Pharmacology and clinical use of GnRh analogs in gynaecology

1. Nothing to disclose

2. GnRH Analogues in
Gynaecology
beyond fertility
Poonam Loomba, M.D.

3. Native Gnrh
 The structure of
Gonadotropin -
releasing hormone
(GnRH) was
discovered by
Guillemin and Schally
in 1967

4. Neurohormone
 GnRH is considered
a neurohormone
 A key area for production
of GNRH is the preoptic
area of the
hypothalamus, which
contains most of the
GnRH-secreting neurons.
 GnRH is found in organs
outside the
hypothalamus and
pituitary
e.g.Placenta,Gonads

5. GnRH Receptors
Breast Prostate
Ovary Endometrium

6. Action
 The portal blood carries the GnRH to
the pituitary gland, which contains
the gonadotropecells, where GnRH
activates its
own receptor, gonadotropin-releasing
hormone receptor (GnRHR).
 This results in the activation of
proteins involved in the synthesis
and secretion of the gonadotropins
LH and FSH. GnRH is degraded
by proteolysis within a few
minutes.Process is regulated by
GnRH pulses and estrogen
/androgen feedback
 Low-frequency GnRH pulses are
required for FSH release, whereas
high-frequency GnRH pulses
stimulate LH pulses in a one to one
manner.[3]

7. GnRH Analogues
 Development of
clinically safe agonist
was simple by
changing one or two
amino acids
 Required 30 years of
trial to develop
antagonist by
changing three or
more amino acids

8. GnRH agonists are derived from native GnRH by
substitution of a D-amino acid for the native L-amino
acid at position 6 in the decapeptide
Modifications mainly at positions 6 and 10 gave rise to
agonists with increased potency, extending the half life
from minutes to hours and raising the binding capacity
more than 100-fold
1 2 43 65 98 1
0
0
7
pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2
activation of
the
GnRH
receptor
regulatio
n
of GnRH
receptor
affinity
regulation of
biologic
activity

9. GnRHa switch off ovaries
temporarily

10. Mechanism of action
 Follicle-stimulating hormone and luteinizing
hormone (LH) secretion from the pituitary requires
a pulsatile secretion of GnRH from hypothalamus,
which allows receptor concentrations to be
replenished between pulses.
 A constant infusion of GnRH causes an initial
agonistic action or the “flare” response, followed
by downregulation of receptor concentrations,
which desensitizes the pituitary to continued
stimulation

11. Action of GnRH agonists
LH + FSH
post-receptor-cascade
GnRH - receptor
GnRH
GnRH - agonistflare up effect
Down
regulation
pituitary suppression

12.  The “flare” response is because of the release of the
gonadotropins which are already produced and stored in pituitary, and
indeed “flare” is greatest in the early follicular phase when GnRH and
estradiol have combined to create a large reserve pool of
gonadotropins.
 Within 3 to 4 weeks, it induces a hypogonadotropic - hypogonadal
state, a situation simulating WHO Group-1 anovulation
(hypogonadotropic hypogonadal anovulation
 Initially, this response is due to desensitization and downregulation
and the same is sustained because of gradual loss of receptors and
the uncoupling of the receptor from its effector system.
 In addition, postreceptor mechanisms lead to secretion of biologically
inactive gonadotropins, which may still be detected by immunoassay..

13. Action of GnRH antagonists
LH + FSH
post-receptor-cascade
GnRH - receptor
GnRH
GnRH - antagonistpituitary suppression

14. Mechanism of action GnRH
antagonist
 Competitive blockage of native GnRH receptors
and block their ability to initiate dimer formation
and signal transduction
 Cause immediate,rapid,reversible suppression of
gonadotropin secreation
 Since there is no receptor loss a constant supply
of antagonist is required to ensure that all
receptors are blocked
 Consequently, they produce an immediate decline
in gonadotropin levels and provide a therapeutic
effect within 24 to 72 hours

15. GnRH agonists preperations
• Agonists with 2 substitutions include:
• leuprolide (Lupron) 3.75mg 11.25mg 22.5mg
• buserelin (Suprefact)
• nafarelin (Synarel)
• histrelin (Supprelin )
• goserelin (Zoladex)
• deslorelin (Suprelorin)
• Triptorelin
• Available as daily injections,depot prep,nasal
sprays,implants(historelin)

16. Preparations of Gnrh
antagonists
 Third generation preparations
 Cetrorelix
 Ganirelix
 Ramorelix
 Antarelix
 Abarelix

17. Therapeutic Uses of Synthetic GnRH
Analogues
• Female and male infertility
• Diagnosis of LH responsiveness
• Endometriosis
• Uterine Fibroids
• Prostate Cancer
 Central Precocious Puberty
 use in sex reassignment of male to female transsexuals,
 management of final height in cases of congenital adrenal
hyperplasia,
 and preserving ovarian function in women undergoing cytotoxic
chemotherapy

18. Endometriosis

19. Endometriosis
Effective in relieving pain in women with endometriosis.
However, once the treatment is stopped, pain of lesser or
equal intensity may recur and the recurrence rate is at around
10 to 20% per year.
The overall cumulative recurrence rate 5 years after treatment
with a GnRH agonist is approximately 55%; it is around 37%
for women with minimal and mild endometriosis but double
the rate, i.e., 74%, for those with advanced disease.
Currently considered as second line therapy when ocp and
progesterones fail or are contraindicated

20. Fibroids

21. Submucous fibroids –grading :
 T0- whole in endometrial cavity
 T1 - >50% in endometrial cavity
 T2- < 50% in endometrial cavity

22. Fibroids
It has been shown that treatment with GnRH agonist
for a 3-month duration results in a 40% to 60%
decrease in the mean uterine volume.
The maximum reduction in uterine volume is usually
noted by the third month of treatment.

24. Premenstrual dysphoric disorder
Long-term treatment with Gnrh analogues was limited
because of hypoestrogenic side effects, loss of bone
mineral density, and cost.
With the advent of add-back therapy, there has been a
resurgence of interest in treating this condition with
GnRH agonists and as expected has been found to be
very useful in markedly alleviating the symptoms of
PMDD and PMS.

25. Abnormal uterine bleeding
 GnRH agonists
given for 8 wks have
been found to be
effective in producing
desired endometrial
thinning before
ablation

27. PRECOCIOUS PUBERTY
• Appearance of secondary sexual characteristics before the age of 8
years in girls and before the age of 9 years in boys
• The overall incidence has been estimated to be 1:5,000 to 1:10,000
children
• The female to male ratio is approximately 10:1
 A GnRH challenge test that demonstrates the pubertal response of
gonadotropin (i.e., LH response > FSH response) is the hallmark of
this diagnosis as is the usual ability to suppress pubertal development
with GnRH agonists
 This results from early maturation of the hypothalamic- pituitary-
gonadal axis
 Idiopathic precocious puberty seems to be the most common cause of
CPP

28. GnRH agonists in precocious puberty:
effects on stature growth
• Predicted height has been shown to improve with long-
term GnRH agonist therapy and the absence of treatment
is associated with reductions of these height predications
• Studies consistently demonstrate that girls presenting
under age six are able to subsequently achieve normal
adult height because of the GnRH agonist therapy

29. • Girls treated in childhood with GnRH a
have normal BMI, BMD, body composition,
and ovarian function in early adulthood
• There is no evidence that GnRH a
treatment predisposes to polycystic ovary
syndrome or menstrual irregularities later
after discontinuation of therapy

30. GONADAL PROTECTION
 Cellular apoptosis is prevented by direct
action of GnRH a on the gonads
 By suppression of HPO axis
 Decreased perfusion of ovaries
 Cause a higher spontaneous rate of
menses and ovulation
 Injections more effective than intranasal
route
 Should be administered during the entire
course of chemotherapy treatment

31. Sex assignment from male to female

32. Hirsutism
Along with reducing hirsutism, GnRH agonists also
decreases serum levels of gonadotropins, total
testosterone, free testosterone, and androstenedione.
Add-back therapy further decreases serum
testosterone levels and also reduces the hypoestrogenic
side effects of analogues
GnRH agonist therapy indicated in women with
ovarian hyperandrogenism who do not respond
adequately to oral contraceptive therapy with or
without use of an antiandrogen.

33. Miscellaneous USES
 Intractable chronic abdominal pain from
functional bowel disease
 Management of severe porphyria
 Combination of GH and GnRH-a have
been found to improve final adult height
in patients with CAH

34. Miscellaneous uses
GnRH agonists have been put to use in treatment of cancers
that are hormonally sensitive and where a hypogonadal state
decrease the chances of recurrence.
This includes the medical management of prostate cancer in
males and also patients with breast cancer.
GnRH agonists have also been found to offset the
hyperprolactinemia fashioned by microprolactinomas.
.[

35. Diagnostic usages
injection of native GnRH in human beings elicits an immediate
response that may be used to evaluate the status of hypothalamic-
pituitary-gonadal function in a variety of neuroendocrine conditions
associated with amenorrhea and infertility. This provocative test has
been used in an attempt to differentiate hypothalamic disorders from
primary pituitary deficiencies.[44–47] Some authorities have also
advocated the use of GnRH-a in diagnosis of endometriosis by what
is called as “therapeutic trial.”[48] This is based on the premise that
empiric medical treatment in patients with chronic pelvic pain and a
high probability of endometriosis often can avoid a diagnostic surgical
procedure.[49]

36. SIDE EFFECTS
 hot flashes, (80% women)
 decreased libido (especially because androgen
production is also suppressed along with
estrogen),arthralgia,myalgia
 breakthrough bleeding,
 vaginal dryness,(30 % women)
 irritability,
 fatigue, frontal headache, depression, changes in
skin texture, and bone mineral depletion.(after 6
months of therapy)

37. Standard GnRH agonist treatment regimens of 6
months cause significant bone loss in both the
trabecular and cortical bone which manifests typically
at lumbar spine and femoral neck, respectively.
The bone loss may even exceed 1% per month.
Once the treatment is discontinued, bone loss recovers
slowly, but may not be completely recovered in all
women.

38. ADD-BACK
Commonly employed "add back" regimens are as follows:
low-dose combined estrogen-progestin;
estrogen-only,
progestins alone;
bisphosphonates;
tibolone;
raloxifene.
Combined estrogen-progestin add-back treatment regimens protect
bone and have the added advantage of preventing hot flushes and
the development of genitourinary atrophy.

39. Is it a wonder drug?

40. Conclusion
 Ongoing research is needed to identify
more indications
 Antagonist with better tolerance need to be
explored
 Injudicious use is not advocated
 Clinicians should be made aware to
realise the drug’s full potential.
 When used appropraitely with full potential
it can be labelled as “wonder drug”