Steroid and Thyroid Hormones. Srbová Martina

Transcription

1 Steroid and Thyroid Hormones Srbová Martina

2 Chemical Classification of Hormones Hormones are chemical messengers that transport signals from one cell to another There are 3 major chemical classes of hormones steroid hormones - i.e. progesterone peptide and protein hormones - i.e. insulin amino acid derivatives - epinephrine

3 Classification of Hormones Endocrine hormones: act on cells distant from the site of their release Paracrine hormones act only on cells close to the cell that released them Autocrine hormones act on the same cell that released them

4 Mechanism of Hormone Action All hormone action is receptor mediated Peptide hormones and catecholamines bind to cell surface receptors Steroid and thyroid hormones act via intracellular receptors Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations

5 Mechanism of Hormone Action

6 Regulation of hormone release Negative feedback Positive feedback (ovulation, childbirth) Cyclic changes (cirkadian rythm, our development)

7 Environmental or internal signal CNS Electrical-chemical signal Hormonal cascade Signal amplification Limbic system Hypothalamus Electrical-chemical signal Inhibiting hormones - statins Releasing hormones (ng) - liberins Anterior pituitary Anterior pituitary hormone (μg) -tropines Target gland The gonads, the thyroid gland, the adrenal cortex Systemic effects Ultimate hormone (mg)

8 CNS Limbic system Hormonal cascade Negative feedback system Long feedback loop Hypothalamus Anterior pituitary Target gland Releasing hormones Anterior pituitary hormones Short feedback loop Ultimate hormone Systemic effects

9 Steroid hormones

10 Structure of Steroid Hormones Steroids are lipophilic molecules. All steroids, except calcitriol, have cyclopentanoperhydrophenanthrene structure (sterane). The parental precursor of steroids - cholesterol

11 Transport of Hormones in the Bloodstream Are not water soluble so have to be carried in the blood complexed to specific binding globulins. Albumin is non-specific Corticosteroid binding globulin (CBG) - transcortin Sex hormone binding globulin (SHBG) Androgen binding protein (ABP) Endocrine cell Carrierbound hormone Free hormone Hormone degradation Hormone Receptor Biological effects Only the free fraction is biologically active usually less than 10%

12 Hormone half life Steroids and thyroid hormone, which are bound to plasma proteins, have a long half life (~ hours) Peptides and catecholamines are watersoluble, they are transported dissolved in plasma generally have a very short half life (~ seconds to minutes)

13 Mechanism of Steroid Hormone Action Because steroid hormones initiate protein synthesis their effects are produced more slowly, but are more long-lasting than those produced by other hormones. Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations

14 Intracellular receptors Model of typical steroid hormone receptor H 2 N Variable domain interacts with other transcription factors 2. DNA-binding domain zinc finger 3. Domain for dimerization a site of dimerization of two receptor-hormone complexes 4. Hormone- binding domain - COOH zinc finger structure Copy from Devlin T.M.: Textbook of Biochemistry with Clinical Correlations

15 Biosynthesis of Steroid Hormones Peptide hormones are encoded by specific genes; steroid hormones are synthesized from the enzymatically modified cholesterol. Thus, there is no gene which encodes individual hormone. The regulation of steroidogenesis involves control of the enzymes which modify cholesterol into the steroid hormone.

16 Hormonal Stimulation of Steroid Hormone Biosynthesis Hormone stimulation depends on the cell type and receptor (ACTH for cortisol synthesis, FSH for estradiol synthesis, LH for testosterone synthesis etc.) St AR StAR steroidogenic acute regulatory protein

17 Biosynthesis of Steroid Hormones Critical step is the cell activity in mobilizing cholesterol stored in a droplets, transport of cholesterol to mitochondrion. The rate-limiting step is the rate of cholesterol side chain cleavage in mitochondrion by enzymes known as the cytochrome P450 side chain cleavage enzyme complex.

18 gnenolone

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20 Steroidogenic Enzymes Common name Old name Current name Cholesteroldesmolase (Side-chain cleavage enzyme) 3b-hydroxysteroid dehydrogenase P450 SCC CYP11A1 3 b-dh 3 b-dh 17a-hydroxylase/17,20 lyase P450 C17 CYP17 21-hydroxylase P450 C21 CYP21A2 11b-hydroxylase P450 C11 CYP11B1 Aldosterone synthase P450 C11AS CYP11B2 Aromatase P450 aro CYP19

21 Steroid Hormone Classes Glucocorticoids Mineralocorticoids Progestins Androgens Estrogens Vitamin D

22 Steroid hormones Steroid hormones play important roles in: - carbohydrate regulation (glucocorticoids) - mineral balance (mineralocorticoids) - reproductive functions (gonadal steroids) Steroids also play roles in inflammatory responses, stress responses, bone metabolism, cardiovascular fitness, behavior, and mood.

23 Steroid Hormones of the Adrenal Cortex Composed of 3 layers (zones): outer zone (zona glomerulosa) produces aldosterone (mineralocorticoid) middle zone (zona fasciculata) produces cortisol (glucocorticoid) inner zone (zona reticularis) produces dehydroepiandrosteron (androgen)

24 Regulation of Adrenal Steroid Hormones Synthesis Steroid hormone Steroid producing cells Signal Second messenger Signal system Cortisol Zona fasciculata ACTH camp, IP 3, Ca 2+ Hypothalamic-pituitary Aldosteron Zona glomerulosa Angiotensin II,III IP 3, Ca 2+ Renin-angiotensin Renin-angiotensin system Factors that stimulate renin release Decreased blood pressure, salt depletion Angiotensinogen renin Angiotensin I converting enzyme Na +, H 2 O resorption Angiotensin II Aldosteron aminopeptidase excretion of K +, H + Angiotensin III

25 Transport of Adrenal Steorid Hormones in the Bloodstream CORTISOL 70% is bound to corticosteroid binding globulin (transcortin) 22% of cortisol is bound to albumin 8% free cortisol ALDOSTERONE 60% of aldosterone is bound to albumin 10 % is bound to transcortin A small amount of aldosterone is bound to other plasma proteins Transcortin is produced in the liver and its synthesis is increased by estrogens.

26 Cortisol - effects Stress adaptation lipids proteins Proteolysis Amino acids concentration in the blood rises Amino acids lipolysis cortisol gluconeogenesis Fatty acids protein synthesis high concentration glucose Immunosupresive effect antiinflammatory effect bone degradation

27 Cortisol

28 Congenital Adrenal hyperplasia CAH (adrenogenital syndrome) Autosomal recessive disease Insufficient amounts of steroidogenic enzymes deficiency of end products, the accumulation of intermediates 21 hydroxylase deficiency ( 90% of cases) cortisol production ACTH adrenal hyperplasia, androgens (virilization) In children with the more severe form of the disorder (mineralocorticoid deficiency), symptoms often develop weeks after birth. Acidosis, hypekalemia, hyponatremia Since 2006 newborn screening

29 Cushing s syndrome Glucocorticoid excess Use of glucocorticoids Pituitary adenoma, adrenal adenoma Lost of diurnal pattern of ACTH and cortisol secretion Hyperglycemia - gluconeogenesis Protein catabolic effects thinning of the skin, osteoporosis, negative N balance Redistribution of fat- buffalo hump Resistence to infections and inflammatory responses is impaired Hypernatremia, hypokalemia, hypertension,edema

30 Steroid Hormones of the Gonades Hormones that affect the development of the reproductive organs and sexual characteristics. Regulation of Sex Hormones Synthesis Steroid hormone Steroid producing cells Signal Second messenger Signal system Testosterone Leydig cells LH camp Hypothalamic-pituitary Estradiol Granulosa cells FSH camp Hypothalamic-pituitary Progesterone Corpus luteum LH camp Hypothalamic-pituitary

31 Testes Leydig cells produce: testosteron Sertoli cells produce: dihydrotestosterone (DHT) but most of conversion of testosterone to DHT occurs outside the testes estradiol a small amount of testosteron is also converted into estradiol by aromatization inhibits testosteron synthesis inhibin polypeptide hormone, which inhibits FSH releasing FSH binds to the Sertoli cells and stimulates the synthesis of androgenbinding protein (ABP). ABP binds testosterone (produced by Leydig cells) and transports it to the site of spermatogenesis

32 Ovaries Estradiol is the main hormone produced during the follicular phase of the menstrual cycle. Responsible for maintenance of the female reproductive system and the development of female secondary sex characteristics Estrogens are formed by aromatisation of androgens After ovulation progesterone is made by follicular cells, which now constitute the corpus luteum. Involved in preparing and maintaining the uterus

33 Menstrual cycle FOLLICLE OVULATION CORPUS LUTEUM Uterine endometrium Menstruation Follicular phase Luteal phase

34 Transport of Sex Hormones in the Bloodstream Testosterone & estradiol bind to sex hormone binding globulin (SHBG). Affinity of SHBG for testosterone is higher than for estradiol. Progesterone binds to transcortin. Before puberty - the level of SHBG is about the same in males and females. At the puberty - there is a small decrease in the level of circulating SHBG in females and larger decrease in males, insuring relatively greater amount of the unbound, biologically active sex hormones. In adults, males have half of the amount of SHBG than females. Testosterone lowers SHBG levels in blood, whereas estradiol raises SHBG levels.

35 Calcitriol - 1,25 (OH) 2 -D 3 Diet Liver 25-hydroxylase OH HO Vitamin D 3 cholecalciferol UV from sunlight Skin HO 25(OH) D 3 Kidney 1α- hydroxylase OH HO 7 7-dehydrocholesterol HO OH 1,25(OH) 2 D 3 (active hormone form)

36 Calcitriol - 1,25 (OH) 2 -D 3 1a-hydroxylation is the rate-limiting step in calcitriol synthesis Regulation of 1a-hydroxylase Activation Hypocalcemia Parathroid hormone Hypophosphatemia Inhibition Calcitriol Calcitriol - increases uptake of Ca 2+ and phosphate from the intestine - stimulates calcium binding protein synthesis - increases reabsorption of Ca 2+ by the kidney

37 Hormone Catabolism and Excretion Inactivation of steroids involves reductions and conjugation to glucuronides or sulfate to increase their water solubility. Most are catabolized by the liver and kidneys. 70% of the conjugated steroids are excreted in the urine, 20 % leave in feces and rest exit through the skin. 3 estron-3sulfate

38 Thyroid Hormones

39 Thyroid Hormones 3,5,3 -triiodothyronine (T 3 ) Thyroxine (T 4 ) 3,5,3,5 -tetraiodothyronine

40 Biosynthesis of thyroxine The main synthetized thyroid hormone is thyroxine, but triiodothyronine is tentimes more potent Precursor molecule for synthesis thyroid hormones is tyrosine derivative Biosynthesis is perfomed on tyrosine residues bound in protein of thyroid gland thyreoglobulin The first step is transport of iodide into follicle cells of thyroid gland Active transport of iodide into the follicle cell is mediated iodide pump (the concentration outside is 25times lower than inside)

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44 Transport of thyroid hormones by blood The main transporting protein is thyroxine binding globulin (TBG). Its affinity for T 4 is 10 times higher than for T 3. The further proteins, binding thyroid hormones, are thyroxine binding prealbumin and albumin. More than 99% of T 4 is bound on plasma proteins.

45 Control of thyroid hormone synthesis and secretion Pituitary hormone thyreotropin (TSH) upregulates activity of iodide pump of follicle cells of thyroid gland Endocytosis of iodinated thyreoglobulin and following secretion of T 3 and T 4 is also upregulated by TSH Production of TSH is upregulated by TRH and controled by thyroid hormones via negative feedback

46 Thyroid Hormones Bind to intracellular receptor, increase expression of numerous metabolic enzyme Stimulate metabolism and influence development and maturation stimulate the consumption of oxygen increase metabolic rate regulate thermogenesis Hyperthyroidism, excessive secretion of thyroid hormones, causes high body temperature, weight loss, irritability, and high blood pressure Hypothyroidism, low secretion of thyroid hormones, causes weight gain, lethargy, and intolerance to cold during fetal and immediate postnatal periods results in irreversible physical and metal retardation cretinism

47 Degradation of thyroid hormones Deiodation Oxidative deamination Conjugation with glucuronate, sulfate

48 Literature Devlin, T. M. Textbook of biochemistry: with clinical correlations. 6th edition. Wiley-Liss, Marks Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M. Lieberman, A.D. Marks) Color Atlas of Biochemistry, second edition, 2005 (J. Koolman and K.H. Roehm)