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Presented By: Dr. Manas Kr. Nath, PGT, Deptt.

of
Pharmacology, SMCH.
Moderated By: Dr. Pinaki Chakravarty, Associate
Professor, Deptt. of Pharmacology, SMCH.
 Introduction.
 General
Considerations.
 GnRH Agonists.
• Mechanism of Action.
• Pharmacokinetics.
• Pharmacodynamics.
• Individual Agents.
• Clinical Uses.
 GnRH Antagonists.
• Mechanism of Action.
• Individual Agents.
• Clinical Uses.
Deptt. of Pharmacology, SMCH. 17-11-2016
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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.
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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.

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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.

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 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.

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 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.
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 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.
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 Various GnRH Agonists available for clinical use
are:
• Gonadorelin.
• Goserelin.
• Nafarelin.
• Triptorelin.
• Buserelin.
• Deslorelin (under trial).
• Histrelin.
• Leuprolide.
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 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.
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 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.
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 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.
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 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.

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 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.

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 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.

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 Half life: 2-4 hours.
 Poorly bound to plasma protein.
 Excreted through urine.
 Contraindicated in cases of Pregnancy,
Lactation & undiagnosed abnormal vaginal
bleeding.

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 Adverse effects:
• Hot flushes.
• Vaginitis.
• Reduced libido, erectile & sexual dysfunction.
• Mood Swings.
• Depression.
• Sweating.
• Acne.
• Diarrhoea.
• Breast Atrophy.
• Peripheral Oedema.
• UTI.
• Bone pain.
• Headache.
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 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.
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 Adverse Effects:
• Acne.
• Hot flushes.
• Mood swings.
• Vaginal dryness.
• Decreased libido.
• Muscle pain.
• Aggravated sinusitis.

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 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.

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 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.

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 Adverse effects:
• Hot flushes..
• Reduced libido, sexual dysfunction.
• Mood Swings.
• Depression.
• Oedema.
• Breast pain.
• Headache.
• Hirsuitism.
• Myalgia.

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 Itis 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.

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 Adverse effects:
• Hot flushes
• Renal impairment (<2% cases).
• Headache.
• Decreased libido
• Erectile dysfunction.

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 Itis 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.
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 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.
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 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.

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 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.
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 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.
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 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.

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 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.

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 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).
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 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.
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 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.
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 Adverse Effects:
• Pelvic pain.
• Ovarian Hyperstimulation Syndrome.
• Abdominal pain.
• Vaginal bleeding.
• Headache.
• Nausea.
• Injection site reactions.

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 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.
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Adverse Effects:.
• Ovarian Hyperstimulation Syndrome.
• Headache.
• Nausea.
• Elevated hepatic enzymes.

 Cetrorelix
has been found to increase
plasma HDL levels.

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 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.
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 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.
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