PKB HIFERI FERITIM

TERAPI HORMONAL PADA

NYERI ENDOMETRIOSIS

DR DR PINDA HUTAJULU SPOG K FER

RSB NABASA /RS DR SUDARSO
PONTIANAK
 Endometriosis merupakan adanya jaringan mirip endometrium di luar uterus
yang disebabkan reaksi peradangan kronis yang sering pada wanita usia
reproduksi dari berbagi etnis dan strata sosial
Gangguan molekuler pada
endometriosis (Bulun 2000).
Mechanism of pain in endometriosis

Beberapa mekanisme terjadinya nyeri : nociseptif, inflamasi, neuropati,

psikogenik atau campuran.
Nyeri nociceptive (somatic atau visceral) dimulai dengan adanya
stimulus yang menginduksi jalur ditransduksi menjadi sinyal
biokimiawi ditransmisikan ke SSP terjadi modulasi di SSP
(menaikkan atau menurunkan intensitas nyeri).
Endometriosis dianggap sebagai proses inflamasi pelvik yg
menghasilkan respon inflamasi signifikan.
Hypotesis nyeri endometriosis dikaitkan proses
inflamasi
Konsentrasi TNF- pada cairan peritoneum lebih tinggi pada wanita
endometriosis disbanding wanita normal. (TNF- menstimulasi ekspresi
PG synthase-2 yang meningkatkan produksi PGE-2 dan PGE-2 )
Konsentrasi Interleukin (IL1, IL-6, dan IL-8) meningkat pada cairan
peritoneum wanita endometriosis.(IL-1 menginduksi sintesis PG dan
menstimulasi proliferasi fibroblast. IL-8 sitokin yang bersifat angiogenik
dan pro inflamasi).
Ekspresi Nerve Growth Faktor (NGF) meningkat pada lesi
endometriosis ( NGF meningkatkan sprouting nociceptor, neuron
sensorik dan ekspresi substance P neuropeptide)
Adanya pertumbuhan serabut saraf pada implant ektopik salah satu
mekanisme timbulnya nyeri.
Medical Treatment

Terapi hormonal untuk infertilitas karena endometriosis belum

memuaskan namun untuk management nyeri pada endometriosis
dengan terapi hormonal cukup berhasil walau masih dapat terjadi
kekambuhan.
 Hormonal mechanism in treatmen of
endometriosis related pain

Implant endometriosis bereaksi terhadap

hormone steroid dengan cara yg mirip dengan
stimulasi endometrium.
Karena estrogen dikenal menstimulasi
pertumbuhan endometriosis, terapi hormonal di
disain untuk menekan sintesis estrogen,
sehingga menginduksi atropi implant
endometrium menghambat stimulasi siklus dan
perdarahan.
Oral Contraceptives

Pil KB kombinasi bekerja pada kelainan endometriosis dengan cara

menekan LH dan FSH serta mencegah terjadinya ovulasi dengan cara
menginduksi pseudo pregnancy, mengurangi aliran menstruasi,
desidualisasi implant endometriosis dan meningkatkan apoptosis pada
eutopik endometrium wanita endometriosis.
Merupakan pilihan efektif untuk mengurangi gejala, aman dan dapat
digunakan jangka panjang terutama pada wanita yang ber KB.
Pengobatan nyeri endometriosis dengan Pil KB kombinasi dibanding
GnRH analog selama 6 bulan tidak didapat perbedaan bermakna. Juga
pada nyeri tidak terkait menstruasi. (Cochrane review 2009)
 Pathologically, oral contraceptive use is associated with
decidualization of endometrial tissue, necrobiosis, and possibly
absorption of the endometrial tissue .
Unfortunately, there is no convincing evidence that medical
therapy with oral contraceptives offers definitive therapy.
Instead, the endometrial implants survive the induced atrophy
and, in most patients, reactivate after termination of treatment.
Any low-dose combination oral contraceptive containing 30 to
35 mg of ethinyl estradiol used continuously can be effective in
the management of endometriosis
Progestins

Progestins may exert an anti endometriotic effect by causing

initial decidualization of endometrial tissue followed by
atrophy.
They can be considered as the first choice for the treatment of
endometriosis because they are as effective as danazol or
GnRH analogues and have a lower cost and a lower incidence of
side effects than these agents.
 Medroxyprogesterone acetate (150 mg) given
intramuscularly every 3 months is effective for the
treatment of pain associated with endometriosis.
Megestrol acetate has been administered in a
dose of 40 mg/d with good results .
Other treatment strategies have included
dydrogesterone (20 to 30 mg/d, either
continuously or on days 5 to 25) and lynestrenol
(10 mg/d).
 Local progesterone treatment with a levonorgestrel-releasing
intrauterine system for 12 months has resulted in a significant
reduction in dysmenorrhea, pelvic pain, and dyspareunia.
Progesterone Antagonists

Progesterone antagonists and progesterone receptor

modulators may suppress endometriosis based on their
antiproliferative effects on the endometrium, without the risk
for hypo-estrogenism or bone loss that occurs with GnRH
treatment
 Mifepristone Mifepristone (RU-486) is a potent
antiprogestagen with a direct inhibitory effect on human
endometrial cells and, in high doses, an antiglucocorticoid
action .
The recommended dose for endometriosis is 25 to 100 mg/d.
mifepristone, 50 to 100 mg/d, reduced pelvic pain and induced
55% regression of the lesions without significant side effects .
 Gestrinone
Gestrinone is a 19-nortestosterone derivative with androgenic,
antiprogestagenic, antiestrogenic, and antigonadotropic
properties.
It acts centrally and peripherally to
free testosterone and sex hormonebinding globulin levels
(androgenic effect),
serum estradiol values to early follicular phase
levels(antiestrogenic effect),
mean LH levels, and obliterate the LH and follicle-stimulating
hormone (FSH) surge (antigonadotropic effect).
Gestrinone causes cellular inactivation and degeneration of
endometriotic implants but not their disappearance .
The standard dose has been 2.5 mg twice a week 6-9 months.
Danazol

Pharmacologic properties of danazol include

suppression of GnRHor gonadotropin secretion,
direct inhibition of steroidogenesis, increased
metabolic clearance of estradiol and
progesterone .
The multiple effects of danazol produce a high-
androgen, low-estrogen environment that does
not support the growth of endometriosis, and the
amenorrhea that is produced prevents new
seeding of implants from the uterus into the
peritoneal cavity
 start treatment with 400 mg daily (200 mg twice a day) and
increase the dose, if necessary, to achieve amenorrhea and
relieve symptoms .
local danazol treatment using a vaginal danazol ring (1,500
mg) has been shown to be effective for pain relief in deeply
infiltrative endometriosis without the classic danazol
sideeffects, or detectable serum danazol levels, while allowing
ovulation and conception
Gonadotropin-releasing Hormone Agonists

GnRH agonists bind to pituitary GnRH receptors and stimulate

LH and FSH synthesis and release.
However, the agonists have a much longer biologic half-life (3 to
8 hours) than endogenous GnRH (3.5 minutes), resulting in the
continuous exposure of GnRH receptors to GnRH agonist activity.
This causes a loss of pituitary receptors and downregulation of
GnRH activity, resulting in low FSH and LH levels.
Consequently, ovarian steroid production is suppressed,
providing a medically induced and reversible state of
pseudomenopause.
A direct effect of GnRH agonists on ectopic endometrium is also
possible because expression of the GnRH receptor gene has been
documented in ectopic endometrium and because direct
inhibition of endometriosis cells has been demonstrated in vitro.
 These agents include leuprolide(leuporide 3.75 mg im monthly),
buserelin, nafarelin, histrelin, goserelin, deslorelin, and triptorelin.
These drugs are inactive orally and must be administered
intramuscularly, subcutaneously, or by intranasal absorption.
The best therapeutic effect is often associated with an estradiol dose
of 20 to 40 pg/mL (75 to 150 pmol/L).
These so-called depot formulations are attractive because of the
reduced frequency of administration and because nasal
administration can be complicated by variations in absorption
rates and problems with patient compliance
OTHER

Aromatase Inhibitors-anastrozole, 1 mg/d,

Selective Estrogen Receptor Modulators-Raloxifen
eshre
EMPIRICAL TREATMENT OF PAIN
SYMPTOMS WITHOUT A DEFINITIVE
DIAGNOSIS
Empirical treatment for pain symptoms presumed to
be due to endometriosis without a definitive diagnosis
includes counselling, adequate analgesia,
progestagens, the combined oral contraceptive (COC)
and nutritional therapy. It is unclear whether the COC
should be taken conventionally, continuously or in
tricycle regimen. A GnRH agonist may be taken but
this class of drug is more expensive, and associated
with more side-effects and concerns about bone
density
Treatment of endometriosis-
associated pain in confirmed disease
Non-steroidal anti-inflammatory
There is inconclusive evidencedrugs
to show whether
NSAIDs (specifically naproxen) are effective in
managing pain caused by endometriosis (Allen et al.,
2005).
Evidence
Level 1a
 Hormonal treatment

Suppression of ovarian function for 6 months

reduces endometriosis associated pain. The
hormonal drugs investigated - COCs, danazol,
gestrinone, medroxyprogesterone, acetate and
GnRH agonists - are equally effective but their
side-effect and cost profiles differ (Davis et al.,
2007 ; Prentice et al., 1999; Prentice et al.,
2000; Selak et al., 2007).
Evidence
Level 1a
 The levonorgestrel intra-uterine
system (LNG IUS) reduces
endomestriosis associated pain.

Evidence Level 1a
 Duration of GnRH agonist treatment

Treatment for 3 months with a GnRH

agonist may be as effective as 6
months in terms of pain relief
(Hornstein et al., 1995).

Evidence Level 1b
GnRH agonist treatment with 'add-
back
Treatment for up to 2 years with combined oestrogen and
progestagen 'add-back' appears to be effective and safe in terms
of pain relief and bone density protection; progestagen only 'add-
back' is not protective (Sagsveen et al., 2003). However, careful
consideration should be given to the use of GnRH agonists in
women who may not have reached their maximum bone density.
Evidence Level 1a
Surgical treatment

Depending upon the severity of disease found, ideal practice is

to diagnose and remove endometriosis surgically at the same
time, provided that pre-operative adequate consent has been
obtained (Abbott et al., 2003; Chapron et al., 2003b; Fedele et
al., 2004a; Redwine and Wright, 2001).
 Ablation of endometriotic lesions plus laparoscopic uterine nerve ablation
(LUNA) in minimal-moderate disease reduces endometriosis associated pain
at 6 months compared to diagnostic laparoscopy; the smallest effect is seen
in patients with minimal disease (Jacobson et al., 2001). However, there is no
evidence that LUNA is a necessary component (Sutton et al., 2001), and
LUNA by itself has no effect on dysmenorrhoea associated with
endometriosis (Vercellini et al., 2003a).
Evidence
Level 1b
 Endometriosis associated pain can be reduced by removing the
entire lesions in severe and deeply infiltrating disease. If a
hysterectomy is performed, all visible endometriotic tissue
should be removed at the same time (Lefebvre et al., 2002).
Bilateral salpingo-oophorectomy may result in improved pain
relief and a reduced chance of future surgery (Namnoum et al.,
1995).
Pre-operative treatment

Although hormonal therapy prior to surgery improves rAFS scores,

there is insufficient evidence of any effect on outcome measures
such as pain relief (Yap et al., 2004).
Evidence
Level 1a
Post-operative treatment

Compared to surgery alone or surgery plus placebo, post-operative hormonal

treatment does not produce a significant reduction in pain recurrence at 12 or
24 months, and has no effect on disease recurrence (Yap et al., 2004).
Evidence Level 1a
Hormone replacement therapy

Hormone replacement therapy (HRT) is recommended after

bilateral oophorectomy in young women given the overall
health benefits and small risk of recurrent disease while taking
HRT (Matorras et al., 2002). The ideal regimen is unclear:
adding a progestagen after hysterectomy is unnecessary but
should protect against the unopposed action of oestrogen on
any residual disease. However, the theoretical benefit of
avoiding disease reactivation and malignant transformation
should be balanced against the increase in breast cancer risk
reported to be associated with combined oestrogen and
progestagen HRT and tibolone (Beral and Million Women Study
Collaborators, 2003).
Evidence
Level 4
 Implants of endometriosis react to steroid hormones in a
manner somewhat, but not exactly,similar to normally
stimulated endometrium.
Because estrogen is known to stimulate the growth of
endometriosis, hormonal therapy has been designed to
suppress estrogen synthesis, thereby inducing atrophy of
ectopic endometrial implants or interrupting the cycle of
stimulation and bleeding.
Manipulation of the endogenous hormonal milieu is the
basis for the medical management of endometriosis.