Therapeutic hormones

1. Therapeutic Hormones

2. Introduction
Harmones
•Most Important group among regulatory
molecules produce by the body.
•Synthesized and released from a specific glands.
•Interacting with a receptor present in/on a
distant sensitive cell brought about a change in
that target cell.
•Hormones travel to the target cell via the
circulatory system.

3. Hormone to be any regulatory substance that
carries a signal to generate some alteration at a
cellular level.
Under such a broad definition all cytokines for
example could be considered hormones.

4. Examples
• Insulin
• Glucagon
• Somatotrophins
• Gonadotrophins
• Adrenaline

5. Insulin
•Insulin is a polypeptide hormone
• Produced by the beta cells of the pancreatic
islets of Langerhans.
•It plays a central role in regulating blood
glucose levels.
.

7. Other examples
• Glucagon maintain blood glucose level.
• Somatotrophin stimulates growth.
• Gonadotrophins control secondary sexual
characters

8. Therapeutic Hormones
• Hormones administered as drug.
• Synthesize in lab /industries.
• Nowaday genetic manipulation techniques are
used to generate therapeutic hormones.
• E.g. rHGH, rInsulin

9. Insulin
• Insulin is a polypeptide hormone
• Produced by the beta cells of the pancreatic islets of
Langerhans.
• Islets of Langerhans: Known as the insulin-producing
tissue

10. • It stimulates glucose transport
• It stimulates intracellular biosynthetic
pathways
• It inhibits catabolic pathways, such as
glycogenolysis

11. Diabetes mellitus
• Failure of the body to synthesize sufficient insulin
results in the development of insulin-dependent
diabetes mellitus (IDDM).
• Also known as type-1 diabetes.
• IDDM is caused by T-cell-mediated autoimmune
destruction of the insulin-producing β-pancreatic
islet cells in genetically predisposed individuals.

12. • genetic predisposition sometimes also
called genetic susceptibility.
Dosage of insulin:
1. Rapid-acting insulin
2. Short-acting insulin
3. Intermediate-acting insulin
4. Long-acting insulin

13. The insulin molecule
• First identified as an anti-diabetic factor in 1921
• Its complete amino acid sequence was determined in
1951.
• The insulin receptor is a tetrameric integral
membrane glycoprotein consisting of two 735 amino
acid α-chains and two 620 amino acid β-chains.
• These are held together by disulfide linkages.

14. Insulin Production

15. Traditionally insulin preparations
• Animal insulin was the first type of insulin to
control diabetes.
• Until the 1980s, animal insulin was the only
treatment for insulin dependent diabetes.
• Animal insulin is derived from cows and pigs.
• Direct extraction from pancreatic tissue of
slaughterhouse pigs and cattle.

16. Disadvantages
• Slight structural difference of 1-3 amino acids
between the animal insulin and human insulin.
• Diabetic patient developed antibodies against the
animal insulin thereby causing allergic reactions.
• large number of animals were to be sacrificed for
extracting the insulin from their pancreas.
• For example: To obtain 5 kgs. Of pancreatic juice
about 75 pigs have to be killed to get insulin for
treating only a single diabetic patient just for one
year.

17. By recombinant DNA technology
• First approved for general medical use in
1982.
• First product approved for therapeutic use in
humans.
• Insulin consist of two polypeptide chains A
and B.
• inserting the A and B chains into two different
E. coli cells.
• Chain A and B separately synthesized.

18. • The A- and B-chains are then incubated under
required parameters.
• Bond formation.

20. Formulation of insulin

21. • Insulin are formulating in number of way to
alert the order of pharmacokinetic profile
• There are two types pharmacokinetic profiling
• Fast (short)-acting insulins
• Slow-acting insulins

22. • In healthy individuals In healthy individuals, insulin is
typically secreted continuously into the bloodstream at
low basal level
• With rapid increases evident in response to elevated
blood sugar levels
• low-acting insulin preparation, however, accurately
reproduces
normal serum insulin baseline level
• fast-acting insulin will not produce
• a plasma hormone peak for 1.5–2 h post injection, and
levels then remain elevated for up to 5 h.

23. Prolong the duration of insulin action
• This is generally achieved in one of two
ways:
• Addition of zinc in order to promote Zn–
insulin crystal growth
• Addition of a protein to which the insulin will
complex
• The proteins normally used are
protamine's

24. Engineered insulins
• Recombinant DNA technology facilitates not only production
of human insulin in microbial systems, but also facilitates
generation of insulins of modified amino acid sequences
• The major aims of generating such engineered insulin
analogues include:
• Identification of insulins with altered pharmacokinetic
properties
• Identification of super-potent insulin forms
• The insulin amino acid residues that interact with the insulin
receptor have been identifi ed (A1,
• A5, A19, A21, B10, B16, B23-25), and a number of analogues
containing amino acid substitutions at several of these points
have been manufactured.

25. Modified insulins
• modified insulins have now been approved for medical
injected at mealtimes rather than1 h before
• Several Engineered insulins are inliste
• Insulin lispro’ (tradename ‘Humalog’) was the first
such engineered short-acting insulin to come to
market
• ‘Insulin Aspart’ is a second fast-acting engineered
human insulin
• It differs from native human insulin in that the prolineB28
residue has been replaced by aspartic acid
• This single amino acid substitution

26. • Optisulin or Lantus are the tradenames given to one such
analogue that gained general marketing approval in 2000
• It differs from native human insulin in that the C-terminal
aspargine
residue of the A-chain has been replaced by a glycine residue
and the β -chain has been elongated(again from its C-terminus)
by two arginine residues
• Levemir (tradename) is an alternative engineered long-
acting insulin product that gained approval for general medical
use in 2004
• This differs from native insulin in that it is devoid of the
threonine B30 residue and (more importantly from a
pharmacokinetic perspective)contains a 14-carbon fatty acid
residue covalently attached to the side chain of lysine residue
B29

27. Glucagon

28. Glucagon
• Polypeptide
• Single chain (29 amino acids)
• Its function is contradictory to insulin.
• Secretes in response to hypoglycemia.
• Promotes catabolic activity.
i.e.
• Break down of stored energy
• stimulates gluconeogenesis.

29. Glucagon
• Source: Pancreas
• Extract from bovine & porcine pancreatic
tissues.
• Used as freeze dried hormone.
• Dosage routes : Subcutaneous &
Intramuscular
• Now Recombinant products are available.
• E.g . Glucagen

31. Human Growth Hormone
• Somatotrophin.
• Hormone : Stimulates growth
• 191 amino acid
• Released by pituitary glands.
• Traditionally extracted from bovine /porcine
source.

32. Therapeutic Uses
• Wide range of applications
• Treatment of dwarfism (1958).
• Stimulation of lactation.
• rhGH was produce in 1980 .
• rhGH was first purified (on a laboratory scale)
by Genentech

33. Gonadotrophins
• Group
• Produced
Proteins Hormones
Gonadotropes cell
Pituitary
glands

34. They directly and indirectly regulate ;
• Reproductive function
• secondary sexual characteristics

35. Hypothalamus
Pituitary glands
GnRH
FSH LH

36. Types
FSH LH HCG

37. Follicle stimulating Hormone
Females
• Helps ovarian follicle to
develop.
• Promotes estrogen
secretion.
Males
• Promotes sperm
development

38. luteinizing hormone
Females
• Stimulation ovulation
• Promotes secretion of
estrogen and
progesterone
Males
• Stimulates production
of testosterone

39. Human Chorionic Hormones
• It is a hormones produced naturally by the
pregnant women to ensure the correct
nourishment of the baby

40. Medical Applications of
Gonadotrophin Hormones

41. • The therapeutic potential of gonadotrophins in
treating subfertility/some forms of infertility.
• Gonadotrophins are also used to induce a
superovulatory response in various animal specie.
• The human pituitary is the obvious source of
human gonadotrophins.
• The urine of post-menopausal women does
contain both FSH and LH activity.

42. • Menotrophin (human menopausal
gonadotrophin) is the name given to FSH-
enriched extracts from human urine.
• Such preparations contain variable levels of LH
activity, as well as various other proteins normally
present in urine.
• hCG exhibits similar biological activities to hLH
and is excreted in the urine of pregnant women

44. Applications:
• Treatment of anovulatory infertility.
• Treatment of females with blocked fallopian
tube.
• Treatment of male subfertility or related
conditions.
• Future additional clinical applications.

45. 1. Treatment of anovulatory infertility.
• In females, menotrophins and hCG are used
for the treatment of infertility.
• Menotrophin is administered to stimulate
follicular maturation, along with hCG to
promote ovulation and corpus luteum
formation.

46. Dosage:
• Gonadotrophin, often given for 12 days or
more, followed by a single dose of hCG.
• Three equal larger doses of menotrophin are
given on alternate days.
• Followed by hCG administration 1–2 days.

47. Dosage Level:
• Dosage of both hormones is given same as the
amount of them produced normally during
the reproductive cycle of fertile females.
• Depending upon the basal hormonal status of
the female, calculation of the optimal dosage
levels can be tricky.
• Overdosage can result in risk of multiple
pregnancy.

48. 2. Treatment of Female Infertility:
• FSH given in more quantity than normal to allow
the female to stimulate multiple follicular growth.
• Often employed when a woman has a blocked
fallopian tube.
• After treatment, the resultant eggs are
collected, incubated in vitro with partner’s
sperm.
• Cultured and incubated untill blastocyts formed
and implanted back.

49. 3. Treatment of Male Subfertility:
• FSH and hCG are also involved in treatment of
male infertility.
• Given to males having hypogonadotrophic
hypogonadism (HH) to stimulate sperm
synthesis.
• hCG has also application in the treatment of
cryptorchidism condition.

50. 4. Clinical Applications:
• Cell surface receptor of LH & hGC is found in a
number of non-gonadal tissue.
• These hormones may possess other than
reproductive functions.
• It is expressed by a number of tissues before
birth, hinting at a potential developmental
role.
• Receptor levels in non-gonadal tissues are
generally much lower than in gonadal tissue.

51. Recombinant gonadotrophins
 Recombinant DNA technology
 rhFSH produced in CHO cells has proven
clinically effective
 When administered to humans, the
preparation is well tolerated and yields no
unexpected side effects
 hypogonadotrophic hypogonadism

52. Recombinant gonadotrophins now
approved for general medical use in
the EU and USA
Product Company Indication
Gonal F (rhFSH) Serono Anovulation and
Superovulation Puregon (rhFSH) N.V. Organon
Anovulation and Superovulation Follistim (rhFSH)
Organon Some forms of infertility
Luveris (rhLH) Ares-Serono Some forms of
infertility
Ovitrelle (rhCG) Serono Selected assisted
reproductive techn

53. Ovitrelle
 Ovitrelle (tradename in EU, sold as Ovidrel in
the USA and also known as
choriogonadotropin alfa) is a recombinant
hCG
Treatment of female infertility due to
anovulation
 It is used to trigger final follicle maturation
and luteinization after follicle stimulation.

54. Veterinary uses of gonadotrophins
 Treat subfertility in animals
 Horses and cattle
 FSH is administered to the animal such that multiple
follicles develop simultaneously
 After administration of LH to help promote ovulation,
the animal is mated, thus fertilizing the released egg
cells
 Embryos are recovered and maintained in cell culture
for a short period of time.
 Single embryo is then usually reimplanted into the
donor female, while the remaining embryos are
implanted into the surrogate mothers

55. e.g. prize winning horses, or high milk-yield
dairy cattle to boost their effective reproductive
capacity

56. Porcine FSH (p-FSH) and Porcine LH
(p-LH)
 p-FSH is extracted from the pituitary glands of
slaughterhouse pigs. The crude pituitary extract is
usually subject to a precipitation step, using either
ethanol or salts.
 The FSH-containing precipitate is normally subjected
to at least one subsequent chromatographic step.
 p-LH is obtained, again, by its partial purification from
the pituitary glands of slaughterhouse pigs.
 The final product often contains some LH and low
levels of additional pituitary derived proteins
 Target recipients are cattle or horses

57. Additional recombinant
hormones now approved
• Three additional recombinant
hormones have recently gained
marketing approval:
• Thyroid-stimulating hormone
• Parathyroid hormone
• Calcitonin.

58. Thyroid stimulating harmone
• Structurally, thyroid-stimulating hormone (TSH or
thyrotrophin) is classified as a member of the
gonadotrophin family, although functionally it
targets the thyroid gland as opposed to the
gonads.
• TSH is synthesized by a distinct pituitary cell type:
the thyrotroph. Its synthesis and release are
promoted by thyrotrophin-releasing hormone.
• TSH exerts its characteristic effects by binding
specific receptors found primarily, but not
exclusively, on the surface of thyroid gland cells.

59. Human parathyroid hormone
• Human parathyroid hormone (hPTH) is an 84
amino acid polypeptide that functions as a
primary regulator of calcium and phosphate
metabolism in bones. It stimulates bone
formation by osteoblasts, which display high-
affinity cell surface receptors for the hormone.
• PTH also increases intestinal absorption of
calcium.

60. Calcitonin
• Calcitonin is a polypeptide hormone that plays
a central role in regulating serum ionized
calcium (Ca2) and inorganic phosphate (Pi)
levels.
• The adult human body contains up to 2 kg of
calcium, of which 98 per cent is present in the
skeleton (i.e. bone). Up to 85 percent of the 1
kg of phosphorus present in the body is also
found in the skeleton.

61. • Calcitonin lowers serum Ca2 and Pi levels,
primarily by inhibiting the process of bone
resorption, but also by decreasing resorption
of Pi and Ca2 in the kidney.
• Calcitonin receptors are predictably found
primarily on bone cells (osteoclasts) and renal
cells.

62. • Calcitonin is used clinically to treat
hypercalcaemia associated with some forms of
malignancy and Paget’s disease. The latter
condition is a chronic disorder of the skeleton
in which bone grows abnormally in some
regions.

63. Conclusion
• Several hormone preparations have a long history of use as
therapeutic agents.
• Usually these are administered when the patients are not
producing enough quantities of endogenous hormones.
• Insulin has saved or prolonged the lives of millions of
diabetic patients.
• Gonadotrophins have allowed thousands of sub-fertile
individuals to conceive.
• GH has improved the quality of life of thousands of people
of short stature.
• Recombinant hormonal preparations, however, are now
gaining greater favour, mainly on safety grounds.

64. Questions ?
If any. Feel free to ask!