gnrh analogues in treatment of fibroid
TRANSCRIPT
GnRH analogues in treatment of fibroidProf Aboubakr Elnashar
Benha university Hospital, Egypt
CONTENTS
1. INTRODUCTION
2.GNRHa
3.GNRHan
4.CONCLUSION
ABOUBAKR ELNASHAR
1. INTRODUCTION
Medical treatment for fibroid(Bartels et al, 2016)
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Medical strategies have been developed to
1. decrease fibroid size
2. decrease symptomatic bleeding
3. increase hematocrit in the period leading up to
surgery
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Surgery
Myomectomy or hysterectomy
Definitive treatment for symptomatic fibroids.
Fibroid size and location may make surgery
technically challenging.
Difficult-to-remove fibroids
prolong surgery
increase operative blood loss
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GnRHa are used in
1. ART
2. Endometriosis
3. Fibroid
4. Hirsutism
5. DUB
6. Premenstrual syndrome.
They were first investigated for fibroid treatment in
the 1980s.
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2. GnRH AGONISTS
One of the first medical therapies utilized for the
treatment of leiomyomas
In 1999:
FDA approved leuprolide acetate for short-term use
as a preoperative adjunct in women with symptomatic
leiomyomas
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Structure:
Native GnRH:
Decapeptide
released from the hypothalamus in a pulsatile
fashion.
GnRHa:
Synthetic peptides structurally analogous to the
natural GnRH decapeptide.
Through the alteration of the amino acids at the 6
or 10 positions
longer half-lives
greater receptor affinity
greater potency
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Types of GnRHa
PriceCompanyDoseRouteNamePreparation
750
1550
540
Abbott3.75 mg/4w
11.25 mg/12 w
2.8 ml, 1 ml daily
IM, SC
IM, SCLupron
Lucrin
Leuprorelin
500Astrazenica3.6 mgSC ZoladexGoserelin
605
266(7syr)
FerringCR: 3.75mg,
0.1mg then 0.05 mg
IM, SCDecapeptylTriptolerin
Sanofi0.5 mg then 0.2 mgNasal, SCsuperfactBuserelin
Pfaizer0.2 mg bidnasalSynarelNafarelin
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Mechanism of Action:
1. GnRH bound to GnRH receptors
initially stimulates: gonadotropin secretion.
desensitization profoundly downregulates
gonadotropin release:
hormone levels similar to those seen after
castration.
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2. GnRHa may have direct effects on leiomyomas by
Increasing matrix metalloproteinase (MMP) production, and decreasing the expression of veriscan, a
chondroitin sulfate proteoglycan that is an important
structure in the extracellular matrix (ECM), influencing
tumor growth and proliferation
Presence of GnRH receptor mRNA as well as
GnRH-specific binding sites within leiomyoma cells
Tumor shrinkage may be directly proportional to
the number of estrogen receptor (ER) positive cells
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When GnRHa are administered in the follicular phase:
An initial stimulation of
FSH and LH release=flare effect.
With continuous (as opposed to pulsatile)
administration
down-regulation of pituitary GnRH receptors
decrease in the production of FSH and LH
and subsequently of gonadal steroids
hypoestrogenic state
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Efficacy:
Within the first 3-6 months of treatment
most women
30-65% reduction in fibroid volume
significant improvement of their symptoms
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Evidence:
1. Cochrane SR , 2001
Significant improvement
preoperative and postoperative hemoglobin
pelvic symptoms
Significant decrease
operative time
hospital stay
uterine volume
fibroid volume
A greater number of surgeries were able to be
performed vaginally.
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2. Before Laparoscopic myomectomy
more beneficial in large myomas (>10 cm)
reduce
operative time
intraoperative bleeding and risk of blood
transfusion
3. Before hysteroscopic myomectomy
useful in (G0-G1)
decrease
operative times
fluid absorption
difficulty
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Disadvantages/Side Effects:
1. The hypoestrogenic state
most common
major limitation for long-term usehot flushes (80%)
mood changes, insomnia, depression, fatigue
vaginal dryness, urogenital atrophy
decreased libido, arthralgia, decreased skin elasticity
breakthrough bleeding.
over the long term: decrease BMD
at a rate of about 6% lost annually.
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2. Changes within the leiomyoma
Degeneration and obliteration of the cleavage
plane between the myoma and pseudocapsule:
1. Enucleation of fibroids difficult
2. Myxoid changes: very small leiomyomas
become too soft: difficult to visualize:± missed
3. In 2% of cases: fibroid degeneration:
significant vaginal hemorrhage.
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3. Relatively high cost of therapy
4. Rapid regrowth of leiomyomas after the cessation
of treatment
leiomyomas typically grow within 3 months
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Add-back therapy
To
1. counteract the loss of BMD
2. offset some of the hypoestrogenic symptoms
Progestins, estrogen and progestin combinations,
tibolone,and raloxifene.
Cochrane SR, 2013
Progestins, estrogen, and tibolone:
reduce the effect of GnRh analogues on
fibroid volume.
Raloxifene
decreases bone density loss
ineffective in mitigating hot flashes.
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Tibolone
a synthetic steroid
weak estrogenic and progestogen activity
does not interfere with symptom improvement
equivalent efficacy in reduction of leiomyoma size
and leiomyoma-related symptoms
2.5 mg, in combination with the GnRHa (goserelin
3.6 mg SC implants monthly), for 3 or 6 months
better preservation of BMD
2% loss in spinal BMD vs 5.5% loss in placebo
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Duration of GnRHa:
at least 3 months prior to surgery
short-term use of 6 months.
{risk of prolonged therapy}
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Limitation:
1. The significant side effects
2. Cost
3. limited durability of response
fibroids regrow within 3 to 4 months after treatment
discontinuation.
4. Bone loss recovers slowly, but may not be
completely recovered in all women
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Indication:
1. should not be used routinely
select preoperative population.
High priority on
type of surgery
Incision
duration of recovery
1. Transverse rather than a vertical
incision
2. laparoscopic rather than abdominal
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2. GnRHa may bridge women to menopause in attempts
to avoid surgery.
depot leuprolide acetate (11.25 mg/90 days) for at
least 6 months as an alternative to surgery in
premenopausal women greater than 45 years old.
similar efficacy between single and repeated dose
reduction in symptoms reported by 88%
no significant differences in self reported sexual
function (Perrone et al.,2014]
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GnRH Antagonists
Structure:First and second generation GnRHan
available for over 25 years, but their use was greatly
limited
{severe side effect profile: histamine release and allergic
reactions}.
Third generation GnRHan
an improved side effect profile: use in the
treatment of women with symptomatic leiomyomas
The antagonistic properties are created by
substituting one amino acid at either the 1, 2, 3, 6 or 8
positions in the original decapeptide GnRH:
GnRHan to compete with endogenous GnRH for
pituitary binding sites. ABOUBAKR ELNASHAR
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PriceCompanyRouteTrade Generic
2500.25 mg
3 mg
SeronoSCCetrotideCetrorelix
192
0.25 mgMSD
MSD
SCGanirelix
Orgalutran
Ganirelix
Types of GnRhan
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Mechanism of action:
GnRHan act immediately to suppress FSH and LH
secretion by competitive blockage of pituitary GnRH
receptors:
reduction in E2:
improvement in bleeding patterns
reduction in leiomyoma size as early as 3
weeks after initiation of treatment
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Antagonist Vs agonist
1. Avoids the initial gonadotropin flare caused by
GnRHa
2. Faster clinical effect, generally within 2 weeks.
3. Similar amounts of fibroid shrinkage
4. Faster symptom relief
5. In women experiencing hypoestrogenic
symptoms, discontinuation of the medication
provides rapid improvement of side effects
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Evidence:
daily administration of ganirelix 2 mg:
42.7% reduction of leiomyoma volume
46.6% reduction of uterine volume over a median
treatment duration of 19 days (Sankaran,andManyonda, 2008)
31% decrease in fibroid volume after 14 days[Taylor et al, 2015].
RCT: cetrorelix, given 4 weeks before surgical
treatment:
significant reduction in tumor volume of 42.3%,
compared with the placebo reduction of 11.1% (Engel et al, 2007)
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Limitations:
1. Available evidence is limited to observational
studies: in the United States, cetrorelix and ganirelix
are rarely utilized in the treatment of fibroids
2. Cost GnRHan is prohibitive, ranging from 15 to 25
thousand dollars per month
3. Daily injections is another major limitation, since
there are no available long acting preparations (Sabry and Al-Hendy,2012)
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Clinicians should generally not use these medications
for the symptomatic treatment of uterine leiomyomas.
1. no significant additional benefits of GnRHan when
compared to GnRHa
2. evidence supporting their use is limited
3. Long-acting GnRHan are unavailable in US in the
correct dosage for fibroids.[De Leo, et al., 2002]
GnRHan started to replace GnRHa in some countries
1. Avoidance of an initial flare effect
2. More rapid onset of action(Bartels et al, 2016)
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CONCLUSIONS
GnRHa
efficacious in the management of AUB secondary to leiomyomas pre-operatively
Perimenopausal women who wish to defer surgical
management.
FDA approved for preoperative management
They are limited by their side effect profile
Cost
The 6-month limit on treatment duration
Add-back therapy may be considered in women with a good response
to lengthen the treatment time
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GnRHan
an alternative
with faster onset
similar effects.
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