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Innovations in conservative endometriosis treatment: An

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3279-GIN

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MINERVA GINECOL 2011;63:1-2

Innovations in conservative
endometriosis treatment: an updated review

F
B. RUHLAND, A. AGIC, J. KRAMPE, K. DIEDRICH, D. HORNUNG

A
O
IC
Endometriosis is a common, benign and University of Schleswig-Holstein
chronic gynecological disorder. It is also an Campus Luebeck, Luebeck, Germany
estrogen-dependent disorder that can result

D
in intractable dysmenorrhea, heavy and/or
irregular periods, painful bowel movements
O

and urination during menstruation and infer-
tility and ultimatively in repeated surgeries.
Although surgery to remove endometriotic
lesions is effective in relieving endometrio-
sis-associated pain, recurrence rates are high
and many women require continuous medi-
R
E
ndometriosis is the most common be-
E
nign, progressive and chronic gyneco-
logical disease of women during their re-
M
productive phase of life. Studies estimate
that 7-15% of women of reproductive age

cal therapy to control symptoms. Symptom may suffer from endometriosis.1 The preva-
relief with palliation of pain and optimiza-
VA

lence rises to 20-50% in infertile women.2-4

tion of the quality of life should be the main
aim of the medical therapy. Different phar-
macologic treatment options are currently
available. The most widely exerted medical
P
Specification of symptoms can vary from
asymptomatic occurrence to mild character-
istics up to severe symptoms. Among pain

therapy for endometriosis involves gonado- symptoms, endometriosis impresses with

R

tropin-releasing hormone (GnRH) agonists intractable dysmenorrhea, heavy and/or ir-

and oral contraceptives. Also progestogens regular periods, painful bowel movements,
E

and androgen derivates are used. New treat-

ment options that are currently under inves-
especially during menstruation, painful uri-
tigation are selective progestogen receptor nation during menstruation and infertility.
IN

modulators (SPRMs), aromatase inhibitors Deep infiltrating endometriosis, especially

(AI), GnRH- antagonists, cyclooxygenase of the bowel, the ureter or the bladder can
(COX)-2 inhibitors, angiogenesis disruptor’s lead to severe dysfunctions of these organs.
und immune modulators. Although these Apart from physical symptoms, women
M

new agents are promising, further confirma-
tion in randomized clinical trials is required.
Key words: Endometriosis - Drug therapy -
Hormones.
Received on ???.
Accpted for publication on ???.
with endometriosis suffer from a decreased
quality of life. This may result not only from
the symptoms of pelvic pain and infertility
but also from the (side-)effects of various
medical and surgical treatments.5

Surgical versus conservative therapy

Corresponding author: D. Hornung, MD PhD, Universi-
ty of Schleswig-Holstein, Campus Luebeck, Department of
Gynecology and Obstetrics, Ratzeburger Allee 160, 23538 Surgical and medical therapies are the
Lübeck, Germany. E-mail: D.Hornung@gmx.de two pillars of endometriosis treatment. All

Vol. 63 - No. 0 MINERVA GINECOLOGICA 1

RUHLAND INNOVATIONS IN CONSERVATIVE ENDOMETRIOSIS TREATMENT
modes of endometriosis therapy are symp-
tomatic but not curative. While endometrio-
sis is a most frequently progressive and re-
current disease, long-term therapy options
with as few side effects as possible are re-
quired. Surgery in particular is important in
acute forms of endometriosis and especially
in deep infiltrating forms of endometriosis,
if an acute organ dysfunction is suspected.
Patients with this kind of endometriosis
as well as with ovarian endometriomata
should be counseled to a surgical treat-
ment. Independent of these indications,
all patients with suspected endometriosis
should have a histological confirmation of
the diagnosis. Emphatically patients with in-
O
fertility need surgical treatment since none
of the medical treatment options are com-
patible with the wish to have children or to
increase the fertility.6-8 Furthermore, surgi-
cal treatment improves the success rates of
O
assisted reproductive therapy.
Objective of a medical endometriosis
treatment is defined by the chronic nature
of this disease.
Palliation of pain with optimization of the
quality of life is one of the most important
R
aims of medical therapy for patients suffer-
VA
ing from endometriosis. Decrease of recur-
rence intervals and consequently reduction
of required surgery are further demands on
a medical treatment option, since 55% of
P
patients suffer from recurrence within 5 to
R
7 years after surgery.9, 10 In addition, a good
tolerance and the possibility of a long-term
E
therapy are important.
While severity of pain does not correlate
IN
with the stage of endometriosis, treatment
is complicated. Therapy of patients with en-
dometriosis should be oriented more on pa-
M
tient’s symptoms than on extension of the
disease.11
Due to expected recurrence rates of en-
dometriosis as well as side effects and sur-
gical complications, an exclusive surgical
approach is insufficient. Patients in their
twenties have the highest prevalence of re-
currence with 72%.12
But also medical treatment has a risk of
recurrence of symptoms after discontinu-
ation of medical therapies. After cessation
2 MINERVA GINECOLOGICA Mese 2011
of therapy, a high prevalence rate of a re-
currence has to be expected. A long-term
follow-up study of GnRH analogue therapy
described relapse rates of 28% after 2 years
and 53% after 5 years of treatment cessa-
tion.13 Consequently, a long-lasting therapy
approach is necessary. As already men-
tioned, the choice of therapy should not be
based only on the improvement of symp-
toms, but also on the potential adverse ef-
fects and patients’ satisfaction.
Use of gonadotropin-releasing hormone
F
(GnRH) agonists, oral contraceptives or
gestagens is the most widely utilized phar-
macological therapy for endometriosis.
A
Further established treatment options are
analgesics from the group of non-steroidal
IC
anti-inflammatory drugs (NSAIDs). Histori-
cally, conventional agents also include an-
drogen derivates, gestrinone and danazol.
D
Apart from NASIDs, all these drugs un-
fold their therapeutic effect particularly in
E
decrease of the serum estrogen level.
Furthermore, new therapy options like
GnRH antagonists, off-lable use of aro-
M
matase inhibitors, estrogen receptor beta
agonists, progesterone receptor modulators,
angiogenesis inhibitors and COX-2 selective
inhibitors are presented in studies.
NSAID
Endometriosis-associated symptoms are
due to an aberrant inflammatory response
in eutopic endometrium and within ec-
topic endometriotic tissue of women with
this disease.14, 15 On this background, the
approach of an anti-inflammatory therapy
with analgesic effect should be taken into
consideration in many patients as first-line
therapy for mild symptoms.
For example, a murine model of endome-
triosis could show a limitation of the pro-
gression of implants under NSAID intake.16
While nonsteroidal anti-inflammatory
drugs (NSAIDs) are the most commonly
used first-line treatment for endometriosis,
Allen et al. performed a Cochrane database
analysis investigating the effect of NSAIDs
in patients with endometriosis. Only one
INNOVATIONS IN CONSERVATIVE ENDOMETRIOSIS TREATMENT RUHLAND
study was included in this review compar-
ing NSAIDs (naproxen) to placebo. This
study could not show a positive effect on
pain relief in women with endometriosis.Al-
len et al discussed that there is inconclusive
evidence to show whether or not NSAIDs
are effective in managing pain caused by
endometriosis 17.
Therefore, many patients suffering from
endometriosis do not get sufficient symp-
tom relief from NSAIDs. In addition, alter-
natives must be available since those drugs
exert side-effects when administered over a
long period of time. If so, patient’s attend-
ance should occur in a multidisciplinary
team including gynecologists, pain spe-
O
cialists and physiotherapists. Occasionally,
these patients need an opioid- based treat-
ment for pain relief according to the WHO’s
pain ladder.18 Regarding the dose and treat-
ment regime in patients with endometriosis,
O
no extensive data are available.
Hormonal therapy
Focus on medical therapy of endome-
R
triosis is the hormonal treatment. It is es-
VA
tablished, that endometriosis development
and continued activity is dependent on es-
trogen. In experimental models, estrogen is
necessary to induce or maintain endometri-
P
osis 19. Medical treatment consists mostly of
R
hormonal suppressive therapy in which the
medication causes a downregulation of the
E
hypothalamus-pituitary-ovarian pathway.
An antiestrogen therapy can lead to regres-
IN
sion of endometriosis and its symptoms. If
pain relief has not been achieved with non-
hormonal concepts, oral contraceptives are
M
used next, and they may be used alone or
in combination with NSAIDs. Concerning
pain relief, all forms of hormonal treatment
can be successful.20, 21 Differences are less
in efficiency of hormonal therapeutics than
in the varying side effects and costs.22, 23
The “long cycle” procedure with oral con-
traceptive pills can decrease the number of
menses, thus improving the quality of life,
although some women will have break-
through bleeding 24.
Vol. 63 - No. 0 MINERVA GINECOLOGICA 3
Hormonal therapy in general can reduce
the pain attributed to endometriosis, but ad-
verse effects are common.
GnRH agonists
Gonadotropin-releasing hormone (GnRH)
agonists are currently one of the most wide-
ly used medical therapies for endometriosis.
GnRH agonists induce a pseudomeno-
pausal state by interacting in the hypotha-
lamus-pituitary-ovarian pathway. By having
F
a higher affinity to the GnRH-receptor than
the body’s own GnRH, they inhibit the natu-
ral female cycle and cause a complete ovar-
A
ian suppression with missing oocytematu-
ration and consequently reduced serum
IC
estrogen levels.25, 26 Leuprolide,goserelin
and triptorelin are used for the treatment of
endometriosis. The typical course of treat-
D
ment is for 3 to 6 months, after which the
patient should be monitored for bone loss.
E
Add-back therapy with an estrogen-/gesta-
gen-combination can reduce this side-effect
significantly.
M
GnRH agonists are very effective in re-
ducing symptoms of pain and other en-
dometriosis- associated aspects, but are
also combined with a high relapse rate. In
50% of cases, a relapse of symptoms is de-
tected within 6 months after discontinua-
tion of GnRH agonist therapy.24 Other stud-
ies describe recurrence rates of 53-73%.13
Schweppe could show in 50% of GnRH ag-
onist treated patients vital endometrial cells
in endometriotic implants.27
Due to hypoestrogenic adverse effects,
such as hot flashes, genital atrophy, vagi-
nal dryness, loss of libido, emotional labil-
ity and reduction of bone mineral density
(2-8%),28 long-term treatment with GnRH
agonists over more than 6 month is inadvis-
able.29
Side effects can be reduced by the add-
back technique. Additional administration
of a progestogen has been shown to relieve
most of these drug related symptoms.Add-
back therapy can be performed by the ad-
dition of a progestogen only, a progestogen
plus bisphosphonate or a progestogen plus
estrogen. Also, bisphosphonates or selec-
RUHLAND INNOVATIONS IN CONSERVATIVE ENDOMETRIOSIS TREATMENT
tive estrogen receptor modulators (SERMs)
like tibolone can be applied. Recent stud-
ies have demonstrated that the use of add-
back enhances compliance and duration of
therapy. Performing an add back therapy
leads to a better tolerance of GnRH agonist
therapy without compromising the efficien-
cy of endometriosis treatment 30 and can be
given up to 2 years without worrying about
osteoporosis.31
Anyway, GnRH agonists should be used as
a second-line therapy, when progestogens
or oral contraceptives fail, are not tolerated
or are contra-indicated.
Oral contraceptives O tion of therapy should occur before restart
Good options in the control of pain symp-
toms in women affected by endometriosis
constitute progestogens and estrogen-pro-
gestogens.32 Their effect is not inferior to
O
that of other drugs used for the disease.
Contraceptive steroidal preparations must
be considered as drugs of first choice since
they are generally well tolerated, have mi-
nor metabolic impact as opposed to dana-
zol or GnRH agonists, are inexpensive and
R
may be used on a long-term basis.33 By in-
VA
hibiting ovulation and creating a pregnan-
cy-like hormonal condition, contraceptives
(OC) progestogens alone or combined with
constant dosage of ethinylestradiol (EE),
P
may reduce the incidence of endometriosis
R
recurrence.Preferably preparations with 15-
30 µg EE with a variable progestogen com-
E
ponent should be used. Desogestrel, di-
enogest, drospirenone, levonorgestrel and
IN
norethisterone acetate are common used
progestogens.
Choose of OC depends on the patients
M
need regarding other wished effects (f.e.
antiandrogenic). With reference to the ef-
fect of endometriosis reduction, no differ-
ences are detected within these different
drugs. In comparison to GnRH agonists,
OCs can achieve a similar reduction of non-
cyclic symptoms as well as an improvement
of dyspareunia. Comparison of the symp-
tom dysmenorrhea is problematic, since
patients under therapy with GnRH agonists
are amenorrheal. But OCs, especially when
4 MINERVA GINECOLOGICA Mese 2011
given in the long cycle, showed a similar
significant reduction of dysmenorrheal.34
Harada et al. confirmed this effect of OCs.
After four cycles of OCs versus placebo, a
significant decrease of dysmenorrhea and
non-cyclic symptoms could be demonstrat-
ed.35 Treatment with OCs can be carried
out cyclic or as a long-cycle use. Women
affected by dysmenorrhea during cyclic use
of an OC may benefit from the shift to a
continuous administration.36-38
Long cycle intake of OCs is always a
F
good alternative treatment option, if cyclic
intake of OCs cannot achieve a satisfactory
symptom relief. In case of breakthrough
A
bleedings, an interval of several days cessa-
IC
of OC use.32
In a study of Seracchioli et al., three hun-
dred eleven women who underwent lapar-
D
oscopic excision for symptomatic ovarian
endometrioma received a follow-up therapy
E
over two years. The women sustained either
no therapy, cyclic or continuous OC admin-
istration (20 µg EE und 75 µg gestodene).
M
The study group could show that long-
cycle use of OC after surgery reduces the
frequency and the severity of recurrent en-
dometriosis-related dysmenorrhea. Reduc-
tion of dyspareunia was only moderate. No
significant difference between cyclic and
long-cycle administration was seen.39
Continuous OCs and GnRH agonists ap-
pear to be equally effective in the treatment
of endometriosis- associated symptoms, but
OCs are less likely to reduce bone mineral
density or to cause other adverse effects
such as hot flushes and vaginal dryness.40
Progestogen
Progestogens are effective in controlling
pain symptoms in approximately three of
four women with endometriosis.
Progestogens operate by deciduation
of both the eutopic endometrium and
endometriotic lesions followed by pseu-
donecrosis and atrophy of lesions. In addi-
tion, they cause suppressed gonadotropin
release and ovarian function followed by
anovulation and low serum estrogen levels.
INNOVATIONS IN CONSERVATIVE ENDOMETRIOSIS TREATMENT RUHLAND
Available drugs are medroxyprogester-
one acetate (MPA), norethindrone acetate
(NETA), lynestrenol (LYN), dydrogesterone,
cyproterone acetate, megestrol acetate and
dienogest. Alternatively to oral administra-
tion, levonorgestrel (LNG) is available as an
intrauterine device application with a con-
tinuous release of LNG. Dienogest is anoth-
er preparation of progestogene especially
designed for long-cycle administration for
patients with endometriosis. Adverse effects
in general include breakthrough bleedings
in up to 58%,41 fluid retention and weight
gain, breast tenderness, anxiety- depression
and sleep disturbances.21, 42 Norethindrone
acetate led to a reduction of dysmenorrhea
O
and non-cyclic pain.41 Compared to other
progestogens, NETA has less distinctive
bleeding dysfunctions and a positive effect
on bone metabolism. Furthermore, it has no
influence on serum lipids and lipoproteins
O
in any negative way.43 Vercellini et al. could
show a satisfaction of therapy in 73% of pa-
tients treated with cyproterone acetate.44 In
another study, Vercellini et al. treated ninety
women with recurrent moderate or severe
pelvic pain after conservative surgery for
R
symptomatic endometriosis with cyproter-
VA
one acetate, 12.5 mg/d, or an oral contra-
ceptive containing ethinyl estradiol, 20 µg,
and desogestrel, 150 µg. No major differ-
ences could be seen regarding the reduc-
P
tion of dysmenorrhea, chronic pelvic pain
R
and dyspareunia. Significant improvements
were observed in health-related quality-of-
E
life, psychiatric profile, and sexual satisfac-
tion in both groups.45 Medroxyprogester-
IN
one acetate has been shown to improve
symptoms in up to 80% of patients with en-
dometriosis. Wong et al could show effec-
M
tiveness in symptom control and prevention
of recurrence in patients with moderate or
severe endometriosis.46
A double-blind, prospective trial treated
62 women with mild-moderate endometrio-
sis with dydrogesterone (40 or 60 mg) or
placebo for 6 months. Pain scores were sig-
nificantly decreased at month 6 compared
with month 1 in the 60 mg dydrogesterone
group but not in the 40 mg dydrogester-
one or placebo groups.47 Also Schweppe
Vol. 63 - No. 0 MINERVA GINECOLOGICA 5
concludes that dydrogesterone is indicated
for the symptomatic management of pain,
bleeding disorders and other symptoms
caused by endometriosis.48
Due to the chronic and recurrent nature,
therapy for endometriosis is generally re-
quired for prolonged periods of time.11 Pro-
gestogens are an appropriate medical man-
agement of endometriosis, given that these
agents are well tolerated, have a limited
metabolic impact compared to other agents
and are inexpensive.11, 49
F
Dienogest
A
As already mentioned, a novel synthetic
oral progestogen, dienogest, was licensed
IC
for endometriosis treatment in 2010. Di-
enogest is a 19-nor testosterone derivative
devoid of androgenic, estrogenic, miner-
D
alocorticoid or glucocorticoid activity, and
with a rather strong anti-androgenic effect.
E
Dienogest is generally well tolerated and is
not considered to be associated with clini-
cally relevant androgenic effects. Dienogest
M
at 2mg orally each day is recommended.50
In randomized clinical trials, dienogest
was significantly more effective than place-
bo in reducing dysmenorrhea, premenstrual
pain, dyspareunia and diffuse pelvic pain
in patients with confirmed endometriosis
and similar in comparison to treatment with
GnRH agonists.
Strowitzki et al. investigated the efficacy
of dienogest 2 mg compared with placebo.
They could show a superiority of dieno-
gest over placebo reducing the values in
the visual analog scale 51. Also, Strowitzki
et al. performed a trial treating patients with
laparoscopically confirmed endometriosis
with dienogest (2 mg/day, orally) or leupro-
lide acetate (3.75 mg, depot i.m. injection,
every 4 weeks) for 24 weeks. They could
demonstrate an equivalent effect of dieno-
gest to leuprolide acetate with less hypoes-
trogenic side effects.52
Harada et al. treated two hundred sev-
enty-one patients with endometriosis with
dienogest (2 mg/day, orally) or with intra-
nasal buserelin acetate (900 microg/day, in-
tranasally) for 24 weeks. Dienogest reduced
RUHLAND INNOVATIONS IN CONSERVATIVE ENDOMETRIOSIS TREATMENT
the scores of lower abdominal pain, lumba-
go, defecation pain and dyspareunia analog
to buserelin. Loss in bone mineral density
was significantly lower in patients treated
with dienogest, but dienogest was associ-
ated with irregular genital bleeding more
frequently.53
No undesired effects on glucose and lipid
metabolism, liver enzymes or haemostasis
as well as on thyroid or adrenal function,
electrolyte balance or haematopoiesis could
be seen in patients treated with high doses
of dienogest (20-30 mg/day for 24 weeks).54
Consequently, a higher dosage of dienogest
would be possible, but increased adverse ef-
fects will be expected. Furthermore, Köhler
O
et al. could not describe an additional effect
by increasing the daily dose of dienogest.55
Momoeda et al. demonstrated as most com-
mon adverse drug reactions metrorrhagia,
headaches and constipation in one hundred
O
and thirty-five patients, which received 2
mg of dienogest in long-term use.56
Attention should be paid to missing market
authorization for contraception in compari-
son to the other progestogens. Patients must
be informed that further contraception is re-
R
quired, since the effect of dienogest on con-
VA
traception was not tested in clinical studies.
Levonorgestrel-releasing intrauterine system
P
An also quite effective therapy option
R
besides oral progestogens to reduce en-
dometriosis- associated pelvic pain is the
E
levonorgestrel intrauterine device. Espe-
cially in pain arising during menses as well
IN
as from lesions in the rectovaginal tissue,
the LNG-IUD can give relief.57 In addition,
intrauterine delivery of progestogen is a
useful system to manage regional therapy
M
and bypass systemic side effects. Levonorg-
estrel exhibits the progestational effect
on the endometrium. Effective agent is a
19-nortestosterone derivative,58 that leads
to an endometrial atrophy. The serum lev-
els of absorbed progestogen are below the
threshold for inhibition of ovulation, so
that most women with the LNG-IUD have
an ovulation frequently.59 This could be a
disadvantage regarding the growth of en-
6 MINERVA GINECOLOGICA Mese 2011
dometriomata. The licensed duration of the
LNG-IUD use is 5 years. Initial release of
hormone averages 20 μg daily, which grad-
ually declines to half this rate by 5 years.60
A systematic review could identify two
randomized controlled trials and three
prospective observational studies show-
ing decreased symptoms after insertion of
a LNG-IUD. All studies involvedonly small
numbers and a heterogeneous group of
patients.61 Lockhat treated patients with
laparoscopically confirmed endometriosis
F
but no further surgical therapy and could
show a significant reduction of dysmenor-
rhea and dyspareunia. The proportion of
A
patients who reported moderate or severe
dysmenorrhoea declined from 96% before
IC
therapy to 50% at 6 months.62 Also Petta et
al. found a similar efficacy of LNG-IUD in
comparison to GnRH agonists.63 Especially
D
in patients with adenomyosis mainly suffer-
ing from dysmenorrhea and patients who
E
do not aim for pregnancy, the LNG-IUD is a
good treatment option.
Altogether, the evidence suggests that the
M
LNG-IUD reduces endometriosis-associated
pain 64 with symptom control maintained
over 3 years.62
Furthermore, LNG-IUD was established
for patients with peritoneal, rectovaginal
and relapsing endometriosis as well as for
postoperative prevention.64-66 Further stud-
ies could show a significant reduction of
ectopic endometrial tissue with a decrease
of surrounding inflammation.32 In summa-
ry, LNG-IUD has the advantages of missing
systemic hypoestrogenic effects, only a sin-
gle intervention leading to a high degree of
compliance as well as the avoidance of first-
pass hepatic metabolism resulting in minor
adverse side effects.
These side effects should not to be ig-
nored.About 20% of LNG-IUD users will
be amenorrheic by the end of 12 months 67
and 70% of users will be oligomenorrheic
or amenorrheic by 24 months.68 But Lockhat
et al. described in their study discontinua-
tion rates with highest levels during the first
12 months. The main reasons for removal of
the LNG-IUD were irregular and intolerable
bleeding (14.7%), one-sided abdominal pain
INNOVATIONS IN CONSERVATIVE ENDOMETRIOSIS TREATMENT RUHLAND
(11.8%) and weight gain (8.8%) as well as
persistent pain.62 Control and effect of non-
cyclic pain is only small.69 The satisfaction
score correlates with how well educated pa-
tients are about the feasible adverse effects
associated with the LNG-IUD. A study that
involved the evaluation of 17 914 question-
naires of current LNG-IUS users showed that
the patients who were informed about the
option of amenorrhea were more satisfied
than the women who were not.70
For women who do not wish to conceive,
this device is an effective local therapy that
offers the possibility of5 years of treatment
following one single intervention.
O Local application of a Danazol-IUDs is a
DMPA
Subcutaneously or intramuscularly in-
jected depot MPA (DMPA) is another op-
tion for non-orally medical treatment of
O
endometriosis. The safety and tolerability
of DMPA-SC 104 was established in clinical
studies.71 Comparable to the effect of GnRH
agonists, reduced endometriosis-associated
symptoms could be achieved.72, 73 Advanta-
geously is the single intervention without
R
problems of compliance. Combined with
VA
the clinical data that show efficacy com-
parable to that of GnRH agonists, DMPA
should be considered as a useful option for
the treatment of endometriosis-associated
P
pain. Patients who plan to conceive in the
R
near future should not get this therapy be-
cause of a long time interval (up to 1 year)
E
until settlement of the cycle. But for patients
suffering from endometriosis-associated
IN
pain after hysterectomy, DMPA is a good
treatment option.32, 72, 73
M
Danazol
Danazol, a synthetic steroid derivative of
ethisterone, produces a hypoestrogenic situ-
ation. The first paper about this drug was
published in the 1970th in the American Jour-
nal of Gynecology and Obstetrics. Dmowski
and Cohen described 99 women treated with
danazol and could report a lower recurrence
rate of endometriosis and a much longer av-
erage time until recurrence.74 The efficacy of
Vol. 63 - No. 0 MINERVA GINECOLOGICA 7
danazol in reducing endometriosis-associat-
ed pain symptoms could be demonstrated in
multiple studies.75-77
During the 1980th, Danazol was the
“gold-standard” in endometriosis therapy.
Danazol induces amenorrhea, increased se-
rum androgen concentrations and lowered
serum estrogen levels. Further adverse ef-
fects brought by androgenic and anabolic
effect are weight increase , oedema, breast
atrophy, acne, seborrhea, hot flushes und
hirsutism.78
F
It is effective, but the incidence of an-
drogenic side effects limits its use,24 so that
Danazol is no longer part of the routinely
A
endometriosis therapy at least in Europe.
IC
potential option with decrease of dysmen-
orrhea, dyspareunia and pain while system-
ic side effects are minimal.79, 80 Intravaginal
D
Danazol may be proposed as an alternative
treatment concept without knowing more
E
about longterm systemic effects.
M
Gestrinon
Gestrinone is a synthetic steroid hor-
mone with antiestrogenic and antiproges-
terone characteristics originally developed
as an oral contraceptive. It disposes simi-
lar efficacy as well as androgenic side ef-
fects as Danazol or GnRH- agonists, but has
significantly more metabolic side effects.81,
82 Gestrinone should be used when pro-
gestogens and oral contraceptives fail, are
not tolerated or are contraindicated.83
The hormonal treatment options used in
endometriosis therapy (combined oral con-
traceptives, danazol, gestrinone, medroxy
progesterone acetate and GnRH agonists)
are equally effective but their adverse ef-
fect and cost profiles differ. Long-term use
is often limited because of poor compliance
resulting from frequently seen side effects.84
Future development of new
drugs for endometriosis
Potential prospective therapy options,
that seem to be effective in clinical trials,
RUHLAND INNOVATIONS IN CONSERVATIVE ENDOMETRIOSIS TREATMENT
are selective progestogen receptor modu-
lators (SPRMs), aromatase inhibitors (AI),
GnRH-antagonists, cyclooxygenase (COX)-
2 inhibitors, angiogenesis disruptor’s und
immune modulators. Currently, these drugs
are only available as a treatment alternative
in clinical trials or as off-label use. There-
fore, they are an option in patients that
have refractory symptoms during conven-
tional treatment.
SPRMs
SPRMs are steroid-derived compounds
that can exert agonistic, antagonistic or
mixed agonist-antagonist effects depending
O
in different tissues, doses and presence or
absence of progestogen. SPRMs can restrain
endometrial growth and constitute a reverse
amenorrhea without hypoestrogenic effect.
Furthermore, they inhibit production of
O
prostaglandines and are effective in analge-
sia.85
Mifepristone (RU-486), the first glucocor-
ticoid and progestogen receptor antagonist,
was developed during the early 1980s and
was originally developed for medical termi-
R
nation of pregnancy. It is an antiprogestogen
VA
and antiglucocorticoid that can inhibit ovu-
lation, decreases endometrial proliferation
and disturb endometrial integrity. With its
antiprogestogene effect, mifepristone pre-
P
vents progestogen from exerting its action.
R
But mifepristone could also be useful in en-
dometriosis therapy. A daily dose of at least
E
2 mg mifepristone blocks ovulation. Koide
found that mifepristone may be effective
IN
for intractable symptoms in extensive en-
dometriosis, although its effect on lesions
has been found to be minimal.86 In another
M
trial, 50 mg mifepristone daily administered
over 6 months resulted in improvement of
pelvic pain and cramping.87 Adverse effects
include hot flashes, fatigue, nausea, and
transient liver enzyme changes.
In a murine model, subcutaneous implan-
tation of mifepristone-loaded capsules was
proven as an effective treatment for long-
term therapy of chronic endometriosis.
Asoprisnil ( J867) is the first SPRM to reach
an advanced stage of clinical development
8 MINERVA GINECOLOGICA Mese 2011
for the treatment of endometriosis. A ran-
domized, placebo-controlled, dose-finding
phase II trial of asoprisnil has been con-
ducted in women with endometriosis-as-
sociated pain. Patients with a laparoscopic
confirmed diagnosis of endometriosis were
treated with asoprisnil or placebo for 12
weeks. Asoprisnil significantly reduced non-
cyclic pelvic pain and dysmenorrhea com-
pared with placebo with favorable safety
and tolerability profiles of asoprisnil during
short-term treatment.88
F
But the clinical utility of SPRM and the
therapeutic mechanisms during long term
SPRM treatment are still not fully elucidated.
A
IC
AI
Aromatase P450 is the key enzyme for
estrogen biosynthesis, catalyzing the con-
D
version of androstenedione and testoster-
one to estrone and estradiol.89 Blockage of
E
aromatase activity in endometriotic lesions
with an aromatase inhibitor is a rational ap-
proach while endometriosis is an estrogen
M
dependent disease.
Multiple AIs with a broad spectrum of
activity are available for clinical use. These
agents are divided into two groups: steroi-
dal/irreversible and nonsteroidal/reversible
AIs. The nonsteroidal aromatase inhibitors
are anastrozole and letrozole, and the ster-
oidal compound is exemestane.90
There are study data suggesting that the
aromatase inhibitor letrozole may be effec-
tive in patients with endometriosis although
it’s use is associated with significant bone
density loss.91
A study from Soysal et al. showed that 6
months of therapy with AI and GnRH ago-
nist compared with the GnRH agonist alone
decreased symptom recurrence rates in pa-
tients after surgical tretament for endome-
triosis. Therapy with an AI did not reduce
quality of life and the bone loss was not
significant.92
In summary, patients with endometriosis
who suffer from refractory symptoms and
do not respond to existing treatments ap-
pear to obtain significant pain relief with
aromatase inhibitors. Although promising,
INNOVATIONS IN CONSERVATIVE ENDOMETRIOSIS TREATMENT RUHLAND
these results require confirmation in rand-
omized clinical trials.
It should be paid attention that aromatase
inhibitor should only be administered to
postmenopausal women or in case of appli-
cation in a premenopausal women always
in combination with an OC or a GnRH ago-
nist because of the risk of developing ovar-
ian cysts.
Immunomodulators
As already mentioned, endometriosis is a
disease with inflammatory tissue reactions.
Based on this knowledge further approach
in the treatment of patients with endome-
O
triosis could be immunomodulators. Dif-
ferent mechanisms seem to play a role in
cytolysis or immunosuppression, f.e. in-
hibition of tumor necrosis factor-alpha.A
forced immunosuppression can be reached
O
by COX- inhibitors and anti-tumor necrosis
factor-alpha inhibitors. Clinical trials docu-
ment a pain reduction in endometriosis pa-
tients caused by these drugs. Pioneer of the
first translational research on endometriosis
is the Belgian researcher d’Hooghe and his
R
team. They performed trials to study patho-
VA
genesis, pathophysiology, spontaneous ev-
olution and new medical treatment options
in endometriosis in the baboon model of
endometriosis. Their results may lead to the
P
discovery of new biomarkers for the devel-
R
opment of new drugs that may prevent or
treat endometriosis.93
E
Former studies describe an increased ex-
pression of COX-2 in endometriotic lesions.
IN
In several trials, preparations like celecoxib
were tested in patients with endometriosis.
Olivares et al. suggest an effect of celecoxib
M
on reduction of endometrial growth.94 Also
Cobellis et al. could show an improvement
of non-cyclic pain and dyspareunia exceed-
ed after the treatment cessation of 6 month
treatment with rofecoxib.95
Another agent from the group of immu-
nomodulators is Etanercept that neutralizes
TNF-alpha activity. It is a fusion protein
consisting of human recombinant soluble
anti-tumor necrosis factor-alpha inhibitors.
TNF-alpha is increased in the serum of
Vol. 63 - No. 0 MINERVA GINECOLOGICA 9
patients with endometriosis. Animal trials
suggest that anti-TNF therapy could be a
novel non-hormonal therapeutic option for
the treatment of endometriosis,96 whereas
unfortunately, studies on humans could not
confirm these results in animal studies.
Infliximab is another agent from the
immunomodulator group. But no effect
of infliximab was observed in a study of
Koninckx et al., who treated patients after
surgery with infliximab or placebo.97
F
Angiogenesis inhibitor
A
Thalidomide is a drug known from the
late 1950th as a sedative drug, but it is also
an angiogenesis inhibitor. It was withdrawn
IC
from the market in 1961 because of the risk
of severe, life-threatening birth defects. A
Japanese study could show that thalido-
D
mide reduces inflammation by down-reg-
ulating the expression of proinflammatory
E
cytokines in tumor cells and inflammatory
cells.98 On this background there is an on-
M
going study on the open label- use of tha-
lidomide in the treatment of women with
endometriosis.99
Because of the known risk of teratogenic-
ity and neuropathy a critical and serious
handling with thalidomide is recommend-
ed.
Studies showed that endometriosis cells
need an increased angiogenisis for survival.
Multiple factors are detectable in peritoneal
fluid of patients with endometriosis. In par-
ticular, vascular endothelial growth factor
(VEGF) is traceable.100, 101 Macrophages and
endometriosis cells itself are responsible for
the elevated levels of VEGF.102
In different in vitro or animal trials, VEGF-
Inhibition with antiangiogenic agents like
endostatin could show a suppressed growth
and progression of endometriotic lesions.103
Riassunto
Innovazioni nel trattamento conservativo dell’ en-
dometriosi: review aggiornata
L’endometriosi è un disturbo ginecologico comu-
ne, benigno e cronico. Si tratta anche di un disor-
RUHLAND INNOVATIONS IN CONSERVATIVE ENDOMETRIOSIS TREATMENT
dine estrogeno-dipendente che può portare a di-
smenorrea non trattabile, per periodi sostenuti e/o
irregolari, a movimenti intestinali e minzione dolo-
rosa durante le mestruazioni, a infertilità e infine a
ripetuti interventi chirurgici. Sebbene gli interventi
chirurgici per asportare le lesioni endometriali siano
efficaci nell’alleviare il dolore associato all’endome-
triosi, i tassi di ricorrenza sono alti e molte donne
richiedono terapie mediche costanti per control-
larne i sintomi. L’alleviamento dei sintomi tramite
palliazione del dolore e ottimizzazione della qualità
della vita dovrebbe essere lo scopo principale della
terapia medica. Sono oggi disponibili diverse op-
F
zioni di trattamenti farmacologici. La terapia medica
per l’endometriosi più diffusa utilizza gli agonisti
dell’ormone liberante gonadotropina (GnRH) e i
contraccettivi orali. Sono, inoltre, utilizzati i deriva-
ti progestinici e gli androgeni. Nuove possibilità di
terapia tramite i modulatori selettivi del recettore
O
del progesterone (SPRMs), gli inibitori dell’aromata-
si (AI), gli antagonisti del GNRH, gli inibitori della
ciclossigenasi (COX)-2, il disgregatore dell’angio-
genesi e gli immunomodulatori sono sempre sotto
analisi. Sebbene questi nuovi agenti siano promet-
tenti, sono richieste ulteriori conferme da parte di
O
studi clinici randomizzati.
Parole chiave: Endometriosi - Terapia farmacologica
- Ormoni.
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