GnRH analogues and addback therapy

mechanism of action, effects, Their role in endometrfiosis, side effects, Addback therapy

1. GnRH Analogues
&
Addback Therapy

3. GnRHAgonist
Produced by Modification of the native
GnRHdecapeptideat 6 & 10 positions
Glp-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-
NH2 -LHRH
Glp-His-Trp-Ser-Tyr-Ser(But )-Leu-Arg-
Pro-Azgly-NH2 -Goserelin

4. HISTORY:
Discovered in 1971
Introduced for medical use in 1980s
Most widely used GnRH is leuprolide and
triptorelin.
Non proprietary names usually end in-relin.

5. 100 times more potent than natural LHRH
After initial agonistic action (flare response),
down-regulation & desensitization of the
pituitary: hypogonadotrophic, hypogonadal
state.
Mechanism

7. Within 12 h of administration:
Flare effect [lasting 24-48 h]
5 fold increase of FSH
10 fold rise in LH
4 fold elevation in E2.
Effects of GnRHAgonist

8. Continuous administration
Opposite effects: internalization of the agonist
/receptor complex & decrease in the number
of receptors (down-regulation).
paradoxical suppression of the pituitary Gnt
synthesis & liberation (desensitization).

10. The decreased levels of FSH & LH:
Arrest of follicular development
Decrease in sex steroid levels to castrate
levels.
Postmenopausal E2 levels are commonly
reached after 21 days.
The pituitary blockade persist during agonist
treatment but it is reversible after therapy.

11. LEUPROLIDE
Most commonly used GnRH agonist for
endometriosis
Two dosing options-11.25 mg once every 3 months
3.75mg
One in each month

12. Endometriosis.
Uterine fibroids.
Thinning agent in DUB (prior to
endometrial ablation).
Pituitary down-regulation (in long protocol
of IVF and induction of ovulation).
Adenomyiosis
Before & during chemotherapy for breast
cancer to preserve ovarian function
Indications

13. GnRHa
An appropriate therapy of Chronic pelvic pain,
even in the absence of laparoscopic
confirmation of Endometriosis.
Provided that a detailed evaluation fails to
demonstrate other cause.
(ACOG Recommendations Grade (B)
Endometriosis

14. GnRHawith Hormone Therapy addbackshould
be considered as 2nd line treatment
No response to CHCs or progestins
Recurrence of symptoms after initial
improvement
(SOGC, 2010)
Indications

16. GnRHa alone: Symptoms of estrogen deficiency
Hot flushes,
Insomnia,
Loss of libido,
Vaginal dryness,
Emotional instability, depression, headache
Loss of Bone Mineral Density, which is not
always reversible
Side Effects

17. Aim: To prevent demineralization of bone &
menopausal symptoms.
GnRhashould not be given as a single agent for
>6 months.
GnRHashould not be used for any length of
time in the absence of HT addback
(SOGC, 2010).
AddbackTherapy

18. There is a threshold serum estrogen
concentration that is
low enough that endometriosis is not
stimulated
high enough that hypoestrogenic symptoms
are prevented (Barbieri,1992)
same as that achieved with physiologic HT
for menopausal women
Add-back Rationale

21. GnRHa: Pain relief 85-100% persisting for 6-
12 months after cessation of treatment.
(Winkel et al,2005 )
GnRHa Vs other hormonal treatment: No
difference with respect to pain relief or
reduction in E deposits (Cochrane library,
2005).
Efficacy

22. Leuprolide
Buserelin
Nafarelin
Histerelin
Goserelin
Deslorelin
Triptorelin
(Available as daily injections, depot preps, nasal
sprays, implants)
GnRHAgonist Preparations

23. Hormonal treatment that aims to reduce the proliferation
of endometrial cells is promising, but there is a paucity of
well-designed studies to guide treatment.
There is a strong need to develop pharmacological agents
that provide an efficient outcome (Farquhar et al, 2006).

24. Commonly employed “add back” regimens
are-
Low dose combined estrogen and
progestrone
Estrogen only
Progestins alone
Bisphosphonates
Tibolone
Raloxifen
Add-Back

25. Synthetic steroid
Estrogenic, progetogenic and androgenic
action
Prevents loss of bone mineral density
Prevents vasomotor symptoms
Dose-2.5mg for 3-6months with GnRHa
Tibolone

26. Synthetic non steroidal drug as an add back
Afferent to SERM
Weak estrogenic action at CNS, CVS and
skeleton
Weak anti estrogenic at reproductive
sites(uterus and breast)
Raloxifen

27. Addback with GnRH agonist
Decreases bone resorption
Alendronate-5mg/day
Improves bone mineral density
Bisphosphonates

28. Combined estrogen and progestin add back
therapy protect the bone and prevents hot flushes
and vaginal atrophy

29. Ongoing research to identify other uses
Antagonists with better tolerance need to be
explored
Injudicious use is not advocated
Clinicians should be made full aware to
realise the drugs full potential
When used appropriately with full potential
it can be labelled as “wonder drug”.
Conclusion