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Presented By: Dr. Manas Kr. Nath, PGT, Deptt. of
Pharmacology, SMCH.
Moderated By: Dr. Pinaki Chakravarty, Associate
Profe...
 Introduction.
 General Considerations.
 GnRH Agonists.
• Mechanism of Action.
• Pharmacokinetics.
• Pharmacodynamics.
...
 A gonadotropin releasing hormone analogue (GnRH
analogue), also known as a luteinizing hormone
releasing hormone agonist...
A gonadotropin-releasing hormone agonist
(GnRH agonist) is an analogue that activates
the GnRH receptor resulting in incr...
A gonadotropin-releasing hormone antagonist
(GnRH antagonist) is an analogue that blocks
the GnRH receptor resulting in a...
 Gonadotropin-releasing hormone is secreted by
neurons in the hypothalamus.
 It travels through the hypothalamic-pituita...
 This pulsatile secretion is governed by the feedback
mechanisms from androgens and estrogens.
 Low-frequency GnRH pulse...
17-11-2016Deptt. of Pharmacology, SMCH.
8
17-11-2016Deptt. of Pharmacology, SMCH.
9
 During the reproductive years, pulsatile GnRH
activity is crucial for successful reproductive
function , which is contro...
17-11-2016Deptt. of Pharmacology, SMCH.
11
 Various GnRH Agonists available for clinical use
are:
• Gonadorelin.
• Goserelin.
• Nafarelin.
• Triptorelin.
• Busereli...
GnRH agonists binds to specific G-protein
coupled receptors on the pituitary
gonadotrophs.
Prolonged activation of GnRH ...
 Gonadorelin can be administered intravenously or
subcutaneously.
 GnRH analogs can be administered subcutaneously,
intr...
 Pulsatile GnRH release is responsible for stimulating
LH and FSH production during the fetal and neonatal
period.
 From...
 In the menstrual cycle, highest amplitude of GnRH
pulses occur during the luteal phase and the highest
frequency occur l...
 During the first 7–10 days, an agonist effect results in
increased concentrations of gonadal hormones in
males and femal...
Gonadorelin is an acetate salt of synthetic
human GnRH.
Half life: Initial  2-10 min, Terminal 10-40
min.
Metabolized...
Half life: 2-4 hours.
Poorly bound to plasma protein.
Excreted through urine.
Contraindicated in cases of Pregnancy,
L...
 Adverse effects:
• Hot flushes.
• Vaginitis.
• Reduced libido, erectile & sexual dysfunction.
• Mood Swings.
• Depressio...
Highly protein bound.
Metabolized by peptidase to small peptides.
Excreted through urine (44%-55%) & feces
(19%-44%).
...
Adverse Effects:
• Acne.
• Hot flushes.
• Mood swings.
• Vaginal dryness.
• Decreased libido.
• Muscle pain.
• Aggravated...
Half life: 3 hours.
Not bound to plasma protein.
Excreted through urine.
Contraindicated in cases of females, children...
Half life: 1-1.5 hours.
Excreted mainly through urine.
Contraindicated in cases of hypersensitivity
reactions, undiagno...
Adverse effects:
• Hot flushes..
• Reduced libido, sexual dysfunction.
• Mood Swings.
• Depression.
• Oedema.
• Breast pa...
It is a nonapeptide synthetic analogue of
GnRH.
Half life: 4-5 hours.
highly bound to plasma protein.
Excreted through...
Adverse effects:
• Hot flushes
• Renal impairment (<2% cases).
• Headache.
• Decreased libido
• Erectile dysfunction.
17-...
It is a synthetic GnRH analogue which projects
on the WHO list of Essential Medicines.
Half life: 3 hours.
Moderately b...
 Adverse Effects:
• Hot flushes.
• Increased sweating, night sweats.
• GI upset.
• Headache.
• Breast swelling or tendern...
Female Infertility
• GnRH agonists can be used to initiate an LH surge and
ovulation in women with infertility who are un...
 Diagnosis of LH Responsiveness
• GnRH agonists can be useful in differentiating delayed
puberty in a hypogonadotropic ad...
Controlled Ovarian Hyperstimulation
• Suppression of endogenous LH surge to prevent
premature ovulation is done by GnRH a...
Prostrate Cancer
• A combination of anti-androgen therapy with GnRH
agonists like Leuprolide, Goserelin, Histrelin &
Trip...
Other Uses
• In breast and ovarian cancer.
• In DUB, before performing endometrial ablation,
thinning of the endometrial ...
17-11-2016Deptt. of Pharmacology, SMCH.
35
Various GnRH Antagonists available for
clinical use are:
• Ganirelix.
• Cetrorelix.
• Degarelix.
• Abarelix.
• Elagolix (...
 GnRH antagonists bind competitively and
reversibly with GnRH receptors on gonadotroph
cell membranes, inhibiting GnRH-in...
Half life: 12.8-16.2 hours.
Onset of Action: within 8 hours.
Highly protein bound.
Metabolized by the liver.
Excreted...
Adverse Effects:
• Pelvic pain.
• Ovarian Hyperstimulation Syndrome.
• Abdominal pain.
• Vaginal bleeding.
• Headache.
• ...
Half life: 20-63 hours.
Onset of Action: within 12 hours.
Highly protein bound.
Excreted through feces and urine.
Pea...
Adverse Effects:.
• Ovarian Hyperstimulation Syndrome.
• Headache.
• Nausea.
• Elevated hepatic enzymes.
Cetrorelix has ...
 Onset of Action: within 3 days.
 Highly protein bound.
 Metabolized by the liver.
 Excreted through feces (70%-80%) a...
 Suppression of Gonadotropin Production
• These agents prevent the LH surge during controlled
ovarian hyperstimulation in...
17-11-2016Deptt. of Pharmacology, SMCH.
44
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GnRH Agonists & Antagonists

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A concise ppt on GnRH analogues.

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GnRH Agonists & Antagonists

  1. 1. Presented By: Dr. Manas Kr. Nath, PGT, Deptt. of Pharmacology, SMCH. Moderated By: Dr. Pinaki Chakravarty, Associate Professor, Deptt. of Pharmacology, SMCH.
  2. 2.  Introduction.  General Considerations.  GnRH Agonists. • Mechanism of Action. • Pharmacokinetics. • Pharmacodynamics. • Individual Agents. • Clinical Uses.  GnRH Antagonists. • Mechanism of Action. • Individual Agents. • Clinical Uses. 17-11-2016 2 Deptt. of Pharmacology, SMCH.
  3. 3.  A gonadotropin releasing hormone analogue (GnRH analogue), also known as a luteinizing hormone releasing hormone agonist (LHRH agonist) or LHRH analogue is a synthetic peptide drug (a decapeptide) modeled after the human hypothalamic gonadotropin releasing hormone (GnRH).  A GnRH analogue interacts with the GnRH receptor and modify the release of pituitary gonadotropins - Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) for therapeutic purposes. 17-11-2016 3 Deptt. of Pharmacology, SMCH.
  4. 4. A gonadotropin-releasing hormone agonist (GnRH agonist) is an analogue that activates the GnRH receptor resulting in increased secretion of FSH and LH. These agents after their initial stimulating action eventually cause a paradoxical and sustained drop in gonadotropin secretion. This phase is reversible. 17-11-2016Deptt. of Pharmacology, SMCH. 4
  5. 5. A gonadotropin-releasing hormone antagonist (GnRH antagonist) is an analogue that blocks the GnRH receptor resulting in an immediate drop in gonadotropin (FSH, LH) secretion. This results in blockage of natural ovulation. 17-11-2016Deptt. of Pharmacology, SMCH. 5
  6. 6.  Gonadotropin-releasing hormone is secreted by neurons in the hypothalamus.  It travels through the hypothalamic-pituitary venous portal plexus to the anterior pituitary, where it binds to G protein-coupled receptors on the plasma membranes of gonadotroph cells.  Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to produce and release LH and FSH. 17-11-2016Deptt. of Pharmacology, SMCH. 6
  7. 7.  This pulsatile secretion is governed by the feedback mechanisms from androgens and estrogens.  Low-frequency GnRH pulses are required for FSH release, whereas high-frequency GnRH pulses stimulate LH pulses.  In males, GnRH is secreted in pulses at a constant frequency while in females, the frequency of the pulses varies during the menstrual cycle, with a large surge of GnRH just before ovulation.  Sustained non-pulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in both women and men, resulting in hypogonadism. 17-11-2016Deptt. of Pharmacology, SMCH. 7
  8. 8. 17-11-2016Deptt. of Pharmacology, SMCH. 8
  9. 9. 17-11-2016Deptt. of Pharmacology, SMCH. 9
  10. 10.  During the reproductive years, pulsatile GnRH activity is crucial for successful reproductive function , which is controlled by the feedback mechanism.  However, once pregnancy is established, GnRH activity is not required.  Pulsatile activity can be disrupted by hypothalamic-pituitary disease.  Increased levels of Prolactin decreases the GnRH activity while increase in Insulin levels increases its pulse activity. 17-11-2016Deptt. of Pharmacology, SMCH. 10
  11. 11. 17-11-2016Deptt. of Pharmacology, SMCH. 11
  12. 12.  Various GnRH Agonists available for clinical use are: • Gonadorelin. • Goserelin. • Nafarelin. • Triptorelin. • Buserelin. • Deslorelin (under trial). • Histrelin. • Leuprolide. 17-11-2016Deptt. of Pharmacology, SMCH. 12
  13. 13. GnRH agonists binds to specific G-protein coupled receptors on the pituitary gonadotrophs. Prolonged activation of GnRH receptors by GnRH agonists leads to desensitization and down regulation of GnRH receptors, thereby suppressing gonadotrophin (FSH & LH) secretion. 17-11-2016Deptt. of Pharmacology, SMCH. 13
  14. 14.  Gonadorelin can be administered intravenously or subcutaneously.  GnRH analogs can be administered subcutaneously, intramuscularly, via nasal spray (nafarelin), or as a subcutaneous implant.  The half-life of intravenous gonadorelin is 4 minutes, and the half-lives of subcutaneous and intranasal GnRH analogs are approximately 3 hours.  Duration of treatment depends on the clinical condition. 17-11-2016Deptt. of Pharmacology, SMCH. 14
  15. 15.  Pulsatile GnRH release is responsible for stimulating LH and FSH production during the fetal and neonatal period.  From the age of 2 years until the onset of puberty, GnRH secretion falls off and the pituitary gland exhibits very low sensitivity to GnRH.  Just before puberty, an increase in the frequency and amplitude of GnRH release occurs and then, in early puberty, pituitary sensitivity to GnRH increases, which is due in part to the effect of increasing concentrations of gonadal steroids. 17-11-2016Deptt. of Pharmacology, SMCH. 15
  16. 16.  In the menstrual cycle, highest amplitude of GnRH pulses occur during the luteal phase and the highest frequency occur late in the follicular phase.  Lower pulse frequencies favor FSH secretion, whereas higher pulse frequencies favor LH secretion.  Pulsatile intravenous administration of gonadorelin every 1–4 hours stimulates FSH and LH secretion.  Continuous administration of gonadorelin or its longer-acting analogs produces a biphasic response. 17-11-2016Deptt. of Pharmacology, SMCH. 16
  17. 17.  During the first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females (flare).  Continued presence of GnRH results in an inhibitory action which manifests as a drop in the concentration of gonadotropins and gonadal steroids.  This occurs due to a combination of receptor down- regulation and changes in the signaling pathways activated by GnRH. 17-11-2016Deptt. of Pharmacology, SMCH. 17
  18. 18. Gonadorelin is an acetate salt of synthetic human GnRH. Half life: Initial  2-10 min, Terminal 10-40 min. Metabolized to small peptides. Excreted via urine. Adverse Effects: • Thrombophlebitis. • Ovarian Hyperstimulation. 17-11-2016Deptt. of Pharmacology, SMCH. 18
  19. 19. Half life: 2-4 hours. Poorly bound to plasma protein. Excreted through urine. Contraindicated in cases of Pregnancy, Lactation & undiagnosed abnormal vaginal bleeding. 17-11-2016Deptt. of Pharmacology, SMCH. 19
  20. 20.  Adverse effects: • Hot flushes. • Vaginitis. • Reduced libido, erectile & sexual dysfunction. • Mood Swings. • Depression. • Sweating. • Acne. • Diarrhoea. • Breast Atrophy. • Peripheral Oedema. • UTI. • Bone pain. • Headache. 17-11-2016Deptt. of Pharmacology, SMCH. 20
  21. 21. Highly protein bound. Metabolized by peptidase to small peptides. Excreted through urine (44%-55%) & feces (19%-44%). Half life: 3 hours. Contraindicated in cases of Pregnancy, Lactation & undiagnosed abnormal vaginal bleeding. 17-11-2016Deptt. of Pharmacology, SMCH. 21
  22. 22. Adverse Effects: • Acne. • Hot flushes. • Mood swings. • Vaginal dryness. • Decreased libido. • Muscle pain. • Aggravated sinusitis. 17-11-2016Deptt. of Pharmacology, SMCH. 22
  23. 23. Half life: 3 hours. Not bound to plasma protein. Excreted through urine. Contraindicated in cases of females, children & hypersensitivity reactions. Adverse effects: • Hot flushes • Skeletal pain. 17-11-2016Deptt. of Pharmacology, SMCH. 23
  24. 24. Half life: 1-1.5 hours. Excreted mainly through urine. Contraindicated in cases of hypersensitivity reactions, undiagnosed abnormal vaginal bleeding, non-hormone dependent prostrate cancer. 17-11-2016Deptt. of Pharmacology, SMCH. 24
  25. 25. Adverse effects: • Hot flushes.. • Reduced libido, sexual dysfunction. • Mood Swings. • Depression. • Oedema. • Breast pain. • Headache. • Hirsuitism. • Myalgia. 17-11-2016Deptt. of Pharmacology, SMCH. 25
  26. 26. It is a nonapeptide synthetic analogue of GnRH. Half life: 4-5 hours. highly bound to plasma protein. Excreted through urine. Contraindicated in cases of Pregnancy, Lactation & Children. 17-11-2016Deptt. of Pharmacology, SMCH. 26
  27. 27. Adverse effects: • Hot flushes • Renal impairment (<2% cases). • Headache. • Decreased libido • Erectile dysfunction. 17-11-2016Deptt. of Pharmacology, SMCH. 27
  28. 28. It is a synthetic GnRH analogue which projects on the WHO list of Essential Medicines. Half life: 3 hours. Moderately bound to plasma protein. Metabolized to smaller inactive peptides. Excreted through urine. Contraindicated in cases of pregnancy, lactation, hypersensitivity conditions & undiagnosed abnormal vaginal bleeding and in children. 17-11-2016Deptt. of Pharmacology, SMCH. 28
  29. 29.  Adverse Effects: • Hot flushes. • Increased sweating, night sweats. • GI upset. • Headache. • Breast swelling or tenderness. • Joint/muscle aches. • Insomnia. • Decreased libido. • Vaginal itching/dryness/discharge/bleeding • Depression. 17-11-2016Deptt. of Pharmacology, SMCH. 29
  30. 30. Female Infertility • GnRH agonists can be used to initiate an LH surge and ovulation in women with infertility who are undergoing ovulation induction with gonadotropins. Male Infertility • These agents can be used to treat male infertility due to hypothalamic hypogonadotropic hypogonadism. At least 3–6 months of pulsatile infusions are required before significant numbers of sperm are observed. 17-11-2016Deptt. of Pharmacology, SMCH. 30
  31. 31.  Diagnosis of LH Responsiveness • GnRH agonists can be useful in differentiating delayed puberty in a hypogonadotropic adolescent is due to constitutional delay or hypogonadotropic hypogonadism. • LH response produced to a single dose of GnRH can distinguish between these two conditions.  Uterine Fibroids • Treatment for 3–6 months with a GnRH agonist reduces fibroid size and, when combined with supplemental iron, improves anemia. • Leuprolide, goserelin, and nafarelin are approved for this indication. 17-11-2016Deptt. of Pharmacology, SMCH. 31
  32. 32. Controlled Ovarian Hyperstimulation • Suppression of endogenous LH surge to prevent premature ovulation is done by GnRH agonists like Leuprolide, Nafarelin, etc., during controlled ovarian hyperstimulation in assisted reproductive techniques for obtaining multiple oocytes. Endometriosis • GnRH agonist induced ovarian suppression reduces the estrogen and progesterone concentration during menstrual cycle thereby abolishing pain of endometriosis. • 6 month therapy with agents like Leuprolide, Nafarelin & Goserelin are approved for this indication. 17-11-2016Deptt. of Pharmacology, SMCH. 32
  33. 33. Prostrate Cancer • A combination of anti-androgen therapy with GnRH agonists like Leuprolide, Goserelin, Histrelin & Triptorelin, and an androgen receptor antagonist is useful in reducing the serum testosterone levels and its effects. Central Precocious Puberty • Continuous treatment with a GnRH agonist is indicated for this condition. 17-11-2016Deptt. of Pharmacology, SMCH. 33
  34. 34. Other Uses • In breast and ovarian cancer. • In DUB, before performing endometrial ablation, thinning of the endometrial lining is achieved with GnRH agonists. • In treating amenorrhea and infertility in women suffering from PCOS. 17-11-2016Deptt. of Pharmacology, SMCH. 34
  35. 35. 17-11-2016Deptt. of Pharmacology, SMCH. 35
  36. 36. Various GnRH Antagonists available for clinical use are: • Ganirelix. • Cetrorelix. • Degarelix. • Abarelix. • Elagolix (under Phase III Clinical Trial). • Relugolix (TAK-385  under clinical trial). • KLH-2109 & ASP-1707 (under development). 17-11-2016Deptt. of Pharmacology, SMCH. 36
  37. 37.  GnRH antagonists bind competitively and reversibly with GnRH receptors on gonadotroph cell membranes, inhibiting GnRH-induced signal transduction and consequently gonadotrophin (FSH & LH) secretion.  In men, the reduction in LH subsequently leads to rapid suppression of testosterone release from the testes while in women it leads to suppression of estrogen release from the ovaries.  These agents have an immediate onset of action without any initial surge. 17-11-2016Deptt. of Pharmacology, SMCH. 37
  38. 38. Half life: 12.8-16.2 hours. Onset of Action: within 8 hours. Highly protein bound. Metabolized by the liver. Excreted through feces (75%) and urine (22%). Peak plasma concentration is attained within 1 hour. Contraindicated in Pregnancy, Lactation & Hypersensitivity responses. 17-11-2016Deptt. of Pharmacology, SMCH. 38
  39. 39. Adverse Effects: • Pelvic pain. • Ovarian Hyperstimulation Syndrome. • Abdominal pain. • Vaginal bleeding. • Headache. • Nausea. • Injection site reactions. 17-11-2016Deptt. of Pharmacology, SMCH. 39
  40. 40. Half life: 20-63 hours. Onset of Action: within 12 hours. Highly protein bound. Excreted through feces and urine. Peak plasma concentration is attained within 1- 1.5 hours. Contraindicated in Renal impairment, Pregnancy, Lactation & Hypersensitivity responses. 17-11-2016Deptt. of Pharmacology, SMCH. 40
  41. 41. Adverse Effects:. • Ovarian Hyperstimulation Syndrome. • Headache. • Nausea. • Elevated hepatic enzymes. Cetrorelix has been found to increase plasma HDL levels. 17-11-2016Deptt. of Pharmacology, SMCH. 41
  42. 42.  Onset of Action: within 3 days.  Highly protein bound.  Metabolized by the liver.  Excreted through feces (70%-80%) and urine (20%- 30%).  Contraindicated in Pregnancy.  Adverse Effects: • Hot flushes. • Injection site pain & reactions. • Weight gain. • Elevated liver enzymes. 17-11-2016Deptt. of Pharmacology, SMCH. 42
  43. 43.  Suppression of Gonadotropin Production • These agents prevent the LH surge during controlled ovarian hyperstimulation in assisted reproduction techniques. • Owing to their immediate onset of action as against GnRH agonists, they can be administered for a shorter duration and in reduced doses.  Advanced Prostate Cancer • GnRH antagonist reduces concentrations of gonadotropins and androgens more rapidly than GnRH agonists and avoids the testosterone surge seen with GnRH agonist therapy. 17-11-2016Deptt. of Pharmacology, SMCH. 43
  44. 44. 17-11-2016Deptt. of Pharmacology, SMCH. 44
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A concise ppt on GnRH analogues.

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