Hormones

Hormones

1. Hormones

2. Introduction Hormones are chemical messengers secreted into blood by endocrine or ductless glands. The term hormone was introduced by Satrling in 1905 and comes from the Greek word “ Hormacin ” meaning “excite” or “arouse”. Hormones are substances synthesized in the body in small quantities but have a profound biochemical effect in the control and regulation of metabolic events and contribute in some cases to intercellular and intracellular communication.

3. Introduction A characteristic of hormones is that they are released, usually by specialized secretory cells in endocrine glands , and are carried by the circulation , to target cells where they have an effect.

4. Introduction The major hormone secreting glands are: Pituitary Thyroid & Parathyroid Adrenal Pancreas Ovaries Testes

5. Introduction Functions of hormones cover four major areas namely: Reproduction, Growth and development, Maintenance of internal environment , and Energy production , utilization and storage .

6. Classification of hormones Hormones can be classified in several ways, according to: Chemical Composition Location of Receptors Solubility Properties

7. Classification of hormones Classification on the Basis of their Chemical Composition Hormones can be classified chemically into three major groups . Steroids Hormones: These hormones are fat soluble compounds like adrenal cortical hormone and sex hormones (androgens and estrogens). Amines: these hormones are small, water-soluble compounds containing amino groups like epinephrine, thyroxine and several derivatives of tyrosine. Peptides/Protein Hormones: these are either large protein or small or medium size peptides e.g., insulin, glucagon and pituitary hormones.

8. Classification of hormones Classification on the Basis of their Mechanism On this basis, hormones can be classified into two categories . Hormones that bind to I ntracellular R eceptors: These include androgens, calcitrol , estrogens, glucocorticoids, mineralocorticoids, progestins , reticnoic acid, and thyroid hormones (T 3 and T 4 ). Hormones that bind to Cell Surface Receptors: T hese can be further classified on the basis of secondary messengers. It can be cAMP , cGMP, DAG, InsP3 and calcium ion.

9. Classification of hormones Classification on the Basis of Solubility On the basis of solubility, hormones can be classified as: Lipid-Soluble Hormones: T he lipid soluble hormones include steroid and thyroid hormones. Water-Soluble Hormones: The water soluble hormones include amines, peptide hormones, and the eicosanoid hormones.

10. Chemistry of Hormones

11. Steroid Hormones These include the sex hormones and the hormones from adrenal cortex. These are synthesized in mammals by the ovary (or testis), adrenal cortex, corpus luteum and the placenta . Sex Hormones Three types of sex hormones are recognized : Estrogens (female or ovarian or follicular hormones) Androgens (male or testicular hormones) Progestins (corpus luteal hormones).

12. Steroid Hormones 1. Ovarian Hormones Mammalian ovary contains ovarian follicles and corpus lutea . Hormones produced mainly in the follicles are known as estrogens. Chemically, the estrogens are derivatives of a C 18 hydrocarbon , estrane .

13. Steroid Hormones The three compounds of this group with hormonal activity are : β- estradiol Estriol Estrone

14. Steroid Hormones

15. Steroid Hormones All these are characterized by the absence of a CH3 group at carbon 10 and by the aromatic nature of ring A, making the OH group phenolic in character. Of all these, b -estradiol is most potent physiologically , estrone less potent and estriol is least active. Their relative potencies are 50 : 5 : 1 respectively . Although ovary is the chief source of estrogens, they are in smaller amounts also produced by the testis and the adrenal cortex.

16. Steroid Hormones 2. Testicular Hormones These hormones are secreted mainly by the testes, the male reproductive organs and are called as androgens . Chemically , these are derivatives of a C 19 hydrocarbon , androstane . They have no side chain on the 17-carbon of steroid skeleton.

17. Steroid Hormones There are many hormones secreted from testes with androgenic activity. The three important ones are : Testosterone Androsterone Dehydroepiandrosterone

18. Steroid Hormones Testosterone is most potent of all these and dehydroepiandrosterone is least active. The relative potency ratio of these three forms is 20 : 7 : 1. A few testicular hormones are also produced by the adrenal gland.

19. Steroid Hormones 3 . Corpus Luteal Hormones The hormones secreted by the ovarian bed, corpus luteum are collectively called as gestagens or progestins . The principal gestogen is progesterone . Progesterone is a C 21 steroid and is secreted by the corpus luteum during the second half of the menstrual cycle . Chemically, progesterone is one of the pregnane derivatives.

20. Steroid Hormones 4. Adrenal Cortical Hormones Adrenal cortex secretes some 40-50 closely related C 21 steroids, collectively called as corticosteroids. The corticosteroids may be grouped under two categories : Mineralocorticoids . — concerned primarily with the transport of electrolytes and the distribution of water in tissues, e . g ., aldosterone and deoxycorticosterone . Glucocorticoids . — concerned primarily with the metabolism of carbohydrates , proteins and fats , e . g ., cortisone, cortisol and corticosterone.

21. Steroid Hormones

22. Steroid Hormones

23. Steroid Hormones The estimated 24-hour production of major compounds of human adrenal gland is : Corticosteroids Cortisol 8-24 mg Corticosterone 1.5−4 mg Aldosterone 0.04−0.2 mg

24. Steroid Hormones Aldosterone is 30 times more active than deoxycorticosterone . Deoxycorticosterone , in its turn , is 4 times more potent than cortisone and cortisol in maintenance of life. Corticosterone is least active in this regard.

25. Steroid Hormones Classes of Steroid Hormones Steroid Class Principal Active Steroid in Humans No. of Carbon Atoms Parent Ring Structure Estrogens Estradiol 18 Estrane Androgens Testosterone 19 Androstane Progestins Progesterone 21 Pregnane Glucocorticoids Cortisol 21 Pregnane Mineralocorticoids Aldosterone 21 Pregnane

26. Steroid Hormones

27. Biosynthesis of Androgens and Estrogens The androgens are synthesized from cholesterol by the gonadal tissues, chiefly from testes. In the testes, cholesterol is converted to pregnenolone, progesterone and 17 a -hydroxyprogesterone. 17 a -hydroxyprogesterone is then converted to androstenedione, which is then converted to testosterone and androsterone. Testosterone can be converted to estradiol by the action of aromatase. Testosterone can also be converted to dihydrotestosterone by 5 a -reductase.

28. Biosynthesis of Progesterone In the corpus luteum, placenta and adrenal cortex, progesterone is synthesized from pregnenolone by 3 b -hydroxysteroid dehydrogenase . Progesterone is an intermediate common to the biosynthesis of all steroid hormone from cholesterol.

29. Steroid Hormones Biosynthesis of Glucocorticoids Progesterone is converted to either 17 a -hydroxyprogesterone by 17 a -hydroxylase or to 11-deoxycorticosterone by 21 a -hydroxylase . 17 a -Hydroxyprogesterone is then converted to 11-deoxycortisol by 21 a -hydroxylase . 11-deoxycortisol is then converted by 11 b -hydroxylase to cortisol. 11-deoxycorticosterone is converted to corticosterone by 11 b -hydroxylase .

30. Steroid Hormones Synthesis of Mineralocorticoids Corticosterone is converted to aldosterone by 18-hydroxylase . This reaction is stimulated by angiotensin II, a hormone produced in angiotensin by angiotensin-converting enzyme.

31. Peptide Hormones Peptide hormones are most prevalent and consist of chains of amino acids. Larger peptides are usually referred to as proteins, while complex protein hormones with carbohydrate side chains are called glycoprotein hormones. Peptide Hormones are classified as: Hormones of the pancreas Hormones of the Hypophysis Hormones of the Parathyroid Hormones of the Gastrointestinal Tract Hormones of the Corpus Luteum

32. Peptide Hormones 1. Hormones of the Pancreas Each pancreas has about 1,00,000 islets of Langerhans, which are clusters of various types of cells . These islets in mammals contain at least 4 major types of cells : α cells β cells δ cells F cells

33. Peptide Hormones The β cells contain granules which manufacture a hormone insulin , store it and eventually release it directly into the bloodstream at the appropriate times . The α cells contain granules which produce another hormone , glucagon . The δ cells secrete a hormone, somatostatin . The F cells secrete pancreatic polypeptide . The α and β cells make up 20% and 75% of the total, respectively.

34. Peptide Hormones Insulin Human insulin is a molecule of 5,734 Da which falls on the borderline between a large polypeptide and a small protein. It is composed of two separate peptide chains, designated the A chain and the B chain. These two chains are joined together by two disulfide bridges. The human insulin A chain consists of 21 amino acid residues and the B chain of 30 amino acid residues. A third disulfide exists in the A-chain between the cysteine 6 and 11.

35. Peptide Hormones Amino acid sequence of the A-chain and B-chain of one insulin molecule.

36. Biosynthesis of Insulin Insulin is synthesized as a pre-prohormone, that is a pre-proinsulin. The initial portion of 23 amino acids is called the leader sequence and directs the synthesis of pro-insulin. The leader sequence is cleaved off. The pro-insulin which is synthesized has the conformation necessary for forming the proper disulphide bridges between A- and B-chains. It undergoes a series of site-specific cleavages forming the mature insulin and an equimolecular amount of connecting peptide (C-peptide) of 31 amino acids.

37. Peptide Hormones Glucagon Glucagon has a molecular weight of 3,485 Da and is comprised of a single amino acid chain of 29 amino acids that is devoid of disulfide linkages . Histidine is the N-terminal amino acid and threonine, the C-terminal amino acid.

38. Peptide Hormones Glucagon’s N-terminal histidine at position #1 is essential for its biological activity. The adjacent residues, #2 (serine) and #5 (threonine), are involved in implementing the adenylyl cyclase activity which is key to the initiation of glucagon-mediated biological responses. Residues #19–#26 (blue color) have an equal potential to stabilize the structure either as β sheets, or as α-helices. The C-terminal two residues, asparagine (#28) and threonine (#29), increase glucagon’s tight binding to its receptor. Unlike insulin, it contains no cystine , proline or isoleucine, but possesses methionine and tryptophan in appreciable amounts.

39. Peptide Hormones

40. Peptide Hormones Somatostatin Two forms of somatostatin exists; S14 and S28, which are single chain polypeptides of 14 and 28 amino acids, respectively. Somatostatin-14 has one disulfide bond. It is produced by the δ -cells of the endocrine pancreas and dispersed cells in the gastrointestinal tract.

41. Peptide Hormones Other Pancreatic Hormones Pancreatic Polypeptide (PP ) Pancreatic polypeptide (PP) is a 36-amino-acid peptide that is known to stimulate the gastric secretion of HCl and pepsin. Most of the PP is expressed and then secreted by the F cells of the pancreas. PP circulates in the plasma as a dimer with a half-life of 6–7 minutes.

42. Peptide Hormones Amylin The pancreatic β- cell islets produce the peptide hormone amylin. It has also been formerly known as islet amyloid polypeptide (IAPP) . Amylin is a 37-amino-acid peptide. Amylin and insulin are co-secreted from the pancreatic beta cells at the time of food intake.

43. Peptide Hormones Constituent Hormones of Endocrine Pancreas Cell Type Hormone Structure a Glucagon 29 amino acids b Insulin Amylin Two chains: a = 21 amino acids b = 30 amino acids 37 amino acids d Somatostatin Two forms: S-14 = 14 amino acids S-28 = 28 amino acids F Pancreatic Polypeptide 36 amino acids

44. Peptide Hormones 2. Hormones of the Hypophysis or Pituitary Gland Hypophysis or pituitary gland consists of 3 lobes: An anterior lobe or adenohypophysis An intermediate lobe A posterior lobe or neurohypophysis All the three lobes secrete substances having hormonal activity.

45. Peptide Hormones The secretion of pituitary hormones is controlled by the hormones (or factors) released from hypothalamus, a region of the brain immediately proximal to the pituitary. These hormones are called as hypothalamo -releasing hormones or hypothalamic factors. Sr. no. Pituitary Hormones Hypothalmic Releasing Hormone 1 Thyroid Stimulating Hormone, TSH Thyrotrophin Releasing Hormone, TRH 2 Adrenocorticotrophic Hormone, ACTH Corticotrophin releasing Hormone, CRH 3 Follicle Stimulating Hormone, FSH Luteinizing Hormone, LH Gonadotrophin releasing Hormone, GnRH 4 Growth Hormone, GH Growth Hormone Releasing Hormone, GHRH 5 Prolactin, PL Prolactin releasing Hormone, PLRH

46. Peptide Hormones Hormones of Anterior Pituitary (Adenohypophysis) Anterior pituitary gland (Adenohypophysis) secrete a number of hormones of vital importance and all of them are protein in nature, and these nourish the secretory activities of other glands. These hormones are called as tropins or trophic hormones .

47. Peptide Hormones A. Thyrotropin or Thyroid-Stimulating Hormone , TSH . The molecule of TSH is a dimer made up of a and b subunits. It is a glycoprotein with molecular weight about 30,000. Each molecule has 8-9 cystine residues and the disulfide groups are present as intrachain linkages rather than interchain linkages.

48. Peptide Hormones B. Corticotropin or Adrenocorticotrophic Hormone , ACTH . Corticotropin is a straight chain polypeptide with a molecular weight of about 4,500 and consists of 39 amino acid residues. The most potent segment of activity is from residue 15 to 18 ( Lys.Lys.Arg . Arg ). The release of ACTH is controlled by CRH.

49. Peptide Hormones C. Gonadotropins or Gonadotrophic Hormones , GTH . Gonadotropins include: Follicle Stimulating Hormone, FSH Luteinizing hormone, LH Prolactin, PRL The gonadotropins, FSH and LH, are both regulated by the hypothalamic gonadotrophin releasing hormone, GnRH .

50. Peptide Hormones Follicle-stimulating hormone, FSH It is a glycoprotein that contains galactose , mannose , galactosamine , glucosamine, sialic acid, fucose and uronic acid. It has a molecular weight of about 30,000 in man . Luteinizing hormone, LH It is a peptide hormone with molecular weight of about 26,000 (in man ). It lacks tryptophan but has a high content of cystine and proline . Each molecule contains 10 glucosamine and 3 galactosamine residues.

51. Peptide Hormones Prolactin PRL, Luteotrophic Hormone, LTH This is also a peptide hormone with 198 amino acid residues and a molecular weight of about 23,500. It has 3 disulfide bonds between cysteine residues at 4-11, 58-173 and 190-198. It differs from FSH and LH in that it contains no carbohydrate.

52. Peptide Hormones Prolactin.

53. Peptide Hormones D. Somatotropin or Somatotrophic hormone , STH or Growth H ormone , GH . Somatotropin obtained from human hypophysis is a protein with molecular weight 27,000. It has 191 amino acids and consists of 2 disulfide bridges between adjacent cysteine residues. The N-terminal and C-terminal residues are both phenylalanine.

54. Peptide Hormones Constituent Hormones of Anterior Pituitary (Adenohypophysis) Cell Type Hormone Structure Basophils or β cells Thyrotropin , TSH Two Protein Subunits: a = 96 amino acids b = 112 amino acids Neutrophils or chromophobe cells Corticotropin , ACTH Polypeptide = 39 amino acids Basophils or β cells FSH Two Protein Subunits: a = 96 amino acids b = 111 amino acids Basophils or β cells LH Two Protein Subunits: a = 96 amino acids b = 121 amino acids

55. Peptide Hormones Constituent Hormones of Anterior Pituitary (Adenohypophysis) Cell Type Hormone Structure Acidophils or α cells Prolactin, PRL Protein of 198 amino acids Acidophils or α cells Growth Hormone, GH or Somatotropin, STH Protein of 191amino acids

56. Peptide Hormones Hormones of Posterior Pituitary or Neurohypophysis Two important hormones are secreted from the posterior pituitary in both males and females. These are: Oxytocin (OT ) Vasopressin (VP), the antidiuretic hormone, T he two hormones are structurally closely related nonapeptides that are derived from a common ancestral gene.

57. Peptide Hormones Oxytocin It is a nonapeptide amide. A disulfide bond is present to link the two cysteine residues present in the molecule. Vasopressin It is also a cyclic nonapeptide amide and resembles oxytocin except that isoleucine is replaced by phenylalanine and leucine by arginine.

58. Peptide Hormones

59. Peptide Hormones Constituent Hormones of Posterior Pituitary (Neurohypophysis) Hormone Structure Oxytocin Polypeptide of 9 amino acids (CYIQNCPLG) C’s are disulfide bonded Vasopressin or Antidiuretic Hormone Polypeptide of 9 amino acids (CYFQNCPRG) C’s are disulfide bonded

60. Peptide Hormones 3. Hormones of the Parathyroid Parathyroids secrete a hormone called parathyroid hormone ( parathormone , PTH) or Collip’s hormone . It is a linear polypeptide consisting of 84 amino acids (molecular weight=9300) with no cysteine residues and hence no disulfide bridges. A fragment of the intact hormone consisting of the first 34 amino acids at the N-terminal region of the molecule is sufficient for the peptide to exert its entire spectrum of characteristic biological effects .

61. Peptide Hormones 4. Hormones of the Gastrointestinal Tract The gastrointestinal hormones are a family of polypeptides produced by specialized endocrine cells present in the stomach, intestine, and colon which function both as traditional hormonal messengers and as neurotransmitters. Of the many regulatory gastrointestinal peptides, following are well understood are considered to be the authentic hormones: Gastrin Secretin Cholecystokinin (CCK)

62. Peptide Hormones Gastrin It is produced G cells in the pyloric mucosa, which is apparently stimulated by the proteins present in food or possibly by HCl . The main form of gastrin obtained from G cells is a heptadecapeptide . At the N-terminal end of the heptadecapeptide , there is a pyroglutamyl residue, and at the c-terminal end, there is a phenylalaninamide residue.

63. Peptide Hormones Two forms of heptadecapeptide exist: One in which the tyrosyl residue at postion 12 is free (Gastrin 1) The other in which it is sulphated .

64. Peptide Hormones Secretin Secretin has only 27 amino acids with molecular weight of 3,056 . The entire molecule of 27 amino acids is required for full biological activity. Secretin is localized to the upper duodenal and jejunal S cells.

65. Peptide Hormones Cholycystokinin , CCK It is also secreted by the upper part of the small intestine. Cholecystokinin is a polypeptide with 33 amino acid residues and a molecular weight of 3,883. It is, however , noteworthy that the last 5 amino acids towards the C-terminal in the gastrin and cholecystokinin are exactly the same. It is in this terminal portion of these hormones that the principal activity resides.

66. Peptide Hormones

67. Amino acid derivatives Thyroidal Hormones The mammalian thyroid gland biosynthesizes, stores, and secretes two molecular species of thyroid hormone: Thyroxine (T4 ; 3,5,3′,5′-tetraiodothyronine) Triiodothyronine (T3 ; 3,5,3′-triiodothyronine )

68. Amino acid derivatives

69. Amino acid derivatives Thyroid hormones are poorly soluble in water, and more than 99% of the T3 and T4 circulating in the blood is bound to a carrier proteins. The principle carrier of thyroid hormones is thyroxin-binding globulin.

70. Amino acid derivatives [ Calcitonin (CT) is a small polypeptide hormone secreted by the specialized C cells that are found primarily in the thyroid gland . It consisting of a straight chain peptide of 32 amino acids, with a seven-membered disulfide ring at the N-terminus and a prolinamide residue at the C-terminus. ]

71. Amino acid derivatives Hormones of Adrenal Medulla The adrenal medulla produces two hormones: Epinephrine or Adrenaline Norepinephrine or Noradrenaline Chemically, these two hormones are catecholamines ( dihydroxyphenylamines ) and are closely related to tyrosine and phenylalanine . Norepinephrine, however, differs from epinephrine structurally in having a hydrogen atom in place of the methyl group.

72. Amino acid derivatives