GnRH analogues and Therapeutics by Dr. Swaroopa

1. Dr. Swaroopa, 2nd year PG,
Department of Pharmacology,
Rangaraya Medical College.
Date: 19-10-2021. 1

2. PREVIOUSLY ASKED QUESTIONS IN UNIVERSITY EXAMS
1. GnRH Antagonists
2. GnRH Agonists and their uses
3. Goserelin
4. Leuprolide
5. Therapeutic uses of GnRH.
2

3. CONTENTS
3
1. INTRODUCTION
2. GONADOTROPINS
3. GONADOTOPIN RELEASING HORMONE
4. GnRH AGONITS
5. GnRH ANTAGONITS
6. ADDBACK THERAPY
7. CONCLUSION
8. REFERENCES.

4. • Gonadotropin-releasing hormone (GnRH) or luteinizing hormone releasing
hormone (LHRH) is a central regulator of the reproductive system in
humans.
• Is a decapeptide.
• Gonadorelin is the synthetic form
• Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus
in a pulsatile fashion, stimulating gonadotrophic cells of the anterior
pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating
hormone (FSH).
• GnRH and its analogues interacts with the GnRH receptor and modify the
release of pituitary gonadotropins.
INTRODUCTION
4

5. HYPOTHALAMUS
GnRH
ANTERIOR PITUITARY
FSH LH
OVARY
OESTROGEN PROGESTERONE
GnRHR
GS/ Gq
IN WOMEN
5

6. HYPOTHALAMUS
ANTERIOR PITUITARY
GnRH
FSH ICSH/LH
TESTIS Interstitial
cells
Sertoli
cells
TESTOSTERONE
Gametogenesis in
the seminiferous
tubule.
GnRHR
(Gs/ Gq)
IN MEN
6

7. GONADOTROPINS
• Gonadotrophins (FSH, LH and HCG) are glycoproteins produced and
secreted by the anterior pituitary (FSH and LH) or chorion and placenta
(HCG).
• The gonadotropins are used for both diagnosis and therapy in reproductive
endocrinology.
• The gonadotropins consecutively act on the gonads to trigger the
gametogenesis, and ultimately the synthesis and release of steroidal sex
hormones in both male and female.
7

8. MENOTROPINS :-
• Also known as Human Menopausal Gonadotropins.
• First commercial purified extract of FSH and LH.
• Was extracted from the urine of post-menopausal women.
• These preparations were used for the stimulation of development of follicles
in women..
8
FOLLICLE-STIMULATING HORMONE :-
• 3 Purified forms of FSH are available
Urofollitropin
follitropin alfa
follitropin beta
2 recombinant forms
• Shorter half-life.
• Stimulate oestrogen more efficiently.
• Little protein contamination.

9. 9
LUTEINIZING HORMONE :-
• Lutropin alfa – 1st and only recombinant form of Human LH.
• Given subcutaneously
• Half-life 10 hrs
Uses :- used in combination with follitropin alfa for stimulation of
follicular development in infertile hypogonadotropic hypogonadal
women with profound LH deficiency (<1.2 IU/L)
HUMAN CHORIONIC GONADOTROPIN :-
• produced by human placenta, extracted and purified from urine.
• Choriogonadotropin alfa (rhCG) is a recombinant form .
• Can be administered by subcutaneous or intramuscular injection.

10. 10
GnRH AGONISTS &
ANTAGONISTS

11. 11
GnRH AGONISTS
• GOSERELIN
• LEUPROLINE
• NAFARELIN
• BUSERELIN
• HISTRELIN
• DESLORELIN
• TRIPTORELIN
GnRH ANTAGONISTS
• GANIRELIX
• CETRORELIX
• DEGARELIX
• ABARELIX
• ELAGOLIX
• RELUGOLIX

12. 12
HYPOTHALAMUS
GnRH
ANTERIOR PITUITARY
FSH LH
OVARY
GnRH
R
GnRH agonists
pulsatile
continuous
GnRH Antagonists
Inhibin
OESTROGEN
• Clomiphene
• Cyclofenil
Danazol

13. 13
GnRH AGONISTS
Modes of administration :-
 Subcutaneous – infusion in pulses
 Nasal
Continuous use :-
 Nasal spray
 As depot preparations
Stimulates Gn release transiently
then inhibits the release because of
down regulation or desensitization of
GnRH receptors in the pituitary.
Therefore, continuous, non-pulsatile administration inhibits
spermatogenesis & ovulation.

14. 14
GOSERELIN
• Zoladex is the trade name for Goserelin
Uses:-
• Prostate cancer
• Breast cancer
• Also used to treat endometriosis (non-
cancerous condition)
• endometrial-thinning agent prior to
endometrial ablation for dysfunctional
uterine bleeding.
• Goserelin is classified as a luteinizing hormone releasing hormone (LHRH)
agonist.
Goserelin Is Given:
• formulated as a subcutaneous
implant (3.6 mg/ month; 10.8
mg/12 weeks).

15. 15
• In treatment of prostate cancer GnRH agonists are often used together with anti-
androgen medications.
• Anti-androgens are substances that block the effects of testosterone.
• Cancer of the prostate depends on the male hormone testosterone for its growth.
If the amount of testosterone is reduced it is possible to slow down or shrink the
cancer.
• Examples of anti-androgens are: Bicalutamide, Flutamide, Nilutamide.

16. 16
Side effects
• Hot flashes
• Loss of interest in sex (decreased libido)
• Inability to obtain or sustain an erection (impotence)
• Increased bone pain due to disease "flare" during first couple weeks of treatment
• Headache
• Vaginal dryness
• Swelling of the breasts (gynecomastia)
• Depression
• Sleepiness
• Skin rash

17. 17
• Goserelin may cause short-term (within first 2 weeks of treatment) increases
in testosterone serum levels. When this is used for prostate cancer the
resulting "tumor flare" can cause temporary increase of bone pain, swelling of
the prostate that blocks urine flow or swelling around tumor in the spine
causing compression of the spinal cord.
• Rare but significant side effects may include heart problems such as
arrhythmias, congestive heart failure or heart attack (<5%).
Side effects

18. 18
• Weakness, numbness or tingling in arms or legs
• Extreme fatigue (unable to carry on self-care
activities)
• Swelling of the feet or ankles. Sudden weight gain.
• Changes in mood or memory
Side effects

19. 19
Precautions:
 Before starting Goserelin treatment, make sure you tell your doctor about any other
medications you are taking (including prescription, over-the-counter, vitamins, herbal
remedies, etc.).
 Do not take aspirin, products containing aspirin unless your doctor specifically permits
this.
Contraindication:-
 Pregnancy category X (Goserelin may cause fetal harm when given to a pregnant woman.
 This drug must not be given to a pregnant woman or a woman who intends to become
pregnant.
 If a woman becomes pregnant while taking Goserelin, the medication must be stopped
immediately and the woman given appropriate counselling).
 Do not breast feed while taking this medication.

20. 20
LEUPROLIDE / LEUPRORELIN
Leuprolide is a peptide-based GnRH receptor super
agonist used for the palliative treatment of prostate cancer,
uterine leiomyomata, endometriosis, and central
precocious puberty.

21. 21
Leuprolide is formulated in multiple doses for injection:
• subcutaneous (1 mg/d),
• subcutaneous depot (7.5 mg/month; 22.5 mg/3 months; 30 mg/4 months;
45 mg/6 months), and
• Intramuscular depot (3.75 mg/month; 11.25 mg/3 months).
• It is approved for endometriosis, uterine fibroids, advanced prostate
cancer, and precocious puberty.
• For endometriosis, leuprolide once-monthly injections (3.75 mg) or 3-
month injections (11.25 mg) are co packaged in combination with once-
daily norethindrone (a steroidal progestin) 5-mg tablets for oral
administration.
• Paediatric formulations of leuprolide also are approved for central
precocious puberty

22. 22
Mechanism of action :-
• This GnRH agonist is a naturally occurring decapeptide that modulates the
hypothalamic-pituitary-gonadal (HPG) axis.
• GnRH binds to corresponding receptors (GnRHRs) on the anterior pituitary
gonadotropes, which in turn release (LH) and (FSH); these, in turn, affect
the downstream synthesis and release of the sex hormones testosterone,
dihydrotestosterone, estrone, and estradiol.

23. 23
Absorption:-
• Leuprolide is typically administered as a single-dose long-
acting formulation employing either microsphere or
biodegradable solid depot technologies.
• Regardless of the initial dose strength, the Cmax is typically
achieved by 4-5 hours post-injection
Route of elimination :- through urine

24. 24
• Leuprolide is indicated for the palliative treatment of advanced prostate
cancer as well as for the treatment of pediatric patients with central
precocious puberty (CPP).
• Leuprolide mesylate, as an injectable emulsion, is indicated for the
treatment of adult patients with advanced prostate cancer.
• In combination with oral NORETHISTERONE (also known as
Norethindrone), leuprolide is also indicated for the initial treatment of the
symptoms of endometriosis.
• In combination with iron supplementation, leuprolide is indicated for the
preoperative hematological improvement of anemic patients with uterine
leiomyomata (uterine fibroids)
Indications :-

25. 25
• women undergoing treatment for endometriosis or uterine leiomyomata, the
initial increase in estradiol levels may worsen symptoms such as pain and
bleeding.
• Long-term use of leuprolide is associated with loss of bone mineral density.
• Patients co-administered with norethisterone may experience sudden vision loss,
proptosis, diplopia, migraine, thrombophlebitis, and pulmonary embolism and
may also be at higher risk of cardiovascular disease.
• Patients with a history of depression may experience severe recurrence of
depressive symptoms.
Side effects:-

26. 26
• In men undergoing palliative treatment for advanced/metastatic prostate
cancer, short-term spikes in testosterone levels may cause tumour flare and
associated symptoms such as bone pain, hematuria, neuropathy, bladder
and/or ureteral obstruction, and spinal cord compression.
• In addition, patients are at increased risk of developing hyperglycaemia,
diabetes, and cardiovascular disease, which may manifest through
myocardial infarction, stroke, cardiac death, or prolonged QT/Q Tc interval.
• Leuprolide may cause convulsions and embryo-fetal toxicity.
Side effects:-

27. 27
In pediatric patients undergoing treatment for central precocious puberty
(CPP), the initial steroidal spike may be associated with increased
clinical signs of puberty within 2-4 weeks of treatment initiation.
In addition, leuprolide may cause convulsions and psychiatric
symptoms, including irritability, impatience, aggression, anger, and
crying.
Side effects:-

28. 28
Acetaminophen Leuprolide may decrease the excretion rate of Acetaminophen
Abacavir,
Amoxicillin,
Ampicillin
Leuprolide may decrease the excretion rate of these drugs
Acarbose The therapeutic efficacy of Acarbose can be decreased when
used in combination with Leuprolide
Aceclofenac,
Acetylsalicylic acid,
Aclidinium
These drugs may decrease the excretion rate of Leuprolide
Acetazolamide Acetazolamide may increase the excretion rate of Leuprolide
which could result in a lower serum level and potentially a
reduction in efficacy.
Amitriptyline,
Amoxapine
The risk or severity of QTc prolongation can be increased
when Leuprolide is combined with these drugs.
Acipimox,
Amphotericin B
The risk or severity of myopathy, rhabdomyolysis, and
myoglobinuria can be increased when Leuprolide is combined
with these drugs
Drug interactions

29. 29
Histrelin :-
• Histrelin is formulated as a subcutaneous implant (50 mg/ 12 months).
• It is approved for central precocious puberty and advanced prostate cancer.
Nafarelin :-
• Nafarelin is formulated as a nasal spray (200 μg/spray).
• It is approved for endometriosis (400 μg/d) and central precocious puberty
(1600 μg/d).

30. 30
Triptorelin :-
• Triptorelin is formulated for depot intramuscular injection (3.75 mg/month;
11.25 mg/12 weeks, 22.5 mg/24 weeks) and approved for advanced
prostate cancer.

31. 31
Clinical uses of GnRH Agonists :-
 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.

32. 32
 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
will improves anaemia.
• Leuprolide, Goserelin and Nafarelin are approved for
this indication.

33. 33
 Controlled Ovarian Hyper stimulation :-
Suppression of endogenous LH surge to prevent premature
ovulation is done by GnRH agonists like Leuprolide, Nafarelin,
during controlled ovarian hyper stimulation in assisted
reproductive techniques for obtaining multiple oocytes.
Endometriosis :-
• GnRH agonist induced ovarian suppression reduces the
oestrogen 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.

34. 34
 Prostate cancer :-
A combination of anti-androgen therapy with GnRH agonists like
Leuprolide, Goserelin, Histrelin & Triptorelin and an analogue 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.
 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 amenorrhoea and infertility in women suffering from PCOS.

35. 35
GnRH ANTAGONISTS
 GnRH antagonists bind competitively and reversibly with GnRH receptors
inhibiting GnRH signal transduction and consequently FSH & LH secretion.
 In men, LH/ICSH reduction leads to rapid suppression of testosterone release
from testis while in women it leads to suppression of oestrogen release from the
ovaries.
 These agents have an immediate onset of action without any initial surge.

36. 36
Ganirelix and Cetrorelix :-
 Ganirelix acetate and Cetrorelix acetate are FDA-approved to suppress the LH
surge and thus prevent premature ovulation in ovarian-stimulation protocols as
part of assisted reproduction technology.
 Both GnRH antagonists are formulated for subcutaneous administration.
 Bioavailability exceeds 90% within 1–2 h, and the t 1/2 varies depending on
the dose.
 Once-daily administration is enough for therapeutic effect

37. 37
 Hypersensitivity reactions, including anaphylaxis, have been noted in post
marketing surveillance with the initial dose.
 When used in conjunction with gonadotropin injections for assisted reproduction,
the effects of estrogen withdrawal (e.g., hot flashes) are not seen.
 GnRH antagonists are contraindicated in pregnant women.
 Cetrorelix is also used off label for endometriosis and uterine fibroids, both of
which are estrogen dependent.

38. 38
Adverse Effects:-
• Pelvic pain
• Ovarian Hyper stimulation syndrome
• Abdominal pain
• Vaginal bleeding
• Headache
• Nausea
• Injection site reaction

39. 39
Degarelix :-
• Degarelix acetate is FDA-approved for treatment of advanced prostate cancer.
• It suppresses testosterone levels to 50 ng/dL or less (i.e., medical castration)
and lowers prostate-specific antigen more rapidly than GnRH agonists without
an initial testosterone surge.

40. 40
ADME:-
• Degarelix forms a depot gel at the site of injection and, as a consequence, is
released in a biphasic pattern with a median plasma t ½ of 42 days for the
starting dose and 28 days for the maintenance dose.
• Degarelix is distributed throughout total body water, is 90% protein bound,
and is degraded by proteolysis via the hepatobiliary system;
• Degraded protein fragments are eliminated in the feces, and unmetabolized
drug is eliminated via the kidneys.

41. 41
Dosage and Route of Administration :-
• Degarelix is administered subcutaneously in the abdomen, with the site of
injection varied on a regular basis.
• The starting dose is 240 mg administered as two injections of 120 mg on
each side of the abdomen, followed by a maintenance dose of 80 mg every
28 days.
Adverse Effects:-
• Adverse effects include injection site reactions, hot flashes, weight gain,
increases in transaminase and γ-glutamyl transaminase levels, prolonged
QT interval, and decreased bone mineral density.

42. 42
Clinical uses of GnRH Antagonists :-
 Suppression of Gonadotropin Production :-
• These agents prevent the LH surge during controlled ovarian hyper
stimulation 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.

43. 43
Add back therapy:-
Aim : to prevent demineralization of bone & menopausal
symptoms.
GnRHa should not be given as a single agent for >6 months and
should not be used for any length of time in the absence of HT
addback.
Allows the treatment of women with relapse of endometriosis-associated pain for
a longer period, with reduced bone mineral density loss, good control of pain
symptoms & better patient quality of life compared with GnRH analogue alone
or oral contraceptive.

44. 44
Add back Rationale :-
There is a threshold serum oestrogen concentration
that is
Low enough, that endometriosis
is not stimulated
High enough that hypo oestrogenic
symptoms are prevented.
* Same as that achieved with physiologic HT for
menopausal women

45. 45
Commonly employed “add back” regimens are
 Low dose combined oestrogen and progesterone
 Oestrogen only
 Progestin alone
 Bisphosphonates
 Tibolone
 Raloxifen
Combined oestrogen and progestin
addback therapy protect the bone and
prevents hot flushes and vaginal atrophy.

46. 46
BISPHOSPHONATES
• Addback with GnRH
agonist
• Decreases bone
resorption
• Alendronate- 5mg/day
• Improves bone mineral
density.
TIBOLONE
• Synthetic steroid
• Oestrogenic,
progestogenic &
androgenic action
• Prevents loss of bone
mineral density
• Prevents vasomotor
symptoms.
• Dose- 2.5 mg for 3-6
months with GnRHa.
RALOXIFEN
• Synthetic non-steroidal
drug as an addback
• Afferent to SERM
• Weak oestrogenic
action at CNS, CVS &
skeletal system.
• Weak anti oestrogenic
at reproductive sites
(uterus and breast)

47. 47
CONCLUSION
• Hypothalamic hormones can be used as diagnostics to determine the
causes of underlying endocrine pathology .
• GnRH antagonists with better tolerance need to be explored. Injudicious
use is not advocated.
• Future directions in hypothalamic and pituitary gland pharmacology will
include design of new drug delivery systems; synthesis of orally active,
non-peptide analogues of hormones; and investigations to better
understand hormone receptor mechanisms and signaling to assist in the
design of new pharmacotherapies.

48. 48
REFERENCES
• Goodman & Gilman's The pharmacological basis of Therapeutics 13th
edition, chapter 42, Hormones and Hormonal Antagonists, page no 780-
781.
• Bertram G. Katzung, Basic & Clinical Pharmacology, chapter 37,
Hypothalamic & pituitary Hormones, page no. 676 – 679.
• Rang & Dales pharmacology 8th edition, section 35, Reproductive system,
page no. 432-433.
• David E.Golan, Principles Of Pharmacology, 4th edition, chapter 27,
Pharmacology of Hypothalamus and Pituitary gland, page no 506-507.

49. 49