralocorticoids, progestagens, and androgens have structural similarities, leading to reduced specificity.
• • Cholesterol is obtained from the diet or synthesized from acetate and about 300 mg of cholesterol is absorbed from the diet daily, and 600 mg is synthesized from acetate.
  • Cholesterol transport requires lipoprotein complexes formed with apoproteins and is stored as esters or is used.
  • In the adrenal cortex, 80% of the required cholesterol for steroid synthesis is captured by LDL receptors, while 20% is synthesized within adrenal cells.
• • The initial synthesis of adrenal steroids involves hydrolysis of cholesterol esters and transfer to the mitochondria's outer membrane.
  • The first enzymatic step is carried out by P450scc, converting cholesterol to pregnenolone.
  • Most steroid hormone synthesis steps involve cytochrome P450 enzymes (CYP).
  • Pregnenolone is converted to progesterone or 17α-hydroxypregnenolone, leading to various steroid hormones.
• • Dimerized GRs use zinc fingers in their DNA-binding domain to interact with specific grooves in the DNA helix, known as hormone response elements (HREs).
  • This interaction, in conjunction with other transcription factors, stimulates or suppresses gene transcription downstream of the glucocorticoid response element (GRE).
  • The DNA-binding domain of glucocorticoid receptors is structurally similar to those of estrogen, androgen, and progesterone receptors, allowing them to bind to the same hormone response element.
• • Cortisol may also exert non-genomic effects through membrane receptors, including cortisol-binding globulin (CBG) and cell surface receptors, activating adenylate cyclase.
  • GRs exist in two forms, GR-α and GR-β, which do not bind glucocorticoids and may regulate glucocorticoid activity independently.
  • Cortisol can bind to the aldosterone receptor in kidney tubules, but its rapid conversion to cortisone in these cells typically prevents binding.
• Progestogens, Glucocorticoids, Mineralocorticoids, Androgens, and Estrogens are the five classes of steroid hormones.

  Corticosteroids include Mineralocorticoids, Glucocorticoids, and Androgens.

  Gonadal Steroids include Progestogens, Estrogens, and Androgens.

  Progestogens are C21 steroid hormones that have various effects on the body, including regulation of the menstrual cycle and development of breasts.
• Progestogens can have slow, genomic actions through progesterone receptors (PR).

  Reduced metabolites of progestogens, called pregnanes, can exert neurosedative effects through the GABA A chloride channel.
• Glucocorticoids are C21 steroid hormones that play a pivotal role in the stress response and elevate plasma glucose levels.

  Glucocorticoids have anti-inflammatory actions and can upregulate IkB and annexin.

  Glucocorticoids are transported by cortisol-binding globulin (CBG) and can have slow, genomic actions through the glucocorticoid receptor (GR).
• Mineralocorticoids, such as aldosterone, are C21 steroid hormones that have various effects on the body, including regulation of electrolyte balance.
• Steroid hormones have different functional groups, including hydroxyl groups (R-OH), ketone groups (R=O), and aldehyde groups.
• Aldosterone is a mineralocorticoid that stimulates sodium resorption and potassium secretion in the distal nephron, colon, and salivary glands.
• Dehydroepiandrosterone (DHEA) is a precursor to other steroid hormones.
• Androstenedione is an androgen that is a precursor to testosterone.
• Testosterone is responsible for phenotypic virilization/masculinization.
• Estrogens: Steroid hormones with a hydroxyl group (R-OH) and an aromatic structure, specifically C18 steroid hormones.

  Estrogens as metabolites: Estrogens can be derived from the metabolism of 7-dehydrocholesterol, a precursor of Vitamin D3 (Calcitriol).
• Phenotypic feminization is the effect of estrogen hormones on the development of female characteristics, regulated by the hypothalamo-pituitary-ovarian (HPO) axis and placenta.
• Slow, genomic actions via ER: Estrogens exert their effects through estrogen receptors (ER) and can lead to long-term changes in gene expression.

  Rapid, non-genomic actions: Estrogens can also have immediate effects that do not involve changes in gene expression, although the specific mechanism is not mentioned.
• Cholesterol is converted to progestogens, androgens, and estrogens through a series of steps.
• StAR protein requires short half-life proteins and interacts with translocator protein (TSPO) in intracellular cholesterol transport.
• Pregnenolone is converted to pregnenedione by 3b-Hydroxysteroid Dehydrogenase (3b HSD), which can produce both D5-steroids and D4-steroids.
• Cholesterol is converted to pregnenolone, which is further converted to various steroid hormones including progesterone, testosterone, estradiol, cortisol, and aldosterone through the action of enzymes such as CYP11A1, CYP17A1, CYP21A2, CYP11B2, and CYP19A1.
• Cytochrome P450 enzymes, such as CYP17A1 and CYP19A1, catalyze hydroxylations in steroid hormone biosynthesis.
• Terminal electron acceptors are involved in the electron flow in cytochrome P450 enzymes.
• Ferrodoxin and Adrenodoxin are involved in electron transfer in cytochrome P450 enzymes.
• NADPH and NADP+ are involved in the electron flow in cytochrome P450 enzymes.
• Cytochrome P450 enzymes, such as CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP19A1, and CYP21A2, are involved in steroid hormone biosynthesis.
• Cytochrome b5 is involved in the activity of CYP17A1.
• Steroid hormone biosynthesis involves intracellular cholesterol transport and metabolism, Cytochrome P450 (CYP) enzymes, and Hydroxysteroid dehydrogenase (HSD) enzymes.
• The biosynthesis pathway includes the conversion of cholesterol to pregnenolone, 17α-Hydroxy-pregnenolone, DHEA, progesterone, 17α-Hydroxy-progesterone, androstenedione, estrone, deoxycortico-sterone (DOC), 11-Deoxy-cortisol, testosterone, estradiol, corticosterone, cortisol, and aldosterone.
• HSD Enzymes catalyze the oxidation of alcohols and reduction of ketones.
• 3β HSD oxidizes pregnenolone to progesterone and DHEA to androstenedione, and has secondary isomerase activity.
• 17β HSD inter-converts 17β OH with 17-ketone in C19 and C18 steroids.
• Testosterone and androstenedione are weak Δ5 steroids, while estrone and estradiol are strong Δ4 steroids.
• Peptide hormones are made via mRNA translation by ribosomes, forming a polypeptide chain called PRE-PRO-HORMONE, containing signal sequence for direction to ER lumen.

  
  

  Enzymes in ER cut signal sequence, creating inactive PRO-HORMONE, and this passes from ER through Golgi complex, where complicated structures are assembled, like disulphide bridges, carbohydrates, and prohormone processing to get many final products.

  
  

  Distinct peptide chains are assembled together in the secretory vesicles, which also contain prohormones and endopeptidase enzymes responsible for their activation.