Middle East Fertility Society Journal (2015) 20, 6169

Middle East Fertility Society

Middle East Fertility Society Journal

www.mefsjournal.org
www.sciencedirect.com

REVIEW

Emerging treatment of endometriosis

Aboubakr Elnashar
Benha University Hospital, Egypt
Received 24 December 2014; accepted 24 December 2014
Available online 25 February 2015

KEYWORDS
Endometriosis;
Treatment

Abstract Current treatment of endometriosis is mainly based on surgery and ovarian suppressive
agents (oral contraceptives, progestins, GnRh agonist and androgenic agents). Hormonal treatments are often associated with unwanted effects, delayed conception and recurrence of disease
and symptoms when stopped. For these reasons, new drugs that aim new targets are required to
cause regression of the disease & symptoms without adverse hypo-estrogenic effects. This review
aims to provide an update on the new drugs used for treatment of endometriosis. These include
the levonorgestrel-releasing intrauterine device, GnRH antagonists, aromatase inhibitors, selective
estrogen-receptor modulators, progesterone antagonist, selective progesterone receptor modulators,
angiogenesis inhibitors, and immunomodulatory drugs.
2015 The Author. Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

Contents
1.
2.
3.
4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Levonorgestrel-releasing intrauterine device (LNG-IUD). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
GnRH antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Aromatase inhibitors (AIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Aromatase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Aromatase inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Uses in postmenopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Uses in premenopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Selective estrogen receptor modulators (SERMs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Peer review under responsibility of Middle East Fertility Society.

Production and hosting by Elsevier

http://dx.doi.org/10.1016/j.mefs.2014.12.002
1110-5690 2015 The Author. Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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6.
7.
8.
9.
10.

A. Elnashar
Progesterone antagonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Selective progesterone receptor modulators (SPRM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Angiogenesis inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Immunomodulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Others. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.1. Matrix metalloproteinase (MMP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.2. 5-Fluorouracil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.3. Thiazolidinediones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.4. Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
Endometriosis is a common estrogen-dependent disorder that
can result in substantial morbidity, including pelvic pain, multiple operations, and infertility. Current treatment of
endometriosis is mainly based on surgery and ovarian suppressive agents. Approximately only half of women with
endometriosis get pain relief from existing medical or surgical
treatments. Currently available medical therapies are designed
to suppress estrogen synthesis, inducing atrophy of ectopic
endometriotic implants or interrupting the cycle of stimulation
and bleeding. Oral contraceptive, androgenic agents, progestins and gonadotropin-releasing hormone analogues have
all been successfully used in the treatment of endometriosis.
Unfortunately, these hormonal treatments are often associated
with unwanted effects caused by a hypo-estrogenic state. Furthermore, recurrence of disease and symptoms is quite common with all available drugs. An ideal treatment for
endometriosis would induce regression of the disease and its
symptoms without any adverse effects associated with a
hypo-estrogenic state. None of these drugs can eradicate the
disease and, in some cases, the substantial side effects limit
the long-term use of these therapies. Current medical therapies
for endometriosis result in delayed conception and have not
been shown to provide any fertile benet subsequent to treatment. For these reasons, new drugs that aim new targets are
under development (1). These include the levonorgestrel-releasing intrauterine device, GnRH antagonists, aromatase
inhibitors, selective estrogen-receptor modulators, progesterone antagonist, selective progesterone receptor modulators,
angiogenesis inhibitors, and immunomodulatory drugs.
2. Levonorgestrel-releasing intrauterine device (LNG-IUD)
Although oral progestogens for treatment of endometriosis are
effective and cheap, their efcacy is signicantly inuenced by
poor compliance and systemic side effects (2). LNG is a potent
steroid widely used in oral contraceptives and subdermally
implanted contraceptive devices. It is a T-shaped intrauterine
system, developed as a contraceptive device which releases
LNG in the uterine cavity. The release rate of LNG
from the intrauterine releasing system is 20 lg per 24 h
during the rst year, and it slowly decreases throughout the
5 years of use. The released progestogen induces endometrial
atrophy although ovulation is usually not suppressed. This
results in hypomenorrhea or amenorrhea and reduced
dysmenorrheal (3).

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An increasing number of publications indicate an emerging

role for the LNG-IUD in the treatment of endometriosis. In
patients with surgically proven peritoneal as well as rectovaginal endometriosis, the rst pilot studies showed a great
improvement in pain control as well as a reduction in ultrasonographic dimensions of the rectovaginal nodules (3,4).
A signicant reduction of pain as well as staging of the disease observed in 34 women with laparoscopically conrmed
minimal to moderate endometriosis over a period of 6 months
(5). The LNG-IUD is an effective hormonal option for treating
symptomatic endometriosis (minimal to moderate). With a
continuation rate of 68% after 6 months, it has the potential
for providing long-term therapy in a substantial number of sufferers. The presence of adhesions was, as expected, not altered.
Two randomized trials (6,7) were published on LNG-IUD
use in endometriosis. The rst (6) study compared expectant
management with immediate treatment with the LNG-IUD
after laparoscopic surgery for symptomatic endometriosis in
40 women. Twelve months after surgery dysmenorrhea scores
were signicantly lower in the LNG-IUD group compared with
the expectant management group. The second trial (7) compared the efcacy of an LNG-IUD and a GnRH-agonist analog
in the control of chronic pelvic pain in 83 women with stage IIV
endometriosis during a period of 6 months. Both, the LNG-IUS
and the GnRH-analogue were effective in the treatment of
chronic pelvic pain-associated endometriosis, although no differences were observed between the two treatments.
Although the exact mechanism of action of the LNG-IUD
is unclear, recent evidence (8) shows that the LNGIUD delivers signicant amounts of LNG into the peritoneal uid, clearing up the local effect on the endometriotic implants which
may be mediated through estrogen and progesterone receptors,
most probably inducing decidualization. As peritoneal uid
levels of LNG were closely related to the levels in serum, this
suggests a dominant hematogenous mechanism by which
LNG reaches the peritoneal cavity.
A Cochrane systematic review evaluated postoperative use
of an LNG-IUD in women with endometriosis (9). Limited
evidence from one small study has shown that postoperative
use of the LNG-IUD reduces the recurrence of painful periods
in women who have had surgery for endometriosis. There is a
need for further, well-designed RCTs of this approach.
In conclusion, for women with endometriosis who need
long-term treatment, the LNG-IUD may be a treatment of
choice since it permits the same system to be used for at least
5 years with no modications in estrogen levels and few hypoestrogenic side effects (7). In the long term it is a low-cost therapy with usually fewer side effects than other progestogenic

Emerging treatment of endometriosis

agents. Among the additional advantages of the LNG-IUS is
the fact it requires only one medical intervention for its introduction every 5 years. This device could therefore become the
treatment of choice for CPP-associated endometriosis in women who do not wish to conceive. Further studies are required
before this device can be recommended as a treatment for
endometriosis-associated pelvic pain.
3. GnRH antagonists
Gonadotropin releasing hormone agonist analogues have one
serious problem; when rst administered, they cause an
increase in LH and FSH secretion and an increase in estradiol
production. For women with pelvic pain, the increase in ovarian estrogen production is associated with increased pelvic
pain and decreased quality of life (10). However, the agonist
phase is typically limited to the rst 510 days of treatment.
Recently, GnRH antagonists that immediately block GnRH
effects have been developed for clinical use in endometriosis,
leiomyoma, breast cancer, premenstrual syndrome, polycystic
ovary syndrome, and ovulation induction for in vitro fertilization (IVF) (11).
The main mechanism of action of the GnRH antagonists is
competitive receptor occupancy, which results in the blockade
of GnRH receptor dimerization, a biochemical process that is
required for receptor activation. The antagonistic properties of
GnRH exert their effect by competing with endogenous GnRH
for pituitary binding sites (12). The GnRH antagonists suppress LH secretion in a dose-dependent manner. At small doses, the suppression of LH is minimal. At large doses, nearcomplete suppression of LH can be achieved.
In one preliminary study, a total of fteen women received
3 mg of cetrorelix (Cetrotide) weekly for eight weeks (13). Circulating estradiol was suppressed to a mean of 50 pg/ml. All
patients reported a symptom-free period during GnRH
antagonist treatment. Regression occurred in more than half
of the cases and the degree of endometriosis declined to a mild
stage on second look laparoscopy.
Another GnRH antagonist, abarelix, has been demonstrated to be effective in the treatment of pelvic pain caused by
endometriosis (14). However, side effects may have slowed
the progress of the development of this antagonist for treatment of endometriosis.
In conclusion, GnRH antagonists seem to be useful in the
treatment of endometriosis in most cases. Furthermore, fewer
side effects, such as postmenopausal symptoms, occur with this
agent and no estradiol add-back is needed. The GnRH antagonist analogues may be superior to GnRH agonists because
they produce immediate suppression of LH and FSH secretion
and avoid the agonist phase of GnRH agonist therapy. In the
future, new nonpeptic GnRH antagonists are expected to be
available for oral administration. Although they are still under
investigation, these agents have the potential to improve
patients comfort and compliance (15).

63
local estrogen biosynthesis by the aromatase enzyme in
endometriotic lesions. Aromatase activity is expressed in several types of cells in the reproductive system including the ovarian granulosa cell, the placental syncytiotrophoblasts and the
testicular Leydig cells (16). Aromatase is the key enzyme in
estrogen biosynthesis. It catalyzes the conversion of C19 steroids to estrogens (estrone and estradiol). Therefore, there are
no important downstream enzymes to be affected, with the
result that aromatase is an excellent target for inhibition of
estradiol synthesis. In addition, because estrogen is needed to
stimulate ectopic endometriotic tissues in patients with
endometriosis and because of the in situ presence of aromatase
in these tissues, blockage of aromatase activity in these
endometriotic sites with an AI is a rational approach to medical treatment of endometriosis (17).
In women with endometriosis, it has been shown that there
is an increased expression of cytochrome P450 aromatase in
endometrial tissue, but not in women without endometriosis
(18). Although the normal endometrium contains no detectable levels of aromatase activity, this enzyme is induced to very
high levels in endometriotic tissue by the inammatory mediator prostaglandin estradiol (E2) to increase local estrogen production in the disease implants.
4.2. Aromatase inhibitors
The AIs are classied into type I and type II inhibitors. Both
types of inhibitors compete for binding to the active site.
Enzyme activity is then permanently blocked due to an
unbreakable bond between the inhibitor and enzyme protein
(19). Several potent and selective third-generation AIs are
available; of these, anastrozole and letrozole have substantial
advantages over earlier agents in terms of efcacy and tolerability. AIs are FDA approved to treat postmenopausal
women with estrogen receptor positive breast cancer refractory
to tamoxifen. Although these agents have been widely used to
treat postmenopausal or anovulatory patients with breast cancer, clinical experience with AIs in women with endometriosis
is still limited (20). AIs act by blocking aromatase, which converts androstenedione to estrone, an estrogen derivative (21).
Its mechanism of action is by decreasing local production of
estrone causing a low estrogen milieu. Decreasing aromatase
in the brain specically is thought to decrease LH and FSH,
which, in turn, leads to a decrease in estrogen levels as well.
Because the initial response to the effects of AIs is a
decrease in estrogen levels, there is an increase in FSH and
LH. This increase in FSH and LH directly stimulates the
ovary. Stimulating the ovary leads to an increased number of
mature follicles (22). Therefore, using an AI can treat pain
associated with endometriosis, but can also treat the infertility
aspect when used for ovulation induction and in IVF protocols. The two AIs mainly used for endometriosis pain and
infertility are anastrozole and letrozole, both third generation
drugs.

4. Aromatase inhibitors (AIs)

4.3. Uses in postmenopause

4.1. Aromatase activity

In the rst published report of the use of an AI (anastrozole)

for the treatment of endometriosis, a 57 year old woman with
severe recurrent endometriosis experienced complete relief of
pain after 2 months of treatment. (23). Recently Mousa et al.

Medical treatments usually are directed at inhibiting estrogen

action or its production from the ovaries and do not address

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(24) found that Letrozole was superior to exemestane in relieving the endometriosis-associated pain in this postmenopausal
woman. This suggests that patients may respond variably to
different AIs. A post-menopausal woman with a large recurrent abdominal wall endometrioma was managed successfully
with the combination of an AI, a progestin, and serial cyst
aspiration (25).
4.4. Uses in premenopause
In premenopausal women, an AI alone may induce ovarian
folliculogenesis, and thus AIs are combined with a progestin,
a combination oral contraceptive, or a GnRH analogue in
order to prevent reex increments in luteinizing hormone
and follicle stimulating hormone. A small pilot study of 10
reproductive aged women demonstrated that a combination
of letrozole (2.5 mg/day), norethindrone acetate (2.5 mg/day),
calcium and vitamin D for 6 months is effective in both reducing laparoscopically visible endometriotic lesions and decreasing pelvic pain scores (26). In another study, two
premenopausal sisters (24 and 26 years old) were diagnosed
with endometriosis by laparoscopy and failed to respond to
conventional treatment including oral contraceptives and
GnRH analogues. An AI (anastrozole 1 mg/day) was given
with progestin (200 mg/day) for 6 months. The treatment
resulted in a rapid progressive reduction in symptoms with
the maintenance of remission of symptoms and absence of
endometriotic lesions for more than two years after treatment
in both cases. Pregnancy was achieved in both cases after two
years. Side effects were minimal and well tolerated by both
patients (27). Two premenopausal patients with bladder
endometriosis were treated with letrozole (2.5 mg/day),
norethisterone acetate (2.5 mg/day), elemental calcium and
vitamin D3 for 6 months (28). The double-drug regimen quickly improved pain and urinary symptoms in both patients. One
patient had no signicant adverse effect and continued the
therapy for 14 months. The other patient developed myalgia
and severe arthralgia; pain and urinary symptoms recurred
few months after the interruption of the 6-month treatment
and the patient underwent laparoscopic partial cystectomy.
AIs improve pain and urinary symptoms in patients with bladder endometriosis; however, severe side effects of treatment
may occur. These agents should be administered only to
patients who refuse surgery and fail to respond to other
therapies.
In a non-randomized initial study, Amsterdam et al.
evaluated 18 reproductive aged women with refractory pain
from endometriosis who failed two other therapies (29). They
were administered anastrozole 1 mg for 6 months in addition
to a continuous oral contraceptive pill to prevent pregnancy.
This study found there was a decrease in pain scores associated
with the combination of anastrozole and OCP.
Very recently, Letrozole given with combined pills achieved
complete regression of recurrent endometriotic cysts and pain
relief in all cases (30). After a 6-month washout of endometriosis hormone therapies, women took letrozole (2.5 mg), one
tablet of 0.15 mg of desogestrel, and 0.03 mg of ethinyl estradiol, calcium (1200 mg), and vitamin D3 (800 IU) daily for
6 months. Disappearance of ovarian endometrioma and reduction in pelvic pain in all cases at the end of 6 months were
observed. The size of ovarian endometriomas was reduced

A. Elnashar
after 3 months. Pain scores decreased only after 1 month of
treatment and continued decreasing in each treatment month.
Overall, no signicant change in bone density was detected.
A prospective, randomized trial showed that 6 months of
treatment with anastrozole (1 mg/day) and goserelin compared
with goserelin alone increased the pain-free interval and
decreased symptom recurrence rates in patients after surgery
for severe endometriosis (31).
4.5. Side effects
Side effects of AIs are rare, but include headaches and diarrhea. Because AIs decrease estrogen in local tissues, it can
increase the risk of osteoporosis (32). One study found no
change in bone density at 6 months after use of an AI with
an oral contraceptive in premenopausal women, and another
found a decrease in bone density with the use of AI with a
GnRH agonist after 6 months of use in premenopausal women
(33). One case report demonstrated that exemestane was used
to successfully treat pain in refractory endometriosis and might
be a better choice than other AIs because it is potentially bone
sparing (24). Larger, randomized, controlled studies will need
to be done to evaluate the effect of AIs on bone density of
reproductive aged women. It is likely that if a true decrease
in bone density is found, there will be time limitations such
as with depo-provera, as well as recommendations to supplement calcium in these patients. Letrozole is the most common
AI used for ovulation induction. It is given cyclically for infertility compared with continuously if used for pain (22). Letrozole is not FDA approved for this indication and there is a
black box warning regarding using this medication in pregnant
women. One study found that in 911 births that were conceived by using either clomiphene citrate (CC) or letrozole
for ovulation induction, the rate of both chromosomal anomalies as well as major congenital malformations was the same in
the CC and letrozole group (34).
In conclusion, all three combinations were shown to
decrease pain in patients with refractory endometriosis. Regimens which include combinations of an AI with a progestin
or oral contraceptive will probably become more popular than
combinations of an AI with a GnRH analogue because the former are cheaper with fewer side effects, and may be administered long term or for repeated courses (21). Limited data
are available on the long-term course of pain symptoms after
completion of treatment with AIs; however, some recent studies suggest that symptoms may recur at short-term follow-up
(35). No severe adverse effect has been reported during treatment with AIs both in pre- and postmenopausal women. On
the basis of the available data, administration of AIs should
now be offered only to the small number of women who have
severe pain despite previous surgical and hormonal therapies.
Further research in the form of larger sample size randomized
controlled trials will be required before recommending the routine use of these agents.
5. Selective estrogen receptor modulators (SERMs)
Non-steroidal anti-estrogens that bind to estrogen receptors
(ERs) and can act as either estrogen agonists or antagonists,
depending on the target tissue, are known as SERMs (36).
They can be targets toward the a- or b-subunits of the estrogen

Emerging treatment of endometriosis

receptor. Raloxifene is a second-generation SERM that has
been shown to prevent osteoporotic fractures and holds promise for the prevention of breast cancer. In contrast to tamoxifen, a rst-generation SERM, raloxifene has an antiestrogenic
effect on endometrial tissue. SERMs are best known for their
use in menopause and breast cancer.
There is emerging data indicating that this class of medication, specically agonists toward the b-subunit, may be able to
be used to treat endometriosis. The b-unit is felt to act on different targets than classic a-SERMs, such as bone, mammary
and endometrium (37). SERMs directed toward the b-subunit
have been found to have anti-inammatory action in several
rat models toward other inammatory mediated diseases, such
as inammatory bowel disease and rheumatoid arthritis (38).
One study demonstrated that SERMS resolved endometriosis
in 4075% of mice treated with a SERM directed toward the
b-subunit (37). Its effects in human clinical studies are not
yet known.
6. Progesterone antagonist
Mifepristone (RU-486) is best known for its use in medical
abortions (39). Mifepristone is an oral active progesterone
antagonist at the receptor level. It also has a high afnity for
progesterone and glucocorticoid II receptors. With its antiprogesterone effect, mifepristone prevents progesterone from
exerting its action. It also has a direct inhibitory effect on
human endometrial cells and it can modulate the estrogen
and progesterone receptor expression in both eutopic and
ectopic endometrium.
Both mifepristone and onapristone another drug with progesterone antagonist properties have been shown to have
promising effects on endometriosis in the rodent model
(40,41). Several non-randomized small trials have demonstrated a reduction of pain, as well as decrease in visible disease at
time of laparoscopy (42,43). These trials have all used
6100 mg. Kettel et al. published a series of studies of administration of different doses of mifepristone in women with
endometriosis. A minimum dose of 50 mg mifepristone for
six months demonstrated a signicant regression in visible
endometriotic lesions and a decrease in clinical symptoms.
On the other hand, treatment of endometriosis patients with
mifepristone 5 mg per day in an uncontrolled pilot study
resulted in pain improvement but no change in endometriosis
lesions, suggesting this dosage is too low to achieve acceptable
efcacy (42). Side effects are usually seen with doses of
P200 mg. These side effects are due to the antagonistic afnity
of the drug to glucocorticoid receptors causing a hypoadrenal
state.
Further large randomized clinical trials on the use of mifepristone in women with endometriosis should be performed in
the future.
7. Selective progesterone receptor modulators (SPRM)
SPRM are novel progesterone receptor ligands with a high
degree of endometrial selectivity that exhibit agonist/antagonist effects based on the target tissue, dose and presence
or absence of progesterone (44). They have the potential to
induce reversible amenorrhea through selective inhibition of
endometrial proliferation, a direct effect on endometrial blood

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vessels and the potential to suppress endometrial prostaglandin production in a tissue-specic manner without the systemic
effects of estrogen deprivation, providing a rationale for the
treatment of endometriosis-related pain (45).
Asoprisnil is the rst SPRM to reach an advanced stage of
clinical development for the treatment of endometriosis. Asoprisnil can suppress both the menstrual cycle and endometrial
growth (46). To date, there is only one published randomized,
placebo-controlled trial (47) of asoprisnil (5, 10 and
25 mg/day) for 12 weeks in 130 women with a laparoscopic
diagnosis of endometriosis who exhibited moderate or severe
pelvic pain at baseline. All doses of asoprisnil reduced nonmenstrual pelvic pain similarly as well as dysmenorrhea; however, the effect on bleeding pattern was dose-dependent. A
separate study with an identical design using different asoprisnil doses showed that 5 mg is the minimum effective dose for
pain relief in subjects with endometriosis (48).
SPRM have many potential benets over other therapies.
First, they can disrupt cycling in patients without the low-estrogen milieu that causes many side effects in GnRH agonists.
In relationship with antiprogesterones, they are more specic
for the progesterone receptors thus not inhibiting the glucocorticoid receptors as well (49). No serious, drug-related adverse
events were reported during the treatment or follow-up period.
A favorable safety and tolerability prole of asoprisnil with no
signs of estrogen deprivation was reported.
8. Angiogenesis inhibitors
Retrograde menstruation with peritoneal attachment is
believed to lead to the development of endometriotic lesions.
However, this shed endometrial tissue requires the establishment of a new blood supply in order to survive in the peritoneal cavity (50). The endometrium has angiogenic
potential, and endometriotic lesions grow in areas with a rich
vascularization, suggesting that angiogenesis is a prerequisite
for endometriosis development. Therefore, inhibition of
proangiogenic factors (e.g. VEGF and MMPs) may offer
new therapeutic opportunities (51). Anti-vascular endothelial
growth factor agents and other angiostatic drugs (i.e.,
TNP470, endostatin, anginex, rapamycin) have been studied
in laboratory and animal models for treatment of endometriosis. The effectiveness of angiostatic compounds in reducing the
growth of endometriotic lesions has been shown in the mouse
model (52). Only one human study (53) has been performed
thus far suggesting that the angiostatic (and immunomodulatory) compound thalidomide may be effective in women with
relapsing endometriosis.
A novel, non-hormonal, approach to treat endometriosis
may be found in the use of statins. Statin originally developed
to treat heart disease and prolong life expectancy, and statins
lower blood cholesterol levels by inhibiting HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, an enzyme
that controls the rate of cholesterol production (51). There
are potentially very exciting other benets, such as reducing
the risks of diabetes, dementia and even osteoporosis. A recent
report (54) demonstrated that statins also inhibit the growth of
human endometrial stromal cells in vitro, which opens a
promising new eld in endometriosis research.
Rapamycin is a widely used drug with antifungal, immunosuppressant and antiangiogenic effects. A recent animal study

66
demonstrated that administration of rapamycin signicantly
reduced the size of the endometriotic lesions (55). This was
associated by inhibition of VEGF-mediated angiogenesis as
indicated by a suppression of endothelial cell sprouting in vitro
and a reduction of microvessel density in endometriotic lesions
in vivo. Rapamycin induces regression of endometriotic lesions
by inhibiting neovascularization and cell proliferation.
Dopamine and its agonists, such as cabergoline (Cb2), promote VEGF receptor-2 (VEGFR-2) endocytosis in endothelial
cells, preventing VEGF-VEGFR-2 binding and reducing
neoangiogenesis (50). Recent study evaluated the anti-angiogenic properties of Cb2 on growth of established endometriosis
lesions. A signicant decrease in the percentage of active
endometriotic lesions and cellular proliferation index was
found with Cb2 treatment. Neoangiogenesis was reduced by
Cb2 treatment, as observed at gross morphological level and
by signicant changes in gene expression. Cb2 treatment in
experimental endometriosis has an anti-angiogenic effect acting through VEGFR-2 activation. These ndings support the
testing of dopamine agonists as a novel therapeutic approach
to peritoneal endometriosis in humans.
Recently, the effect of dopamine agonist quinagolide on
endometriotic lesions in patients with endometriosis-associated
hyperprolactinemia was evaluated (56). Quinagolide induced a
69.5% reduction in the size of the lesions, with 35% vanishing
completely. By interfering with angiogenesis, enhancing brinolysis, and reducing inammation, quinagolide reduces or
eliminates peritoneal endometriotic lesions in women with
endometriosis.
The potential, limitations and challenges of antiangiogenic
therapy for the treatment of endometriosis have been explored
(57). Antiangiogenic agents tested so far have proven effective
for preventing neo-vascularization of endometriotic lesions
and are likely to be efcient for early-stage disease. However,
antiangiogenic treatments may alter reproductive function by
impairing physiological angiogenesis, the greatest concern
being the potential risk of teratogenicity. The initial promise
of vascular therapy has not yet been fullled, mainly due to
the limited selectivity of the vascular therapies available. The
ongoing evolution in genomics and proteomics is revolutionizing the discovery of novel, disease specic endothelial markers,
leading to improved ligand-based treatments. Combining
angiostatic agents and VDAs with medical and surgical therapies in an adjuvant setting, e.g. with a view to preventing
relapse or improving drug efcacy, may serve to accelerate
the introduction of vascular drugs in the context of
endometriosis treatment. This would probably be the quickest
and most efcient way of enhancing current treatment
modalities.
In conclusion, the vasculature is a promising target because
of its genetic stability, easy access via the circulation and
amplifying action during treatment. The administration of
antiangiogenic drugs has been proved to reduce the establishment, maintenance and progression of endometriotic lesions in
different laboratory and animal models; however, further
investigations are required before clinical trials can be planned
in humans. The role of antiangiogenic compounds in the treatment of endometriosis remains to be dened. It appears unlikely that antiangiogenic drugs may cure the symptoms caused by
large endometriotic nodules that are mainly composed by
bromuscular tissue (58); on the contrary, these agents may
have a role in the postoperative treatment of endometriosis

A. Elnashar
to increase the pain free interval and decrease the recurrence
of the disease.
9. Immunomodulators
The mounting evidence shows that altered immune function
plays a crucial role in the genesis and development of
endometriosis. It has become clear that pelvic inammation,
increased macrophage activation and invasion of the extracellular matrix are potential targets for endometriosis treatment
and/or prevention (51). Immunomodulators are thought to
work by decreasing the inammatory response to disease.
The molecules that allow for ectopic endometrial cells to
implant on the peritoneum and begin growing are thought to
be mediated through this process (1). Most of these compounds have not been thoroughly tested in humans, but initial
studies in rodent models are promising. This broad group of
medications includes loxoribine, IFN-a 2 b and TNF-a
inhibitors.
Loxoribine is thought to stimulate natural killer cells, which
then do not allow endometrial cells to implant in ectopic tissues. One small study in rat models showed that there was a
signicant reduction in amount of disease (59).
IFN-a 2 b is another immunomodulator that has been
shown to decrease endometriosis in animal models and in tissue cultures (1). The route of administration of this medication
is by intraperitoneal placement during laparoscopy or by subcutaneous injections. Due to this invasive administration, this
drug would likely be approved only for refractory disease. One
small, prospective randomized study found that intraperitoneal treatment with IFN-a 2 b during surgery with a GnRH
agonist postoperatively increased recurrence risk after surgery
(60).
One of the most promising interventions seems to be the
selective blocking of TNF-a production. Therapeutic
manipulation of the immune system through TNF-a inhibitors
may be benecial in women with endometriosis (61) TNF-a
inhibitors, such as etanercept, are a new form of therapy mostly used for rheumatoid and autoimmune diseases. They work
by decreasing production or release of TNF-a from macrophages. TNF-a inhibitors may have role in preventing disease
progression or causing regression of early stage disease. In the
rodent (61) and baboon model (62), it has been shown that
TNF-a binding protein is able to inhibit the development of
endometriosis and endometriosis-related adhesions. In
humans, however, the evidence is not so promising. There is
one case report of patient with advanced endometriosis who
was on a TNF-a inhibitor and who showed no improvement
of infertility or endometriosis based on laparoscopy after several years of taking the medication (63). A randomized placebo-controlled trial was designed with 21 women with severe
pain and a rectovaginal nodule (64). After 1 month of observation, three infusions of an anti-TNF-alpha monoclonal antibody (iniximab; 5 mg/kg) or placebo were given. Surgery
was performed 3 months later and follow-up continued for
6 months. Pain severity decreased during the treatment by
30% in both the placebo and iniximab groups. However,
no effect of iniximab was observed for any of the outcome
measures. After surgery, pain scores decreased in both groups
to less than 20% of the initial value. Iniximab appears not to
affect pain associated with deep endometriosis.

Emerging treatment of endometriosis

In conclusion, there is no enough evidence to support the
use of anti-TNF-alpha drugs in the management of women
with endometriosis for the relief of pelvic pain (65). No evidence of clinical benets of iniximab was found for
endometriotic lesions, dysmenorrhea, dyspareunia or pelvic
tenderness.
Several cytokines may also play a role in the treatment of
endometriosis. A major function of interleukin-12 (IL-12)
and IL-18 is the regulation of the adaptive immune response
(66). IL-12 induces other cytokines, particularly interferon-c
(IFN-c), which coordinate the ensuing immune response.
Intraperitoneal injection of IL-12 in a murine model of
endometriosis demonstrated a signicant reduction of ectopic
endometrial implantation (67).
Pentoxifylline, a phosphodiesterase inhibitor, is the rst
immune-modulator agent investigated for the treatment of
endometriosis (68). Pentoxifylline inhibits phagocytosis and
generation of toxic oxygen species and proteolytic enzymes
by macrophages and granulocytes in vitro and in vivo. Moreover, pentoxifylline inhibits both TNF-a production by macrophages, and the proinammatory action of TNF-a and IL-1 on
granulocytes in vitro. One randomized controlled trial evaluated the effect of pentoxifylline on future fertility in infertile
women with asymptomatic minimal or mild endometriosis
(69). Patients were allocated to receive either a 12 month
course of oral pentoxifylline (800 mg/day) or an oral placebo.
The 12 month actuarial overall pregnancy rates were 31 and
18.5% in the pentoxifylline and placebo groups respectively.
However, this difference was not statistically signicant.
Therefore, there is no evidence from this study that
immunomodulation with pentoxifylline aids fertility in those
women with minimal or mild endometriosis. A Cochrane systematic review to determine the effectiveness and safety of pentoxifylline, in the management of endometriosis in subfertile
women showed that pentoxifylline had no signicant effect
on reduction of pain (70). There was no evidence of an increase
in clinical pregnancy events in the pentoxifylline group compared with placebo.
In conclusion, there is no enough evidence to support the
use of pentoxifylline in the management of premenopausal
women with endometriosis in terms of subfertility and relief
of pain outcomes. Further studies including more infertile
patients with endometriosis are desirable.
10. Others
10.1. Matrix metalloproteinase (MMP)

67
nicant decreases in the implant areas compared with the controls. Low-dose Dox caused regression of endometriosis in
experimental rat model.
10.2. 5-Fluorouracil
Recent study investigated the effects of antiproliferative drugs
(anastrozole, methotrexate, and 5-uorouracil [5-FU]) on the
proliferation of endometriotic cells in vitro and in vivo (74).
Although anastrozole, methotrexate, and progesterone were
ineffective, 5-FU signicantly decreased the proliferation of
endometriotic cells in vitro and controlled the growth of both
cells from ovarian endometrioma and deep inltrating
endometriosis. Considering common features between
endometriotic cells and tumor cells, the use of 5-FU could be
an option in the management of severe endometriosis.
10.3. Thiazolidinediones
Thiazolidinediones (TZDs) do not impede conception and
have been shown to reduce endometriotic lesions in animal
models. One human study evaluated the effectiveness of a
TZD in treating endometriosis-related pain. Participants were
given rosiglitazone, 4 mg daily, for 6 months (75). Two of the 3
patients exhibited improvement in severity of symptoms and
pain levels with a concurrent decrease in pain medication,
while one experienced no change. Rosiglitazone was well tolerated by all patients. Combined with data gathered from studies
in rats and nonhuman primates, the results from this study
offer positive justication for using TZDs as a well-tolerated
treatment for endometriosis that can address pain without
impeding ovulation and without the need for add-back
therapy.
10.4. Metformin
In a rat model, Oner et al. (76) found that metformin and
letrozole caused a statistically signicant regression of
endometriotic implants. Metformin suppresses the inammatory response, the activation of aromatase enzyme and the proliferation in endometriotic stromal cells after culture in a sterile
medium (77). In human, metformin 500 mg three times daily
for 6 months resulted in a signicant reduction in the patients
complaints (P < 0.01) and in the serum levels of IL-6, IL-8 &
VEGF, suggesting that it may have a therapeutic potential as
an anti-endometriotic drug (78).
Conict of interest

The MMPs are a family of endopeptidases that are capable of

degrading components of the extracellular matrix. It is important to many physiological and pathological processes, including embryo implantation, cyclic endometrial breakdown and
endometriosis, and is regulated by its natural occurring inhibitor, tissue inhibitors of matrix metalloproteinase (TIMPs) (71).
Suppressing the action of secreted MMPs from human ectopic
endometrium with TIMP-1 signicantly inhibited the establishment of endometriosis lesions in a nude mice model (72).
Doxycycline (Dox) has a number of non-antibiotic properties. One of them is the inhibition of matrix metalloproteinase
(MMP) activity. Recent study assessed the effects of Dox in a
rat endometriosis model (73). Treatment with Dox caused sig-

The author declares that there is no conict of interest.

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