Pharmacologic therapies in

endometriosis: a systematic review

rgio Reis Soares, M.D.,a Alicia Martínez-Varea, M.D.,b Juan Jose
Se
Hidalgo-Mora, M.D.,c
and Antonio Pellicer, M.D.b,d
a
Instituto Valenciano de Infertilidad, IVI Lisboa, Lisbon, Portugal; b Hospital Universitario y Polite
cnico La Fe, Valencia;
c
Hospital Comarcal de Vinaroz, Castello
n; and d Instituto Universitario IVI, Universidad de Valencia, Valencia, Spain

To assess the literature on preclinical and clinical efficacy and safety data of pharmacologic groups proposed in the treatment of en-
dometriosis, we performed a systematic review of publications from March 2002 to January 2012 via PubMed search. Additional rel-
evant articles were identified from citations within these publications. A high number of medications were tested in preclinical models
of endometriosis due to their theoretic capacity of disrupting important pathophysiologic pathways of the disease, such as inflammatory
response, angiogenesis and cell survival, proliferation, migration, adhesion, and invasion. Tumor necrosis factor a-blockers, nuclear
factor kB inhibitors, antiangiogenic agents, statins, antioxidants, immunomodulators, flavonoids, histone deacetylase inhibitors, ma-
trix metalloproteinase inhibitors, metformin, novel modulators of sex steroids expression, and apoptotic agents were all effective in
in vitro/animal models. Most of these agents have not been tried in the clinical setting, mainly because of the high risk of adverse effects.
However, some of them can be used in humans. Dopamine agonists and valproic acid have already been tested in pilot studies with good
results. Etanercept, metformin, and statins are used in humans for other indications, and endo-
statin is now being tested in phase 2 oncologic trials. These drugs may constitute alternatives to
conventional therapy with estrogen inhibitors and anti-inflammatory agents. (Fertil SterilÒ Use your smartphone
2012;98:529–55. Ó2012 by American Society for Reproductive Medicine.) to scan this QR code
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P
harmacologic therapy is based involved in the fundamental aspects tractant protein (MCP-1),
on targeting molecular steps of the pathophysiology of endometri- granulocyte macrophage colony-
that are relevant for the patho- osis. It is the core of the rich and intri- stimulating factor (GM-CSF), and
physiologic process of a disease. The cate interconnection that exists TNF-a and IL-1b themselves (1–4).
pathophysiology of endometriosis among them. Cytokines such as tumor 2. Nitric oxide (NO) and vascular endo-
comprises the inflammatory response, necrosis factor a (TNF-a) and interleu- thelial growth factor (VEGF), the
cell survival, proliferation, migration, kin-1b (IL-1b), released by peritoneal most prominent proangiogenic fac-
adhesion and invasion, and neoangio- macrophages and ectopic endometrial tor in endometriosis (5).
genesis. The molecular pathways in- cells, activate transcription factors 3. Matrix metalloproteinases (MMPs)—
volved in these processes are all such as nuclear factor-kB (NF-kB) and MMP-1, MMP-2, MMP-3, MMP-7,
integrated (Fig. 1). Medications capable activator protein 1 (AP-1). Active tran- and MMP-9—involved in the degra-
of affecting the activity of one molecule scription factors bind to the DNA of ec- dation and remodeling of the extra-
very often interfere with several pro- topic endometrial/endometriotic cells cellular matrix of the peritoneal
cesses simultaneously. Moreover, in and induce the transcriptional activity surface (4–7).
a number of cases, one agent may actu- of genes that encode for the following 4. Increased antiapoptotic gene profile
ally have a direct impact on more than products: (6, 8, 9).
one pathophysiologic target. 5. Adhesion molecules, such as CD-44s
The ‘‘major proinflammatory cyto- 1. Other cytokines, such as IL-6, IL-8, (a cell surface glycoprotein involved
kines/transcription factors axis’’ is the macrophage migration inhibitory in the adhesion of endometrial cells
crossroads of the molecular pathways factor (MIF), monocyte chemoat- to peritoneal mesothelial cells), in-
tercellular adhesion molecule 1
Received June 5, 2012; revised July 16, 2012; accepted July 17, 2012.
S.R.S. has nothing to disclose. A.M.-V. has nothing to disclose. J.J.H.-M. has nothing to disclose. A.P. has
(ICAM-1, also a cytokine), and vas-
nothing to disclose. cular cell adhesion molecule 1
Reprint requests: Se
rgio Reis Soares, M.D., Instituto Valenciano de Infertilidad, IVI Lisboa, Av. Infante
Dom Henrique, 333-H, 1800–282 Lisbon, Portugal (E-mail: sergio.soares@ivi.es).
(VCAM-1) (4–6).
Therefore, the definition of thera-
Fertility and Sterility® Vol. 98, No. 3, September 2012 0015-0282/$36.00
Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc.
peutic agents as ‘‘anti-inflammatory,’’
http://dx.doi.org/10.1016/j.fertnstert.2012.07.1120 ‘‘immunomodulators,’’ or ‘‘inducers of

VOL. 98 NO. 3 / SEPTEMBER 2012 529

VIEWS AND REVIEWS
FIGURE 1
A model of the most relevant molecular pathways in epithelial and stromal ectopic endometrial cells involved in the pathophysiology of
endometriosis. *Major proinflammatory cytokines are produced by both peritoneal macrophages and endometriotic cells. **Altered peritoneal
cell-mediated immunity seen in endometriosis is related to inflammatory cytokine expression profile. (Source: References 1–9.)
Soares. Drug therapies in endometriosis. Fertil Steril 2012.
apoptosis’’ is, to a non-negligible extent, too reductionist, es-
pecially if they relate to the major proinflammatory cytokines/
transcription factors axis. Still, for the sake of organization,
some classification cannot be avoided. Whenever possible,
we have tried to classify a pharmacologic agent according to
its most immediate and direct molecular effect. For instance,
any molecule that inhibits estrogen production may ulti-
mately lead to, among other things, reduced angiogenesis,
but this agent is classified as a sex steroid expression modula-
tor rather than an antiangiogenic agent. Pharmacologic
groups were divided in two: those only tested in experimental
in vitro and animal models, and those with at least one agent
already tested in the treatment of endometriosis in humans.
MATERIALS AND METHODS
We provide a systematic review of the literature available in
the PubMed database on clinical and experimental in vitro
and animal studies on pharmacologic therapy in endometri-
osis, published in English or in Spanish, from March 2002
to January 2012. Classic therapies for which the most relevant
studies were published more than 10 years ago have already
been extensively reviewed—such as gonadotropin-releasing
hormone (GnRH) agonists, danazol, and oral contraceptive
pills (OCPs)—and are not included in this systematic review.
530
Table 1 shows the list of medications searched for. Terms
were searched in combination with the word ‘‘endometriosis,’’
as in this example: ‘‘endometriosis AND TNF-a blockers.’’ Ad-
ditional relevant articles were identified from citations within
these publications. References with abstracts that demon-
strated them to be unrelated to the pharmacologic treatment
of endometriosis were excluded without a full text assess-
ment, as were reviews and case reports. All original articles
with abstracts that indicated them to be within the scope of
this study were fully assessed; when this assessment was con-
firmed, they were included in the review (10). Figure 2 sum-
marizes the steps involved in literature selection based on
Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) guidelines. Institutional review
board approval did not apply.
PHARMACOLOGIC GROUPS TESTED IN
IN VITRO/ANIMAL MODELS OF
ENDOMETRIOSIS
Tumor Necrosis Factor a Blockers
The inflammatory cytokine TNF-a is a potent inducer of the
activation of transcription factors that determine the
production of proteins that coordinate the pathophysiology
of endometriosis. Specific TNF-a blockers or general
VOL. 98 NO. 3 / SEPTEMBER 2012
 Fertility and Sterility®

from patients has been shown to be significantly inhibited

TABLE 1
by this agent (13).
Terms searched at Pubmed: medications in combination with
The effects of etanercept on endometriotic implants in
‘‘endometriosis.’’ a rat model were evaluated in randomized controlled studies
Anginex (14–17). Treated animals showed significant changes in the
Angiostatin volume of lesions, histopathologic scores, and molecular
Anti-oxidants parameters such as serum levels of VEGF, IL-6, and TNF-a.
Apoptotic agent(s)
Aromatase inhibitors
The same effect was observed with the use of infliximab (a
Clomiphene citrate monoclonal antibody against TNF-a) (17). Both etanercept
Contraceptive AND patches and infliximab reduced endometriotic implants and plasma
Contraceptive AND vaginal ring NO levels, while the levels of asymmetric dimethyl arginine
COX-2 inhibitors
Dopamine agonists (ADMA), an endogenous nitric oxide synthase (NOS) antago-
Endostatin nist, were increased.
Etanercept The use of etanercept in spontaneous peritoneal endome-
Flavonoids
GnRH-antagonists
triosis in baboons was tested in a randomized, controlled,
Histone deacetylase inhibitor blinded study that included 12 animals that received either
Hyaluronic acid etanercept or placebo (18). In spite of the small sample size,
Imiquimod a statistically significant decrease in red lesion surface area
Interleukin-12
Isoflavones was noted in the treatment group.
Leflunomide The efficacy of c5N, a specific anti-TNF-a monoclonal an-
Levamisole tibody (mAb), in the reduction of established lesions in exper-
Matrix metalloproteinase inhibitor imental endometriosis induced in baboons was also tested in
Melatonin
Metformin a randomized controlled study (19). Laparoscopic controls
Mitogen activated protein kinase inhibitor were made the moment medication was administered and 25
Nuclear factor kappa B inhibitors days after treatment. The antibody significantly decreased the
Patches
Peroxisome proliferator activated receptor
total number, surface area, and volume of endometriosis-like
Progesterone lesions, mainly through a reduction in the most active red le-
Progesterone receptor binding sions. No impact on the menstrual cycle was found. Later, the
Progesterone receptor modulator same animals included in this study were resubmitted to intra-
Rapamycin
Selective estrogen receptor beta agonist venous (IV) doses of c5N, and two of them died of unspecified
Selective estrogen receptor modulators causes (11). Adverse events associated with TNF-a inhibitors
Soluble flt-1 such as malignancies and activation of latent infections were
Statins
Thalidomide
reported (20). However, studies with animals and humans
TNF-a blockers have yet to definitively tie etanercept, the TNF-a inhibitor cur-
TNP-470 rently used for the treatment of various inflammatory diseases,
VEGF blockers to such side effects (11). The use of other agents from this phar-
VEGF inhibitors
macologic group in the treatment of endometriosis demands
Soares. Drug therapies in endometriosis. Fertil Steril 2012.
caution and should not be considered at present.

anti-inflammatory agents may interfere with this process
(11). In this section, we focus on specific TNF-a blockers
(anti-inflammatory agents are described later).
Soluble TNF-a receptor 1 (also known as TNF-binding
protein, or TBP) has been demonstrated to block the transcrip-
tion of inflammatory cytokines involved in endometriosis in
the immortalized 12Z epithelial endometriotic cell line (4).
In human endometriotic stromal cell (hESCs) cultures, small
interfering RNA (si-RNA) that silences the TNF-a gene was
shown to determine the down-regulation of the expression
of IL-8 and genes that inhibit apoptosis, which are major
markers of the TNF-a activated NF-kB pathway (12).
Etanercept is a fusion protein consisting of human re-
combinant soluble TNF receptor 2 (p75) conjugated to a hu-
man Fc antibody subunit, which neutralizes TNF activity. It
is used for rheumatoid arthritis, juvenile rheumatoid arthritis,
and psoriatic arthritis, with no known serious adverse effects
with long-term usage. In vitro, enhanced proliferation ob-
served in epithelial and hESCs cultured with peritoneal fluid
Nuclear Factor kB Inhibitors
The NF-kB peptide family comprises the most important
group of transcription factors involved in the inflammatory
and immune responses seen in endometriosis. Nuclear factor
kB is activated by cytokines such as TNF-a and IL-1b and
binds to DNA to determine key transcriptional activity (1,
21). A number of substances have been presented in the
literature on endometriosis as NF-kB inhibitors: molecules
that act directly at NF-kB blocking, such as IkB protease
inhibitor (TPCK), thalidomide, BAY 11-7085, the urinary
preparation human chorionic gonadotropin A (hCG-A),
pyrrolidinedithiocarbamate (PDTC), and costunolide; or
others, such as GnRH agonists, known to treat
endometriosis by inducing hypoestrogenemia (2, 3, 5–9, 21).
Most of the studies of NF-kB activation inhibitors as po-
tential therapeutic agents in endometriosis use the model of
in vitro culture of hESCs or, less frequently, the 11Z and
12Z immortalized epithelial endometriotic cell lines (2, 3,
5–9). The effects of cell culture exposure to NF-kB

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VIEWS AND REVIEWS
FIGURE 2
Preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram summarizing the steps involved in the systematic review of
pharmacologic therapy in endometriosis.
Soares. Drug therapies in endometriosis. Fertil Steril 2012.
inhibitors have been studied at the molecular and the cellular
level. In the former, a reduction in NF-kB activation and
corresponding inhibition of the expression of genes that
encode for inflammatory cytokines (IL-6, IL-8, MCP-1, GM-
CSF), extracellular matrix remodeling mediators (MMP-2,
MMP-3, MMP-7, MMP-9), apoptosis inhibitors, CD-44 and
VEGF and their protein products were consistently docu-
mented (2, 3, 5–9, 21). At the cellular level, cell
proliferation, motility, adhesion, and invasion ability tested
in vitro were significantly reduced, and apoptosis was
increased (6, 8, 9).
It is interesting that whenever molecular and cellular ef-
fects were also tested in eutopic endometrial cell cultures they
were shown to be statistically significantly less intense than
those seen in endometriotic cells (5, 6, 9). This finding is
positive when considering the eventual use of these
molecules in women of reproductive age.
Pyrrolidinedithiocarbamate (PDTC) was also tested in
peritoneal endometriosis induced in rats (22). The average
volume of lesions and their vascularity were statistically sig-
nificantly reduced in the treated group in comparison with
controls.
Statins
Statins are molecules that lower cholesterol synthesis by
blocking the conversion of 3-hydroxi-3-methylglutaryl-
532
coenzime A into mevalonate, a cholesterol precursor. They
also have been demonstrated to inhibit cell proliferation in
a number of biologic systems, such as in vitro cultures of eu-
topic endometrial stromal cells, by mechanisms that have yet
to be clarified (23). Attenuation of growth-regulating signal-
ing and anti-inflammatory, antioxidant, and antiangiogenic
properties have been proposed (24).
In vitro cultures of hESCs to which simvastatin was added
have displayed a statistically significant, dose-dependent re-
duction in the number of viable cells and cell adhesion as well
as increased apoptosis (25, 26). Altered cell morphology
related to the F-actin cytoskeleton also was a consistent
finding, which can be associated with impaired cell
adhesion and motility. It is interesting that inhibition of
MMP-3 protein was also documented, and MMPs are known
to participate in tissue remodeling, a process that depends on
cell adhesion and motility (27). Lovastatin was also capable of
inhibiting stromal cell invasion and angiogenesis in a three-
dimensional fibrin matrix culture system (28). Finally, ator-
vastatin significantly inhibited the expression of the
inflammatory and angiogenic genes COX-2 and VEGF, and
increased the expression of anti-inflammatory genes such
as peroxisome proliferator-activated receptor g (PPAR-g) in
cultures of both eutopic stromal and human endometriotic
stromal cells (29).
The peritoneal model of endometriosis in rodents was
used to test atorvastatin (24, 30). In a dose that
VOL. 98 NO. 3 / SEPTEMBER 2012

approximately doubles the maximal dose prescribed for the
treatment of hypercholesterolemia in humans, it was
associated with statistically significant reductions in the
expression of VEGF and MMP-9 and a statistically significant
increase in the marker of antioxidant activity superoxide dis-
mutase (SOD). However, it has achieved conflicting results in
endometriosis-like lesions: one study found a statistically sig-
nificant reduction in the lesions area, but in another only in-
traperitoneal atorvastatin was able to reduce their weight and
volume significantly (24, 30). On the other hand, simvastatin
led to a significant and dose-dependent reduction in the num-
ber of animals developing endometriosis-like lesions and in
the number and size of the lesions (27).
The anti-inflammatory properties of simvastatin and me-
vastatin have been demonstrated by both in vitro culture of
endometrial cells and endometriosis induced in mice (31). In
both models, monocyte chemotactic protein-1 (MCP-1) ex-
pression was inhibited by these drugs in a dose-dependent
fashion.
As the use of statins is considered as a preventive/
therapeutic option for endometriosis, extreme caution must
be exercised in the avoidance of its association with danazol,
since pancreatitis and fatal rhabdomyolysis were described
(32, 33).
Melatonin
Endometriosis is a condition associated with imbalanced ox-
idative stress. Reactive oxygen species (ROS) are up-regulated
and antioxidants depleted in the peritoneal fluid of affected
women (34, 35). The indole N-acetyl-5-methoxytryptamine,
or melatonin, is the major secretory product of the mamma-
lian pineal gland. Melatonin is a free radical scavenger and
a broad-spectrum antioxidant, and it may therefore interfere
with the oxidative stress seen in endometriosis. It may also
have an impact on the extracellular matrix remodeling seen
in this disease, through the regulation of the zinc-requiring
proteolytic enzymes MMPs (34–36).
In controlled studies with the murine model of endometri-
osis, daily melatonin led to a significant reduction in the vol-
ume and weight of endometriosis-like lesions. Molecular
markers of oxidative stress such as malondialdehyde (MDA)
were statistically significantly reduced, and antioxidant ac-
tivity, measured by SOD and catalase (CAT), was statistically
significantly increased (34, 35).
The impact of melatonin on the development of endome-
triosis through oxidative stress balancing was elegantly dem-
onstrated by a study in which pinealectomized rats with
induced endometriosis developed lesions of a volume statisti-
cally significantly higher than seen in a control group in
which endometriosis was induced with no previous pinealec-
tomy (37). In the pinealectomy group, the level of MDA was
statistically significantly higher, and SOD and CAT activity
was statistically significantly lower. Administration of mela-
tonin reversed this picture: lesions in treated animals became
similar to those seen in the controls.
The possible effect of melatonin on the regulation of en-
dometriosis by interfering with MMP activity was tested in
the mice model. Melatonin down-regulated proMMP-9 and
VOL. 98 NO. 3 / SEPTEMBER 2012
Fertility and Sterility®
MMP-3 expression and activity, and enhanced the expression
of a natural inhibitor of MMPs known as TIMP-1 (tissue in-
hibitors of metalloproteinases) in a dose-dependent manner.
The preventive and therapeutic action in endometriosis-like
lesions was confirmed, with an increased apoptotic index
(36, 38).
Mitogen-Activated Protein Kinase Inhibitors
P38 mitogen-activated protein kinase (p38 MAPK) is an intra-
cellular signal-transducing molecule that is part of the path-
way responsible for the connection between inflammatory
and other extracellular signals and intracellular responses
such as gene expression. Because activation of p38 MAPK
may be involved in the pathogenesis of endometriosis, spe-
cific inhibitors of this molecule have been tested as a thera-
peutic option (39, 40).
The p38 MAPK inhibitors SB203580 and FR167653 were
tested in a murine model of endometriosis. Statistically sig-
nificant reductions in p38 MAPK phosphorylation and in
the weight and size of lesions were observed. In the peritoneal
fluid and cells of treated animals, IL-1b, TNF-a, MMP-2 and
MMP-9 mRNA levels and IL-6 and MCP-1 protein levels were
statistically significantly decreased, evidencing an improve-
ment in the inflammatory environment generated in the
endometriotic-like peritoneal cavity of rodents (39, 40).
Immunomodulators
Peritoneal immune surveillance systems are impaired in en-
dometriosis (41, 42). In the peritoneal fluid of affected
women, decreases in natural killer (NK) cell activity,
dysfunction of T lymphocytes, infiltration of macrophages,
and aberrant concentrations of immune-related cytokines
are observed (42). The following agents with immune proper-
ties have been investigated in the treatment of endometriosis.
In rats with induced endometriosis, peritoneal adminis-
tration of IL-12 enhanced the cytotoxicity of splenic NK cells
and decreased the development of endometriosis-like lesions
(42). The depletion of NK cells with b chain monoclonal anti-
body (anti-IL-2Rb mAb), a specific anti-IL-2 receptor, re-
versed this effect. These facts indicate that IL-12 acts in
lesions through NK-cell activation.
Other immunomodulators had been tried in the murine
model of endometriosis. Imiquimod, an imidazoquinoline,
stimulates monocytes, macrophages, and dendritic cells to
produce cytokines that are important inducers of cell-
mediated immunity. It is currently used as a topical immune
modifier for the treatment of condylomata acuminata (41).
Leflunomide, used mainly in rheumatoid arthritis, has anti-
inflammatory, antipyretic, and analgesic effects. At high
doses, its active metabolite A77 1726 suppresses IL-1 and
TNF-a production (43). Levamisole is currently used as an an-
thelminthic drug and as an adjuvant in the treatment of colo-
rectal adenocarcinomas. Moreover, this molecule can
stimulate the formation of antibodies to various antigens, en-
hance the cellular immune response provided by T cells, and
potentiate monocyte, macrophage, and neutrophil functions
(44). All these agents were shown to statistically significantly
533
VIEWS AND REVIEWS
reduce the volume of endometriosis-like lesions, with regres-
sion of both glands and stroma, when compared with controls
(41, 43–45). Their precise mechanisms of action in
endometriosis are still unknown.
Temsirolimus is one of the mTOR (mammalian target of
rapamycin) inhibitors that are currently available for clinical
use and has been approved for the treatment of renal cell car-
cinoma. This mTOR is a protein kinase that controls protein
synthesis related to cell growth and proliferation, and all
mTOR inhibitors act by binding to mTOR with high specificity
(46). Human endometriotic cells display a hyperproliferative
phenotype that is associated with activation of the mTOR
pathway. In epithelial and stromal cells extracted from
women with deep infiltrating endometriotic nodules, mTOR
inhibition by temsirolimus alters the phenotype in both
in vitro and in vivo mouse models of deep infiltrating endo-
metriosis (46). Blockage of the mTOR pathway may be consid-
ered a novel line of research in the treatment of endometriosis.
Matrix Metalloproteinase Inhibitors
The endometrium undergoes cyclic extracellular matrix re-
modeling. Matrix metalloproteinases (MMPs) are a series of
proteolytic enzymes that are involved in the degradation
and reconstruction of the extracellular matrix, and derange-
ment of MMP regulation is considered to be a critical factor
in the development of pathologic conditions such as endome-
triosis (36, 47, 48). Therefore, MMP inhibitors might interfere
with the development of the disease.
A mouse model of adenomyosis induced by grafting the
anterior pituitary gland into the uterine lumen was used to
test the TIMP known as ONO-4817 (48). Oral administration
of the compound determined a lower grade of progression
of adenomyosis than in control mice. Other drugs described
elsewhere in this review, such as statins, melatonin, MAPK in-
hibitors, and metformin, have also been reported to interfere
with the pathophysiology of endometriosis by inhibiting
MMP expression, though this is not their sole or most impor-
tant mechanism of action.
Despite the possible effectiveness of MMP inhibitors in
the prevention and treatment of endometriosis, care must be
taken regarding the side effects of excessive TIMP activity
on reproduction. In the rat model of endometriosis, recombi-
nant TIMP-1 administration is associated with reproductive
abnormalities such as fewer ovarian follicles and fewer and
altered zygotes (49). The fact that treatment with a TIMP-1
function-blocking antibody statistically significantly
improved all these parameters goes a long way toward estab-
lishing TIMP-1 as a cause of reproductive problems.
Apoptotic Agents
Evidence has been gathered that endometrial cells from
women with endometriosis overexpress antiapoptotic genes
such as Bcl-2, and strongly inhibit proapoptotic genes such
as Bax (50, 51). This general antiapoptotic gene profile
seems to be important for the survival and proliferation of
endometrial cells when they reach the peritoneal cavity, and
becomes a prerequisite for endometriosis to occur.
534
Molecules that can alter this profile are candidates to treat
the disease.
Curcumin, a natural polyphenolic compound used in pop-
ular medicine as an anti-inflammatory agent, is also reported
to be a NF-kB inhibitor and to induce p53-mediated apoptosis
(52, 53). In endometriosis induced in rodents, it was capable of
both preventing and treating established lesions (54, 55). With
the highest oral dose in use (150 mg/kg per day), ectopic
glandular tissue disappeared, and VEGF expression and
microvessel density were proportionately reduced. This
effect was not found in eutopic endometrium (54).
Some investigators believe that the effects of curcumin
in endometriosis are a result of its anti-inflammatory
action, generated by the inhibition of TNF-a and IL-1b in-
duced NF-kB activation. In fact, this effect has been con-
firmed, and it explains the reduced expression of VEGF
and MMP-3 seen in vivo and the reduced expression of
IL-6, IL-8, MIF, MCP-1, ICAM-1, and VCAM-1 in in vitro
cultures of hESCs (56–58). On the other hand, comparison
of curcumin with celecoxib, an anti-inflammatory agent
that specifically inhibits COX2, has shown that the statisti-
cally significant increases in the Bax/Bcl-2 ratio, the ex-
pression of p53 (a potent apoptosis inducer), and the
apoptotic index of stromal and epithelial endometriotic cells
that are seen in animals treated with curcumin are not seen
with celecoxib (55).
Other apoptotic agents that have been tested are bufalin
and b-hydroxyisovalerylshikonin (b-HIVS). Bufalin is a major
digoxin-like C-24 steroid obtained from the skin and parotid
venom glands of toads, and b-HIVS is an adenosine triphos-
phate (ATP) noncompetitive inhibitor of protein-tyrosine
kinase. Both medications have demonstrated apoptosis-
inducing activity in oncologic treatments. In hESCs cultures,
they statistically significantly reduce the number of viable
cells, statistically significantly inhibit DNA synthesis, and
statistically significantly increase DNA internucleosomal
fragmentation (59, 60). With bufalin, all these effects are
statistically significantly less pronounced in eutopic
endometrial stromal cell culture. The effects of b-HIVS are
stronger and less selective, with a more significant effect on
eutopic endometrial cells. Confirmation that the effects of
bufalin and b-HIVS on hESCs are due to the induction of
apoptosis was obtained by the observation of down-
regulation of the expression of cyclin-A, Bcl-2, and the Bcl-
XL proteins; the expression of Bax, p21, and cleaved
caspase-3, 8, and 9 proteins are all up-regulated (59, 60).
Metformin
Metformin, an insulin sensitizer from the family of the bigua-
nides, is widely used in the treatment of diabetes and polycystic
ovary syndrome. A modulator effect on the inflammatory re-
sponse and on sex-steroid production has also been reported (61).
Cultures of hESCs preincubated with metformin show
statistically significantly reduced IL-b1-induced IL-8 produc-
tion in a dose-dependent fashion (61). The same effect was
observed in the capacity of stromal cells to convert androste-
nedione into estrone (a step that depends on aromatase activ-
ity) and also in DNA synthesis (a marker of cell proliferation).
VOL. 98 NO. 3 / SEPTEMBER 2012

Metformin did not inhibit IL-8 secretion from eutopic endo-
metrial stromal cells.
Metformin used on abdominal endometriosis induced in
rats resulted in a statistically significant reduction of volume,
weight, and mean surface area of established lesions compared
with no reduction observed in controls (62, 63). Histologic
analysis of the lesions showed that treatment with metformin
was associated with a stronger reduction in epithelial cells
and smaller, less severe adhesions compared with controls. In
the lesions of the treated rats, SOD and TIMP-2 activity was sta-
tistically significantly higher, and VEGF and MMP-9 levels
were statistically significantly lower (63).
Hyaluronic Acid
Hyaluronic acid (HA) has been used topically as an adjuvant
option during surgery for preventing post-surgical adhesions.
The capacity of HA to prevent the establishment of endo-
metriotic lesions and to treat established lesions has been
tested in vivo and in vitro.
In an in vitro study with a coculture model of endome-
triosis generated by the seeding of human eutopic endome-
trial cells on cultured peritoneal cells of mice, preseeding
exposure of peritoneal cells to a gel of ferric hyaluronate
prevented the adhesion of endometrial cells in a dose-
dependent manner (64).
In vivo, a model generated by placing autologous endo-
metrial fragments between the abdominal muscle and skin
of rats was used to test the capacity of HA hydrogel in treating
established lesions (65). Endometriotic-like cysts were aspi-
rated, and HA hydrogel was injected into them. No histologic
changes were observed with the HA gel injection.
The role of HA in prevention and its lack of role in therapy
were both reinforced by a study in which endometrial frag-
ments were injected into the peritoneal cavity of mice (66).
The animals received peritoneal injections of HA on the day
of endometriosis induction and/or 7 and 14 days later. Three
weeks after the induction of endometriosis, comparison of the
endometriosis-like lesions in the different groups indicated
that the number and weight of lesions was statistically signif-
icantly reduced in the cases that had received HA at the time
of endometrial-fragment inoculation; in contrast, HA perito-
neal injections 7 and 14 days after the induction of the disease
had no impact on the lesions. The investigators proposed that
HA acts through interference with CD-44 action.
Table 2 summarizes the relevant aspects of the studies of
pharmacologic agents that have been tested in the
endometriosis-induced murine model but not in humans.
Some of these agents belong to pharmacologic groups from
which at least one agent has been tested in humans, hence
the appearance of those groups in the next section.
PHARMACOLOGIC GROUPS ALREADY TESTED
IN THE TREATMENT OF ENDOMETRIOSIS IN
HUMANS
Fewer medications to treat endometriosis have been tested in
humans than in experimental models. Among those tested,
some medications have been extensively studied, whereas
VOL. 98 NO. 3 / SEPTEMBER 2012
Fertility and Sterility®
others have featured only in single pilot studies. Table 3 sum-
marizes the studies of pharmacologic agents used in the treat-
ment of endometriosis in humans.
Antiangiogenic Agents
Although many aspects of the pathogenesis of endometriosis
are still a matter of debate, it is clear that angiogenesis is nec-
essary for the development and maintenance of ectopic im-
plants. Based on this observation, many molecules capable
of inhibiting blood vessel formation have been tested to treat
the disease. Because endometriosis specifically affects women
of reproductive age, selective angiogenesis inhibition is an es-
sential feature of antiangiogenic-agent candidates; many
physiologic angiogenic processes—namely, follicle matura-
tion, corpus luteum function, eutopic endometrial prolifera-
tion, and embryo development—must not be disrupted.
The most important angiogenic agent in endometriosis is
VEGF (104). In general, only immature blood vessels (with
the endothelium not surrounded by pericytes) are responsive
to VEGF and its withdrawal (105, 106). Once pericytes
(smooth muscle mesenchymal cells) cover the endothelium,
vessels become mature and stable, and resist to the
withdrawal of VEGF (107). More than 80% of blood vessels
seen in endometriotic lesions in humans are pericyte-free,
a proportion that is significantly higher than that seen in
the eutopic endometrium of women with and without endo-
metriosis (67).
Blockers of VEGF/VEGFR-2 binding. Binding of VEGF-
VEGFR-2 is impaired by the use of a truncated soluble
VEGF receptor, blockage of VEGFR-2, anti-VEGF antibodies,
and other antiangiogenic agents (67, 68, 108).
Antihuman VEGF-A antibodies and soluble flt-1, a trun-
cated VEGF-A receptor that competes with VEGFR-2 for
VEGF binding, have been tested as inhibitors of neoangiogen-
esis and endometriotic lesion formation in the mouse model
(67, 68, 69). As in human endometriosis, very few blood
vessels of lesions from this model are covered by pericytes
(67). The use of VEGF antibody was associated with
statistically significantly reduced cell proliferation in
lesions, increased apoptotic index, and reduced vascular
density and VEGF concentration in peritoneal fluid (69). It
was also capable of reducing lesion size, either when
administered immediately after the grafting of the explants
(67) or when given 2 to 3 weeks later after endometriotic
lesions were already stable (68, 69). This suggests that
neoangiogenesis is important not only for endometriotic
lesion establishment, but also remains relevant for its
maintenance and growth. The confirmation of this
assumption would lead to the possibility that targeting
angiogenesis might not only prevent but also treat
peritoneal endometriosis. Soluble flt-1 also statistically sig-
nificantly reduced the number of endometrial explants in
nude mice (67). In most of the cases, treatment led to the dis-
appearance of lesions, and histologic study of the few remain-
ing lesions showed the virtual absence of microvasculature.
In a prospective randomized study with Rhesus monkeys
with induced endometriosis, the use of anti-flk 1 antibody (a
VEGF-receptor antibody) was associated with the presence of
535
536

VIEWS AND REVIEWS

TABLE 2

Relevant aspects of studies of pharmacological agents tested in endometriosis induced in the murine model but not tested in humans.
Already used in humans
Medication Route of administration Dose Initiation of therapya Reduction in lesions (%)b for other indications Reference
TNF blockers
Etanercept SC 2 mg/kg, 3 times/wk, 2 wk After 43–46(v); 100(a) Yes 14–17
(ref. 13); 0.4 mg/kg,
1 time/wk, 4 wk (ref. 14, 15)
Infliximab IV 15 mg/kg/dose, 2 doses After 75(a) Yes 17
with a 2-wk interval
NFkB inhibitors
PDTC IP 100 mg/kg/d, 7 d After 51(v) No 22
Statins
Atorvastatin Oral 0.5–2.5 mg/kg/d, 21–28 d After 0–45(a); 61(v) Yes 24, 30
IP 2.5 mg/kg/d, 28 d After 77(w); 93(v) Yes 24
Simvastatin Oral 5–25 mg/kg/d, 10 d Before 54–85(n); 43–97(v) Yes 27
Melatonin IP and IM 10 mg/kg/d, 14–28 d After 70–78(v) Yes 34, 35, 37
MAPK inhibitors
SB203580 IP 1 mg/mg/d, 24 d Before 59(w) No 39
FR 167653 SC 30 mg/kg, BID, 23 d Before 59(w) No 40
Immunomodulators
IL-12 IP 0.15 mg/0.4 mL/d, 5 d Before 63(w); 67(a) Yes 42
Imiquimod IP 10 mg, twice a wk, 8 wk After 85(v) Yes 41
Leflunomide Oral 35 mg/kg/d, 31 d Before 77(v); 77(w) Yes 43
Oral 35 mg/kg/d, 28 d After 83(v); 81(w) Yes 45
Levamisole SC 2 mg/wk, 8 wk After 52(v) Yes 44
MMP inhibitors
ONO-4817c Oral Laboratory chow at After 48(invasion) No 48
concentrations from
0–1%, for 4 wk
rTIMP-1 IP 2.8 mg/kg, every 3 d, 3 doses After Fewer follicles and fewer and No 49
altered zygotes (no reference to
endometriotic lesions)
Apoptotic agents
Curcumin Oral 50–150 mg/kg/d, 28 d After 54–83(v) Yes 54
IP 12–48 mg/kg/d, 3 d Before 77(nd) Yes 55
Metformin Oral 100–200 mg/kg/d, 28 d After 87–90(a) Yes 62
Oral 25–50 mg/kg/d, 28 d After 87–93(v); 77–78(w) Yes 63
Hyaluronic acid Topic (inside the cyst) A single injection After No effect(nd) Yes 65
IP Weekly injections on days 0, Before/After Before: 53(n); 46(w) Yes 66
7, and/or 14 after induction After: no effect
VOL. 98 NO. 3 / SEPTEMBER 2012

of endometriosis
Antiangiogenic agents
Anti-VEGF-A antibody SC 5 mg/d, 10 d Before 67(ne) Yes 67
SC 3 mg/kg/d, 14 d After 58(n) Yes 68
IP 5 mg/kg/3d, 14 d After 17(n); 58(v) Yes 69
Soares. Drug therapies in endometriosis. Fertil Steril 2012.
VOL. 98 NO. 3 / SEPTEMBER 2012

TABLE 2

Continued.
Already used in humans
Medication Route of administration Dose Initiation of therapya Reduction in lesions (%)b for other indications Reference
Soluble flt-1 SC 5 mg/d, 10 d Before 77(n) Yesf 67
Cabergoline Oral 0.05–0.1 mg/kg/d, 14 d After 40–49(n); 18(a) Yes 70, 71
SU5416 IP 25 mg/kg/d, 14 d Before 4(a) No 72
SU6668 IP 75 mg/kg/d, 14 d Before 25(a) No 72
Rapamycin IP 1.5 mg/kg/d, 14 d After 48(a) Yes 73
2-ME Oral 10–100 mg/kg/d, 7–35 d Before 21–63(a) Yes 74
Endostatin SC 2 mg/kg/d, 14 d After 75(n) Yes 68
IP 2 mg/kg/d, 14 d After 34(v); 30(w) Yes 75
SC 20 mg/kg/d, 28 d Before/After Before: 38(n); 79(a); After: 14(a) Yes 76
Anginex SC 8 mg/kg/d, 14 d After 46(n) No 68
TNP-470 SC 20 mg/kg/2 d, 14 d After 64(n) No 68
Caplostatin SC 30 mg/kg/2 d or 2.8 mg/kg BID, 35 d Before 59(a) No 77
Lodamin Oral 15 mg/kg/d, 7 d Not available 19(a) No 78
Angiostatin IP viral vector (gene therapy) 1
109 pfu After 100(n) No 79
HBA IP 100 mg/kg/d, 14 d Not available 54(a) No 80
Anti-inflammatory agents
Celecoxib Oral 5–200 mg/kg/d, 28 d After 77–81(a); 65(n); 83(v) Yes 81–83
NS398 Oral 10 mg/kg/d, 56 d After 22(a) Yes 84
Parecoxib IM 3 mg/kg/d, 30 d After 34(a) Yes 85
Nimesulide SC 25 mg/kg/d, 14 d After No effect (v) Yes 86
Ciglitazone IP 1 mg/d, 28 d After 52(v); 70(w) Yes 87
Rosiglitazone Oral 0.16–0.2 mg/kg/d, 28 d After 20(n); 45–77(v) Yes 83, 88
Oral 0.2 mg/kg/d, 31 d Before 35(v); 40(w) Yes 89
Fenofibrate Oral 10–100 mg/kg/d, 21 d After 54–82(a) Yes 90
Antioxidants
NAC Oral 100 mL of a 10 mg/mL solution, 5 d/ Before 60(w) Yes 91
wk, 3 wk (average 44 mg/kg/d/
animal)
IP 60 mg/mouse, 3/wk, 4 wk After 41 (histologic score based on Yes 92
angiogenic and glandular
organization)
CAPE IP 10 mmol/kg/d, 28 d After 76(v) No 93
Sex steroids expression modulators
ERB-041 (selective ER b-agonist) Oral 10 mg/kg/d, 15–17 d After 100% (a) in 40–75% of mice Yes 94
(different series)
Progesterone receptor binding
molecules
RU-486 SC 30 mg/kg/d, 28 d After Increase of 20(v) Yes 95

Fertility and Sterility®

Asoprisnil SC 10 mg/kg/d, 28 d After 8(v) Yes 95
Bazedoxifene (selective IP 3 mg/kg/d, 56 d After 65(a) Yes 96
estrogen receptor modulator)
Flavonoids
Puerarin Oral 60–600 mg/kg/d, 28 d After 50–85(w) Yes 97
Soares. Drug therapies in endometriosis. Fertil Steril 2012.
537
VIEWS AND REVIEWS

endometriotic-like lesions in one out of six (17%) primates in

Note: BID ¼ twice a day; CAPE ¼ caffeic acid phenethyl ester; ER ¼ estrogen receptor; EGCG ¼ epigallocatechin-3-gallate; HBA ¼ 4-hydroxybenzyl alcohol; HDAC ¼ histone deacetylase; IL ¼ interleukin; IM ¼ intramuscular; IP ¼ intraperitoneal; IV ¼ intravenous;
MAPK ¼ mitogen-activated protein kinase; MMP ¼ matrix metalloproteinase; NAC ¼ N-acetylcysteine; NFkB ¼ nuclear factor-kB; PDTC ¼ pyrrolidinedithiocarbamate; RU-486 ¼ mifepristone; SC ¼ subcutaneous; rTIMP ¼ recombinant tissue inhibitors of metal-
for other indications Reference

100–102
the study group and in five out of six (83%) in controls (108).

103
99
98
This difference was statistically significant.
It can be concluded from all these studies that angiogen-
Already used in humans

esis inhibition (namely, VEGF blocking) negatively affects the

establishment and in some cases the maintenance of endo-

Given in percentages that refer to mean reductions in either the number (n), volume (v), weight (w), or area (a) of lesions after treatment. For example, if average area reduces from 10 to 1 mm2, this change is represented as follows: 90(a).
Yes
metriotic lesions and constitutes a therapeutic possibility in
Yes
Yes
Yes

human endometriosis. However, most of the available VEGF

blockers may provoke severe adverse effects that can limit
their use due to interference with physiologic angiogenesis
(109). The search for molecules with high specificity is para-
mount for their use in non-life-threatening conditions such
as endometriosis.
Reduction in lesions (%)b

VEGF-inhibitors. Dopamine agonists. The mechanisms by

which dopamine agonists (DAs) inhibit VEGF action and an-
giogenesis are not fully established. Two possibilities have
been more extensively considered: [1] binding to the dopa-
43–50(a); 85(n)

mine receptor-2 (Dp-r2), leading to the inhibition of the

No effect

VEGFR-2 phosphorylation and downstream intracellular sig-

naling (the presence of Dp-r2 in eutopic and ectopic endome-
54(a)
38(a)

trium is confirmed); [2] inhibited VEGF and VEGFR-2

Initiation of therapya

expression (70).
Study on a mouse model of adenomyosis. The effect of medication is measured by the percentage of reduction of glandular tissue invasion into the myometrium.

Mice with established peritoneal endometriosis were

treated with daily doses of oral cabergoline (Cb2) or quinago-
lide (both DAs) (70, 71). The use of DAs was associated with
After

After
After
After

a statistically significant reduction in the number of active

endometriosis-like lesions, lesions with reduced stromal cel-
lularity and tissue organization, and increased necrotic areas.
Reduced neoangiogenesis and expression of VEGF and
VEGFR-2, overexpression of the antiangiogenic Ang-I, and
reduced phosphorylation of VEGFR-2 tyrosine 951 reinforce
50–65 mg/kg/d, 14–21 d

the possibility that DAs may inhibit angiogenesis by more

50–200 mg/kg/d, 14 d
Dose

than one mechanism (70, 71).

500 mg/kg/d, 21 d

0.5 mg/kg/d, 28 d

In humans, a pilot study was performed in 10 patients

who had severe endometriosis and a recent diagnosis of hy-
perprolactinemia (prolactin >30 ng/mL), in whom a first lap-
The extramembrane part of VEGF-A receptor was used in humans with molecular modifications.

aroscopy (L1) had been performed (110). The location and size
of isolated lesions were documented, and oral quinagolide
loproteinases; TNF ¼ tumor necrosis factor; VEGF ¼ vascular endothelial growth factor.

was initiated. Therapy lasted for 18 to 20 weeks. At treatment

Studies in which (n) refers to the number of glands observed at histologic analysis.
Route of administration

termination, a second laparoscopy (L2) was performed.

One of the initial 10 patients had to discontinue the med-
ication due to vomiting when the final dose was achieved, and
she was excluded from the study. No other major side effects
were recorded. The mean reduction of the area of the lesions
Before or after endometriosis-like lesions were established.

observed at L2 was 69.5%. In two out of nine patients, all in-

In this case, (n) refers to the number of mice with lesions.

Soares. Drug therapies in endometriosis. Fertil Steril 2012.

dex endometriotic lesions disappeared.

Oral

SC
IP
IP

Histologic analysis after the treatment showed that the

matrix of the stroma had become looser and less cellular, in-
dicating tissue regression. Cytokine CCL10, a potent antian-
giogenic regulator, was up-regulated by quinagolide, while
three proangiogenic cytokines (CCL2, RUNX1, and AGGF1)
were down-regulated in L2 lesions. Production of VEGF
was reduced, and the density of VEGFR-2 was lowered by
HDAC inhibitors

half.
Trichostatin
Genistein
TABLE 2

Medication
Continued.

So far, this pilot study has been the single nonrandomized

EGCG

study of DA in humans to treat endometriosis. For definitive

conclusions to be drawn, this medication must be tested in
a randomized study.
b

d
a

e
c

538 VOL. 98 NO. 3 / SEPTEMBER 2012

VOL. 98 NO. 3 / SEPTEMBER 2012

TABLE 3

Relevant aspects of studies of pharmacologic agents tested in endometriosis in humans.

Main parameters Significant side
Medication Route of administration Type of study evaluated Results effects/risks References
Antiangiogenic agents
Quinagolide (DA) Oral Pilot study (n ¼ 10) Mean reduction in lesion 69.5% Dizziness, nausea, and 110
area vomiting (significant
in one patient)
Anti-inflammatory
agents
Rofecoxib Oral RCT (n ¼ 28) Pain relief Significant improvement Not reported 122
Pentoxifylline Oral RCT (n ¼ 88 and 104) Occurrence of pregnancy No significant differences Not reported 130, 131
and recurrence of
signs and symptoms
after surgery
Oral RCT (n ¼ 34) Recurrence of pain after Significant improvement Not reported 132
surgery
Antioxidants Oral (diet change) Prospective uncontrolled Peripheral blood Significant improvement Not reported 134
(n ¼ 83) antioxidant markers
Sex steroid expression
modulatorsa
OCPs Oral Reviews Pain relief and reduction Significant improvement Increased risk of 135–139
of the stage of the thromboembolic
disease events after the age
of 35 (worse in
smokers)
GnRH agonist IM or SC Reviews Pain relief and reduction Significant improvement Bone density loss, 135–138, 140, 141
of the stage of the worsening of lipid
disease profile, depression,
hot flashes,
genitourinary
atrophy, and
decreased libido
Danazol Oral, vaginal, or IUS Reviews Pain relief and reduction Significant improvement Oral route: weight gain, 135–138, 142, 143
of the stage of the acne, seborrhea, oily
disease hair, headache,
changes in lipid
parameters and liver
function, vaginal
atrophy, endometrial
changes, and cycle
irregularity. Ovarian

Fertility and Sterility®

cancer? (to be
confirmed)
GnRH antagonist SC Pilot study (n ¼ 15) Pain relief Improvement in 100% of Irregular genital bleeding 146
patients (20% of patients)
Anastrozole (AI) Vaginal Pilot study (n ¼ 10) Pain relief Improvement in 90% of Not reported 154
patients
Oral RCT (n ¼ 80) Pain relief after surgery Significantly longer pain Higher bone mass loss 162
free interval
539

Soares. Drug therapies in endometriosis. Fertil Steril 2012.

540

VIEWS AND REVIEWS

TABLE 3

Continued.
Main parameters Significant side
Medication Route of administration Type of study evaluated Results effects/risks References
Oral Prospective uncontrolled CA-125 levels, Significant reduction in High rate of pregnancy 165
(n ¼ 20) endometrioma size CA-125 and lossc
and IVF outcome endometrioma, high
rate of pregnancy
lossc
Anastrozole and Oral Pilot studies (n ¼ 4–16) Pain relief Improvement (mainly in Irregular genital 147, 155–160
letrozole (AI)b dysmenorrhea and bleeding, weight
dyspareunia) gain, joint pain, and
ovarian cysts
Letrozole Oral Prospective controlled, Pain relief Significant improvement Joint pain, myalgia 161
nonrandomized
(n ¼ 82)
CDB-4124 Oral Prospective uncontrolled Endometrial histologyd Atypical histologic Not reported 166
(progesterone (n ¼ 27) changes
receptor binding
molecule)
Raloxifene (selective Oral RCT (n ¼ 93) Recurrence of symptoms Significant worsening Recurrence of pain and 171
estrogen receptor need of a second
modulator) surgery
Contraceptive vaginal Vaginal vs. transdermal Cohort study (n ¼ 207) Pain relief and tolerability Better results with the Vaginal discomfort and 172
ring vs. (patches) of treatment vaginal ring irregular genital
transdermal bleeding more
systeme frequent with the
ring; headaches more
frequent with the
patches
Progesterone delivery IUS Ref. 178: RCT (n ¼ 40); Recurrence of Significant improvement Pain, irregular genital 178–181
systems refs. 179–181: dysmenorrhea after bleeding, and weight
prospective surgery gain
observational (n ¼ 42
and 43)
IUSf RCT (n ¼ 22 to 82) Pain relief, CA-125 levels Equivalent results Pain and irregular genital 182–186
and reduction of the (Exception: ref. 187 – bleeding; symptoms
stage of the disease IUS significantly of hypoestrogenism
worse than GnRH-a) and altered lipid
profile were worse
with GnRH-a
VOL. 98 NO. 3 / SEPTEMBER 2012

IUS vs. IM RCT (n ¼ 30) Pain relief after surgery Equivalent results in pain Irregular genital bleeding 187
and tolerability of relief and postponing bad enough to lead
treatment recurrence; higher to withdrawal was
tolerability with the more frequent with
IUS the IM route, as was
bone density loss
Soares. Drug therapies in endometriosis. Fertil Steril 2012.
VOL. 98 NO. 3 / SEPTEMBER 2012

TABLE 3

Continued.
Main parameters Significant side
Medication Route of administration Type of study evaluated Results effects/risks References
IMg RCT (n ¼ 274 and 300, Pain relief and tolerability Equivalent results in pain Irregular genital bleeding 135, 189
respectively) of treatment relief more frequent with
IM progesterone;
hypoestrogenic
symptoms and
transitory bone
density loss more
frequent with
GnRH-a
IM vs. subdermal RCT (n ¼ 41) Pain relief and tolerability Equivalent results in pain Irregular genital bleeding 190
of treatment relief and tolerability in the subdermal
group; severe
depression, hot
flashes, and pelvic
pain in the IM group
Flavonoids
Pycnogenol Oral Prospective randomized Pain relief, lingering More discrete pain relief None; no effect on 195
(isoflavone) trial (n ¼ 58); effect and CA-125 and CA-125 menstrual cycle
compared with LA (a levels reduction, but
GnRH-a) longer-lasting effect
HDAC inhibitors
Valproic acid Oral Pilot study (n ¼ 3); Pain relief Complete relief of pain in Transient nausea and 204
patients with (dysmenorrhea); all cases and an vomiting (one
endometriosis and uterine size average reduction of patient)
adenomyosis 33% in uterine size;
reduction/
disappearance of cul-
de-sac nodules
Note: AI ¼ aromatase inhibitor; CA-125 ¼ cancer antigen 125; CDB-4124 ¼ telapristone acetate; DA ¼ dopamine agonist; GnRH-a ¼ gonadotropin-releasing hormone agonist; HDAC ¼ histone deacetylase; IM ¼ intramuscular; IUS ¼ intrauterine system; LA ¼ leuprolide
acetate; OCP ¼ oral contraceptive pill; RTC ¼ randomized controlled trials; SC ¼ subcutaneous.
a
Data on classic sex steroid expression modulators (namely, OCP, GnRH-a, and danazol) are summarized based on extensive reviews, as explained in the text.
b
References 163 and 164 were not included in the table because there were no intergroup differences in AI therapy.
c
Study of a long in vitro fertilization protocol with the association of GnRH-a and AI before the initiation of ovarian stimulation.
d
No reference is made in the study to the impact of medication on symptoms related to endometriosis.
e
Both the vaginal ring and the transdermal system with an estrogen-progestogen combination.
f
Studies that compared the levonorgestrel-releasing intrauterine system (LNG-IUS) with GnRH-a.
g
Studies that compared IM medroxyprogesterone acetate (MDA) with GnRH-a
Soares. Drug therapies in endometriosis. Fertil Steril 2012.

Fertility and Sterility®

541
VIEWS AND REVIEWS
SU5416 and SU6668. Both SU5416 and SU6668 inhibit the
effect of VEGF by binding to the intracellular domain of the
tyrosine kinase receptor VEGFR-2 in endothelial cells and in-
hibiting its phosphorylation and downstream signaling. The
difference between them is that SU6668 not only binds to
VEGFR-2 but also to fibroblast growth factor receptor
(FGFR-1) and platelet-derived growth factor receptor
(PDGFR-b) in stromal cells and pericytes (72).
In a very interesting study, rodents with induced endome-
triosis were treated with either SU5416 or SU6668 (72). Both
therapies had a negative impact on vascularization of
endometriosis-like lesions, but SU6668 had a statistically sig-
nificant stronger effect on vessel formation and on the size of
the lesions, strengthening the concept that angiogenesis de-
pends on a net of intercellular interactions.
Other VEGF-inhibitors. Some molecules have antiangiogenic
properties by mechanisms that are not clear, although VEGF
involvement is likely.
Rapamycin, a bacterial macrolide with antifungal and
immunosuppressant activity, is widely used to prevent rejec-
tion of transplanted organs. Its antiangiogenic property was
initially proposed after its capacity to inhibit tumor develop-
ment and endothelial cell sprouting was observed in cultures
of vascular tissue. In cultures of endometrial cells, an inhibi-
tory effect on VEGF expression has been observed (73).
In vivo, Syrian golden hamsters with induced endometriosis
treated with rapamycin showed a statistically significant re-
duction in implants compared with controls. At microscopy,
cellularity and microvessel density of lesions were also statis-
tically significantly reduced (73).
A metabolite endogenously formed from estradiol is 2-
methoxyestradiol (2-ME2). This metabolite was previously
thought to be inactive, but in the last decade it was shown
to have anticancer properties (111). Its use in a murine model
of endometriosis has been associated with suppression in the
growth of lesions in a dose-dependent and time-dependent
fashion (74). Early but not mature endometriotic lesions are
hypoxic. Hipoxia-inducible factor-1a (HIF-1a) is a promoter
of VEGF transcriptional activity, and its expression parallels
local hypoxic conditions in control animals. However, in an-
imals treated with 2-ME2, HIF-1a expression is strongly sup-
pressed, as is VEGF transcription activity. The investigators
have proposed that 2-ME2 inhibits the development of
endometriotic-like lesions through HIF-1a inhibition.
Endostatin, a proteolytic fragment of collagen XVIII, acts
as an endogenous antiangiogenic protein (112). Human eu-
topic endometrium transplanted onto chicken chorioallantoic
membrane (CAM) and treated with endostatin showed statis-
tically significantly reduced development and angiogenesis
(113). Increased necrosis of lesions also was observed. Treat-
ment of established mouse peritoneal endometriosis showed
a statistically significant reduction in the number of implants
compared with controls (68). Microvessel density was dramat-
ically reduced due to fewer immature, newly formed vessels.
Other antiangiogenic agents were tested in this study (TNP-
470 and anginex); among these, endostatin was associated
with the fewest lesions and the highest reduction in microves-
sel density (see Table 2). Similar studies have reported con-
542
flicting results: one of them reported the same findings,
with confirmation of reduced VEGF expression in lesions,
but another found that only treatment initiated before the es-
tablishment of lesions resulted in reductions compared with
controls (75, 76). Regarding the safety of endostatin, treated
mice displayed estrous cycling, estradiol or progesterone
production, and corpora lutea numbers similar to those seen
in the control group. In brief, the treated group did not
differ from the controls in any aspect related to fertility,
pregnancy progression, or offspring malformation,
development, and fertility (76). The identification of a short
stable nontoxic endostatin fragment with biologic activity
has already been achieved, which may ease the way to the
substance's clinical use (114). Endostatin is being tested in
phase 2 studies of cancer treatment (115).
Anginex is the synthetic antiangiogenic agent tested in
the mouse and the CAM models of endometriosis mentioned
earlier (68, 113). In mice, anginex statistically significantly
reduced the number of endometriotic implants and their
microvascular density to a degree similar to that seen with
endostatin (68). The same pattern of effects was observed in
the implants on chicken CAM, but the reduction in lesion
formation achieved with anginex was more modest in this
case (113).
A synthetic analogue of the fungus-derived antibiotic fu-
magillin, TNP-470 is a powerful angiogenesis inhibitor. It was
included in the studies that evaluated endostatin and anginex
(68, 113). Unfortunately, its free form has been shown to
impair reproductive function (116). The toxicity of TNP-470
stimulated the development and testing of nontoxic forms
of the molecule such as caplostatin. In the mouse peritoneal
model of endometriosis, caplostatin delayed the development
of lesions and statistically significantly suppressed final le-
sion dimension and microvessel density with no impact on
the number of estrous cycles (77). Lodamin, an oral nontoxic
formulation of TNP-470, was tested in the same model; after 1
week of treatment, the endometriosis-like lesion area was sta-
tistically significantly smaller than in the control group (78).
The investigators also studied the interesting concept that
bone marrow-derived endothelial progenitor cells (EPC) are
correlated with the neovascularization needed for the devel-
opment of endometriosis. They found that circulating blood
EPC levels were statistically significantly higher in the endo-
metriosis model compared with mice submitted to a sham op-
eration and that these cells were incorporated into the
vasculature of endometriotic implants. Lodamin administra-
tion was associated with a statistically significant reduction
of circulating endothelial cells in general and of EPC in
particular.
Angiostatin is an endogenous angiogenesis inhibitor that
can have its cellular production enhanced by a gene therapy
that inoculates a replication-deficient adenovirus vector
(AdAngiostatin). Mice with induced peritoneal endometriosis
and treated with intraperitoneal viral therapy (n ¼ 14) had le-
sions eradicated, whereas the disease remained fully ex-
pressed in 11 out of 13 controls (79). Histologic study of
peritoneal tissue at different time points of treatment showed
that the extension, number, and area occupied by vessels were
reduced until only scar tissue was found, with no endometrial
VOL. 98 NO. 3 / SEPTEMBER 2012

tissue remaining. Unfortunately, different doses of gene ther-
apy with angiostatin to normal cycling mice resulted in sup-
pression of ovarian activity, with a reduction in the size of the
organ, reduced estradiol and progesterone serum levels, re-
duced uterine weight and eutopic endometrial thickness,
and increased body weight mainly determined by increased
fat tissue in the abdominal cavity.
The phenolic plant compound 4-hydroxybenzyl alcohol
(HBA) has analgesic, sedative, antioxidant, anti-
inflammatory, and antiangiogenic properties. The in vitro
aortic ring assay showed that HBA completely suppressed
vascular sprouting. In vivo, HBA statistically significantly de-
creased functional capillary density and the size of lesions in
endometriosis induced in the skinfold chamber of mice. No
toxic effects on normal blood vessels under physiologic con-
ditions were observed (80).
Anti-Inflammatory Agents
COX-2 inhibitors. Cyclo-oxygenase 1 (COX-1) and COX-2
are isoenzymes that participate in the synthesis of prostaglan-
dins (PGs). Overexpression of COX-2 has been detected in eu-
topic and ectopic endometrium from patients with
endometriosis. Specific inhibitors of COX-2 have anti-
inflammatory properties and the ability to block cell growth
and induce apoptosis (117).
In vitro/animal models. In vitro, the COX-2 inhibitor cele-
coxib inhibited cell proliferation and induced apoptosis
in cultures of endometrial epithelial and stromal cells
from endometriotic patients (118, 119). The levels of
PGE2 and VEGF released by these cells were also
statistically significantly reduced. Another COX-2 inhibitor,
NS-398, investigated in adenomyosis-derived mesenchymal
stem cell cultures not only increased the apoptotic
activity in these cells, but also inhibited migration and in-
vasiveness (120).
In vivo, celecoxib statistically significantly reduced the
number and size of peritoneal endometriosis-like lesions in
mice when administered either before or after the induction
of lesions (81–83). Other specific COX-2 inhibitors—rofe-
coxib, NS-398, and parecoxib—also have been demonstrated
to statistically significantly reduce the size of endometriosis-
like implants, inducing their atrophy and regression (84, 85,
121). The effect of rofecoxib was equivalent to that
obtained with a GnRH agonist (121). The impact of COX-2 in-
hibitors on lesions seems to be partially achieved by interfer-
ing with peritoneal macrophages and angiogenesis, as
decreased microvessel density and VEGF expression were ob-
served as well as a decreased number of macrophages, an im-
portant source of VEGF produced in inflammatory areas (84,
85, 121).
However, not all COX-2 inhibitors seem to be effective in
the murine model. Mice treated with nimesulide showed no
statistically significant difference in the volume estimate of
tissue load compared with controls (86). Nor were any visually
identifiable reductions in blood vessel development or macro-
phage or myofibroblast infiltration found.
Humans. Rofecoxib was tested in the management of pain
related to endometriosis. The use of 25 mg/day for 6 months
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Fertility and Sterility®
was associated with safe and more effective pain control in
women with minimal or mild endometriosis when compared
with a placebo group (122). No additional studies have been
published on this topic.
Peroxisome proliferator-activated receptor g-agonists. Per-
oxisome proliferator–activated receptor g-ligands modulate
cell growth and angiogenesis, likely because of down-
regulation of proinflammatory mediators in macrophages
(123). In addition, they are reported to inhibit estrogen bio-
synthesis by inhibiting aromatase cytochrome P450 (124).
Ciglitazone, pioglitazone, and rosiglitazone are thiazoli-
dinediones, a class of compounds with high affinity for
PPAR-g. Cultures of hESCs or stromal/fibroblast-like cell
lines exposed to these drugs display reduced TNF-a induced
IL-8 secretion and statistically significant inhibition of cell
proliferation in a dose-dependent fashion (125, 126).
Ciglitazone and rosiglitazone reduced the volume and
weight of lesions in the murine model of endometriosis com-
pared with controls (83, 87–89). Inhibition of cell proliferation
and vascularization and increased apoptosis were
documented with the use of rosiglitazone (83, 88, 89). In
general, the potential negative effects on reproductive
function were not assessed, but no evidence of interference
with the estrous cycle or folliculogenesis has been reported
with ciglitazone (87).
In baboons, pioglitazone was used in the treatment of in-
duced endometriosis. Endometrial tissue to be implanted in
animals had also been previously incubated in a solution
with this molecule. The surface area and the volume of
endometriosis-like lesions and specifically the number and
surface area of red lesions were statistically significantly
lower in pioglitazone-treated baboons compared with con-
trols (127). The investigators did not assess the effect of the
drugs on reproductive function. In the same model, rosiglita-
zone produced a statistically significant reduction in the sur-
face area of lesions, with no interference with median serum
estradiol or progesterone levels (123). Oral fenofibrate,
a PPAR-a ligand, also produced a statistically significant re-
duction in the mean area of implants in a rat model of endo-
metriosis (90).
Pentoxifylline
Pentoxifylline, a methylxanthine with anti-inflammatory
and antioxidant properties, has been used in the treatment
of peripheral vascular diseases. It decreases platelet aggrega-
tion by inhibiting platelet phosphodiesterase. Through the
inhibition of phosphodiesterase in monocytes and macro-
phages, the drug suppresses cytokine production, mainly
TNF-a in macrophages. Thus, it also has been used in the
treatment of rheumatoid arthritis and inflammatory bowel
disease (128, 129). Based on the same indirect anti-TNF-a
mechanism, this drug has been considered for the treatment
of endometriosis.
In vitro/animal models. In the rat model, implants of endo-
metrial tissue in different locations (subcutaneous tissue,
peritoneal surface, and ovarian area) were used to test the ef-
fect of pentoxifylline on lesions (128, 129). Statistically
significant reductions in the weight, volume, and number of
543
VIEWS AND REVIEWS
lesions were documented (128, 129). Other findings probably
associated with TNF-a inhibition were reduced total white
blood cells with increased lymphocyte count in serum, and
reduced VEGF-C expression. No negative effect on the estrous
cycle was documented (128).
Humans. Several studies have evaluated the impact of oral
pentoxifylline initiated after conservative laparoscopy on
the incidence of spontaneous pregnancy and the recurrence
of signs and symptoms of endometriosis (130–132). In two
of these studies, no statistically significant impact on
pregnancy rate or recurrence of signs and symptoms of the
disease were observed compared with controls (130, 131). It
must be emphasized that the follow-up period for the occur-
rence of a pregnancy was of only 6 months in both studies. A
third study assessed the recurrence of pain after surgery. Only
34 patients completed a 3-month follow-up period. In spite of
the small sample size and the short follow-up period, a statis-
tically significant reduction in pain scores was observed in the
study group (132).
Antioxidants
As previously mentioned, increased oxidative stress with high
levels of ROS is a feature of the peritoneal environment of
women with endometriosis and is related to increased cell
proliferation (34, 35). Antioxidant molecules have been
tested as candidates to impair cell growth in endometriosis.
In vitro/animal models. The exposure of in vitro cultures of
hESCs to the antioxidants vitamin E, ebselen, and N-acetyl-
cysteine (NAC) inhibited cell proliferation, while oxidative
stress induced by hypoxanthine/xanthine oxidase and H2O2
had the opposite effect (133).
In vivo, NAC and the natural flavonoid-like compound
caffeic acid phenethyl ester (CAPE), isolated from the honey-
bee propolis, produced a statistically significant reduction in
the volume and weight of endometriosis-like lesions induced
in rodents, compared with controls (91–93). No evidence of
toxicity was reported. In addition, samples from treated
mice showed a reduction in both COX-2 gene expression
and protein, and gene expression and activity of MMP-9
(91). Peritoneal levels of MDA and activities of SOD and
CAT were statistically significantly lower when compared
with nontreated animals, which reflects reduced oxidative
stress (93).
Humans. In a prospective study, oxidative stress and antiox-
idant markers were measured in the peripheral blood of 83
women with endometriosis who received either a high antiox-
idant diet or a control diet for 4 months (134). In previous in-
terviews of these women and others without endometriosis,
using a Food Frequency Questionnaire, women with endome-
triosis were shown to have a statistically significantly lower
intake of vitamins A, C, E, zinc, and copper. Among women
with endometriosis, those who received the antioxidant diet
had an increase in the blood vitamin concentrations and an-
tioxidant enzyme activity as well as a decrease in oxidative
stress markers when compared with women who had received
the control diet. Unfortunately, the study did not evaluate
clinical symptoms.
544
Sex Steroids Expression Modulators
Estrogens are essential for the development of endometriosis,
acting by a number of key mechanisms such as macrophage
activation, activation of major proinflammatory cytokines,
and induction of mitosis. Strategies to block their effects
have been the mainstream of pharmacologic treatment of en-
dometriosis. The classic therapies include oral contraceptive
pills (OCPs), GnRH agonists, and danazol. The most relevant
studies of these therapies were published more than 10 years
ago, and they have been extensively reviewed since then.
Thus, they are not included in this systematic review, but
we will provide a brief summary of their role in the treatment
of endometriosis.
Oral contraceptive pills. Oral contraceptives inhibit gonadal
estrogen production through negative hypophyseal feedback
(135–137). By suppressing ovarian activity, they may also
reduce prostaglandin production secondary to endogenous
estrogens and therefore decrease the inflammatory status
(137). Due to better tolerability and lower metabolic impact
than GnRH agonists and danazol, cyclic and continuous
OCPs are considered the first-line chronic treatment for endo-
metriosis (135–137), either as a strategy to avoid surgery or as
a postoperative adjuvant therapy to prolong the symptom-
free interval (136, 137).
Patients with severe dysmenorrhea and ultrasonographi-
cally diagnosed endometriosis treated with OCPs have
statistically significant improvement in dysmenorrhea, non-
menstrual pelvic pain, and the size of endometriomas when
compared with controls (137, 138). Long-term regimens of ei-
ther continuous or cyclic OCPs reduce the frequency and se-
verity of recurrent dysmenorrhea and anatomic relapse of
endometriosis after surgery (137, 139). Continuous OCPs
therapy is better than cyclic OCPs for controlling pain (136,
138). There has been no consensus in the literature
concerning the role of OCPs in the primary prevention of
endometriosis (136).
The limitations of OCPs are that, in most cases, endo-
metrial implants are reactivated after cessation of treat-
ment. Also, their use by women older than 35 years who
smoke is associated with a statistically significantly higher
risk of myocardial infarction, stroke, or venous thromboem-
bolism (136).
An alternative for the management of endometriosis is
oral progestogens, which induce decidualization of not only
eutopic but also ectopic endometrium with the subsequent at-
rophy of lesions (136, 137). Progestins effectively decrease
endometriosis-related pain and its recurrence after surgical
management, with no statistically significant difference
when compared with OCPs. Estrogen-induced risks are
avoided (136), but recurrence of symptoms tends to occur af-
ter the cessation of treatment (137).
GnRH agonists. GnRH agonists are derived from native
GnRH by amino acid substitution, leading to a decreased met-
abolic clearance. Continuous hypophyseal exposure to GnRH
agonists leads to down-regulation of GnRH receptors, which
desensitizes the pituitary gland. The hypogonadotropic-
hypogonadal state generated deprives existing endometriosis,
while secondary amenorrhea prevents new peritoneal
VOL. 98 NO. 3 / SEPTEMBER 2012

seedlings. Direct local action in the endometriotic tissue also
occurs. Goserelin, leuprolide, nafarelin, buserelin, and triptor-
elin have proved effective in both relieving endometriosis re-
lated pain and decreasing the size of endometriomas (140).
Therapy with GnRH agonists is as effective in pain control
as OCP, gestrinone, or danazol, and is currently considered
as a second-line therapy when OCP or progestins fail, are
not tolerated, or are contraindicated (136–138, 141).
The administration of GnRH agonists after surgical treat-
ment for endometriosis provides a statistically significant im-
provement in pelvic pain and a longer interval before further
surgical treatment is required (136, 138). However, the
evidence supporting its beneficial effect in the prevention of
postsurgical adhesion formation is not consistent (138).
Limitations of GnRH-agonist therapy include the high
recurrence rate (50% of patients show a relapse of symptoms
within 6 months after therapy discontinuation) and side ef-
fects associated with the transitory pharmacologic meno-
pause condition created: bone density loss, worsening of
serum lipoprotein cholesterol distribution, depression, hot
flashes, genitourinary atrophy, and decreased libido
(135–138, 141). In adolescents treated with GnRH agonists,
bone mineral density must be monitored with special
care (140).
To overcome these and other effects of prolonged induced
hypogonadism, add-back therapy (exogenous administration
of sex steroids) has been proposed in combination with GnRH
agonists. With this approach, GnRH-agonist administration,
which was initially limited to 6 months, could be prolonged
up to 2 years. Common regimens are low-dose combined
estrogen-progestin, estrogen or progestins alone, bisphosph-
onates, tibolone, and raloxifene. Combined estrogen-
progestin therapy protects bone mass and prevents hot
flashes and genitourinary atrophy (136, 137, 140). However,
uncertainties persist about the safe time limit of GnRH
agonist plus oral steroids therapy (138, 140).
Danazol. The synthetic androgen 2,3-isoxazol (danazol),
a derivative of 17a-ethynyl testosterone, has mild androgenic
but strong antiestrogenic activity. It induces the inhibition of
gonadotropin release, determines the competitive inhibition
of steroidogenic enzymes, modulates immunologic function,
and suppresses cell proliferation (135–138).
Multiple studies have demonstrated the efficacy of danazol
in reducing endometriosis-associated pain symptoms (135, 137,
138, 142). Nevertheless, as with other suppressive therapies,
symptoms return after treatment discontinuation (138).
Equivalent effects were found with both danazol and
GnRH agonists in reduction of pain score after surgical treat-
ment of stages III and IV endometriosis. The same results were
found in the evaluation of lesions at second-look laparos-
copy. However, side effects were more frequent in the danazol
group. Weight gain, acne, seborrhea, oily hair, headache,
changes in serum lipoprotein cholesterol distribution and
liver function and vaginal atrophy, endometrial changes, or
interference on the regularity of menstrual cycles are seen
with its oral use (135, 136, 138).
Side effects of oral danazol led to the search for other
routes of administration (138). Danazol-loaded intrauterine
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Fertility and Sterility®
systems and danazol-loaded vaginal rings significantly de-
crease dysmenorrhea, dyspareunia, and chronic pelvic pain
in women with deeply infiltrating and rectovaginal endome-
triosis. Rectovaginal nodules are reduced (136–138). Locally
administered danazol is associated with lower serum
concentrations than the oral route. Systemic and
gynecologic side effects are seldom observed, and lipid
parameters and liver function are reported to be unaltered
(136–138). Unfortunately, the use of danazol has been
associated with a statistically significantly increased 3.2-
fold (95% confidence interval [CI], 1.2–8.5) risk of ovarian
cancer. On the other hand, a similarly increased risk has
been observed in women with endometriosis (odds ratio
[OR] 2.9; 95% CI, 1.0–8.5), which raises uncertainties as to
whether the increased risk is related to the medication or to
the disease itself (143).
GnRH antagonists. Gonadotropin-releasing hormone antag-
onists bind to the same pituitary GnRH receptor as GnRH ag-
onists and result in an immediate suppression of
gonadotropins and gonadal steroids production and release.
Down-regulation of receptors is not induced (144, 145).
A pilot study was performed with 15 patients with endo-
metriosis who were treated with weekly subcutaneous cetror-
elix for 8 weeks. All of them reported a reduction of
symptoms. The degree of the disease was improved (from
stage III to stage II) in 60% of cases. Irregular genital bleeding
occurred in 20% of patients, and no other side effects were re-
ported (146). Further studies must be conducted before any
solid conclusions can be drawn regarding the advantages
and drawbacks of this therapy.
Aromatase inhibitors. The third-generation aromatase inhib-
itors (AIs) anastrozole, letrozole, exemestane, and vorozole
are more potent than the original aminoglutethimide and
are more specific for the aromatase enzyme. In addition, the
associated side effects (headache, nausea, and diarrhea) are
fewer. By inhibiting aromatase activity, these AIs impair the
conversion of androgens to estrogens, and, like danazol, sup-
press ovarian and local estrogen formation in endometriotic
tissue (147).
In vitro/animal models. In vitro studies with eutopic endo-
metrial cell cultures exposed to anastrozole and letrozole con-
sistently demonstrate that, in opposition to what might be
expected, cell proliferation is enhanced (148–150). Nor do
endometriotic cells appear to have their in vitro
proliferation inhibited by these agents (150).
In vivo, the use of letrozole in the murine model of endo-
metriosis determined statistically significantly smaller lesions
(62, 151, 152). The addition of estrogen therapy increased the
size of lesions, but even then these were statistically
significantly smaller than those seen in animals under
estrogen-only therapy (151). Letrozole also statistically sig-
nificantly decreased VEGF immunoreactivity and prostaglan-
din E levels and increased apoptosis (152, 153).
Humans. A number of uncontrolled studies of small groups
of patients with endometriosis treated with AIs (either as
a single therapy or in combination) have been published
(147, 154–160). Patients with chronic pelvic pain refractory
545
VIEWS AND REVIEWS
to conventional therapies, rectovaginal or colorectal
endometriosis, were included. The number of patients varied
between 4 and 16 in each series, and the AIs used were
letrozole or anastrozole (mainly the former). The AIs were
combined with progestogens, contraceptive pills, calcium,
and/or vitamin D, and therapy lasted predominantly for 6
months. Pain reduction was reported in all series, with
a clear effect on dysmenorrhea and dyspareunia and on
physical and social functioning. Unfortunately, a global
pattern of recurrence of pain was observed after treatment
termination. The reported side effects were irregular
bleeding, weight gain, and joint pain. Ovarian cysts were
also documented, especially with the combination of AI and
desogestrel (159).
After these pilot studies, a few controlled trials were pub-
lished. In a prospective trial, 82 women with pain secondary
to rectovaginal endometriosis were managed either with le-
trozole and norethisterone acetate or with norethisterone ac-
etate alone for 6 months (161). Patients who also received
letrozole showed statistically significantly lower pain inten-
sity and lessened deep dyspareunia at the 3-month and 6-
month evaluations. However, they experienced statistically
significantly more adverse effects, particularly joint pain
and myalgia. Both groups of patients reported recurrent
pain symptoms after completing treatment at a 6-month
follow-up visit.
A randomized, double-blind study compared 6-month
administration of goserelin plus anastrozole to goserelin
alone (162). Eighty patients were enrolled in the study, and
therapy was initiated after surgery for severe endometriosis.
A statistically significantly longer time to symptom recur-
rence was observed in women who received the combined
regimen (>24 months vs. 17 months). No differences between
the groups were reported in quality of life or bone mass at 2
years after treatment.
In another prospective randomized study including 35
women, 6-month treatments with letrozole plus norethister-
one acetate versus letrozole plus triptorelin were compared
(163). Both groups showed a similar statistically significant
reduction in pain symptoms during treatment, but endometri-
otic nodules had a statistically significantly greater reduction
in the group who received GnRH agonists. On the other hand,
more patients managed with progestin considered their treat-
ment satisfactory, and adverse effects were less frequent. The
most common side effects in the progestin group included
weight gain, breakthrough bleeding, and decreased libido,
whereas the group managed with GnRH agonists experienced
arthralgia, decreased libido, hot flashes, and depression. Min-
eral bone density only showed a statistically significant de-
crease during treatment in the GnRH-agonist group.
Reproductive performance was ascertained in two studies
of AIs in the treatment of endometriosis. A prospective ran-
domized trial enrolling 144 women compared 2-month ther-
apy with letrozole alone to letrozole plus triptorelin, both
initiated after surgery (164). Pregnancy rates or recurrence
of endometriosis showed no statistically significant differ-
ence between the groups for at least 12 months after restora-
tion of regular menses. In a prospective uncontrolled study
including 20 infertile women with endometriomas undergo-
546
ing in vitro fertilization/intracytoplasmic sperm injection, pa-
tients received subcutaneous goserelin on treatment days 1,
28, and 56 coupled with one daily tablet of anastrozole
from days 1 to 69 (165). From day 70 on, controlled ovarian
stimulation was initiated. This prolonged combined down-
regulation statistically significantly reduced both endome-
trioma volume and serum cancer antigen 125 (CA-125) levels
and was associated with a 45% pregnancy rate, but a high rate
of pregnancy loss was reported: the clinical pregnancy rate
was 25%, and the delivery rate was 15%.
Progesterone receptor-binding molecules. Progesterone re-
ceptor modulators interact with the progesterone receptor to
block or modify downstream effects. In premenopausal
women, they induce secondary amenorrhea, accompanied
by decreased systemic levels of progesterone and estradiol.
Modulators with potent progesterone antagonist activity,
comprising the progesterone antagonist mifepristone (RU-
486) and the selective progesterone receptor modulators
(SPMRs) asoprisnil and CDB-4124 (a 21-substituted-19-nor-
progestin), have been proposed as therapeutic agents for
endometriosis (166, 167).
In vitro/animal models. In vitro cultures of endometriotic tis-
sue and eutopic endometrial cells from women with endome-
triosis exposed to RU-486 displayed a statistically significant
down-regulation of the expression of both estrogen and pro-
gesterone receptors (168). On the other hand, in an in vivo rat
model, RU-486 and asoprisnil were unable to decrease the
volume of endometriosis-like cystic lesions (95).
Humans. Fifty-eight premenopausal women, 27 with endo-
metriosis and 31 with uterine fibroids, were treated with
CDB-4124 (166). Most of the endometrial biopsy samples
(103 out of 174) obtained after 3 or 6 months of therapy
with oral daily doses of 12.5, 25.0, or 50.0 mg showed histo-
logic changes such as cystic architecture and mixed nonphy-
siologic epithelial changes. Knowledge of these endometrial
changes is important to prevent misinterpretation by pathol-
ogists, mainly as disordered proliferative or hyperplastic en-
dometrium (166). No data about the impact of medication
on clinical symptoms of endometriosis were made available.
Selective estrogen receptor b-agonist. Estradiol activates
peritoneal macrophages, a key step in the pathophysiology
of endometriosis. Macrophages from these patients display
an overexpression of estrogen receptor-a (ER-a) and ER-
b in comparison with women without endometriosis. In addi-
tion, estradiol is a strong direct inducer of metabolic activity
of endometriotic cells. Whereas ER-a agonists mediate most
of the classic effects of estrogen, ER-b-selective agonists pos-
sess anti-inflammatory properties (169).
In vitro/animal models. ERB-041 inhibits in vitro
lipopolysaccharide-induced NO synthase production by peri-
toneal macrophages from women with endometriosis, possi-
bly due to repression of NF-kB (169). In the mouse model of
endometriosis, ERB-041 induced complete regression of le-
sions in 40% to 75% of animals from different series, and re-
covered lesions expressed ER-a but not ER-b-mRNA (94).
Selective estrogen receptor modulators. The tissue selective
activity of the selective estrogen receptor modulators
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(SERMs) enables these molecules to have predominantly
ER antagonism in the breast and uterus and ER agonism
in the skeleton, on serum lipid metabolism, and on some
coagulation factors. The SERM raloxifene, which has been
shown to not stimulate endometrial proliferation in rats,
was approved for the management of postmenopausal
osteoporosis (96).
In vitro/animal models. Daily oral administration of raloxi-
fene to rats with induced endometriosis statistically signifi-
cantly decreased the volume of implants after 14 days of
treatment (170). Bazedoxifene, another SERM that was
demonstrated to not stimulate the endometrium in postmen-
opausal women or to antagonize conjugated estrogen-
induced uterine stimulation, was also capable of decreasing
the mean size of endometriosis-like implants in rodents (96).
Humans. In a double-blind prospective study, 93 women
with endometriosis-related pelvic pain after surgical treat-
ment were randomly allocated to daily raloxifene or placebo
for 6 months. The study was halted early because the raloxi-
fene group had statistically significantly earlier pain and
necessity of a second surgery. Therefore, SERMs may act in
the modulation of lesions and chronic pelvic pain like an es-
trogen (171).
Contraceptive Methods
Contraceptive vaginal ring/patch. The same types of hor-
mone combinations used in OCPs can be delivered by
monthly vaginal rings and weekly transdermal patches with-
out the discomfort of daily administration. These alternative
routes of administration provide constant plasma drug levels
and avoid first-pass hepatic metabolism (172).
Humans. In a cohort study, 207 patients with recurrent
endometriosis-related pelvic pain after surgical treatment re-
ceived a continuous estrogen-progestogen combination from
either a vaginal ring or a transdermal system for 12 months
(172). Women using the ring (n ¼ 123) were statistically sig-
nificantly more satisfied and showed better compliance with
treatment than those who chose the patch (n ¼ 84). Both de-
livery systems reduced pain; the ring was the most effective
in treating dysmenorrhea and rectovaginal lesions (although
no specific data were provided about these symptoms). A to-
tal of 36% of ring users and 61% of patch users withdrew
from treatment because of side effects, preference for OCPs,
or ineffectiveness of treatment. Vaginal discomfort was sta-
tistically significantly more common in patients treated
with the vaginal ring, and headache was statistically signifi-
cantly more common in the patch users. Irregular bleeding
was frequently reported as an important side effect in both
groups.
Progesterone delivery systems. As opposed to estrogens,
progesterone has an antimitotic effect on endometrial cells,
making it a natural candidate to treat endometriosis. In vitro,
progesterone alone or coupled with estradiol induced decidu-
alization of eutopic and ectopic hESCs cultured in floating
collagen lattices (173). Moreover, decidualization inhibited
cell contractility, which may be related to impaired tissue re-
modeling ability. The 19-nortestosterone derivative dienogest
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Fertility and Sterility®
(DNG) inhibited aromatase and COX-2 expression and PGE2
production in cultures of hESCs (174).
Humans. Biopsy samples of endometriotic tissue from
women treated with a levonorgestrel-releasing intrauterine
system (LNG-IUS) for 6 months showed a decrease in the
expression of glandular and stromal ER-a, ER-b, and proges-
terone receptor, reduced cell proliferation index, and in-
creased Fas expression (175, 176). Significant levels of LNG
appeared in the peritoneal fluid of these women (177).
In an open-label controlled trial in which 40 women with
symptomatic endometriosis were randomized to receive either
LNG-IUS or no treatment after a laparoscopic surgery, LNG-
IUS statistically significantly reduced the recurrence of mod-
erate or severe dysmenorrhea for 1 year (178). This finding
was confirmed by other prospective observational studies
with similar sample sizes, in some cases with failed previous
medical and surgical attempts to treat pain (179, 180).
Reported compliance beyond 6 and 12 months in different
series were 68% and 82%, respectively (179, 180). Eighty
percent of removals took place within the first year after
insertion and were determined mainly by persistent pain,
although irregular bleeding and weight gain were also
reported (179, 180). Longer follow-up periods of up to 3 years
revealed a statistically significant reduction in dysmenorrhea
scores, with up to 87.5% of patients who maintained the de-
vice reporting improvement in pain according to a visual an-
alogue scale (VAS) (180, 181). In addition, the reduction in
quantified menstrual loss was statistically significant from
the third month of treatment onward (181).
The effectiveness of a 6-month therapy with LNG-IUS or
GnRH agonists to treat endometriosis-related chronic pelvic
pain was compared in a number of randomized trials (182–
186). In one study of 40 patients who had persistent pain
after conservative laparoscopy, the VAS score did not
improve, and patient satisfaction was lower in the LNG-IUS-
treated group (186). In the other studies, both treatments
were equally effective in statistically significant pain reduc-
tion. In a multicenter trial with 82 women with chronic pelvic
pain, a stronger pain-reduction effect was reported in stage III
and IV patients (182). Long-term follow-up observation of
these patients revealed that 59% were still using the device 3
years after its insertion; in 82.6% of these women, the VAS
score was %3 (185). These results were in line with a prospec-
tive, randomized study of 22 patients in whom the VAS score
showed a statistically significant reduction in pain after 24
weeks of either treatment, with no intergroup differences
(184). Second-look laparoscopies revealed that the extent of
pelvic endometriotic lesions was reduced in 60% of patients
treated with LNG-IUS and 37.5% who received GnRH agonists,
although the sample size was too small to make the difference
statistically significant. In a study of 44 women with pelvic
pain, CA-125 levels were lowered equally with either therapy
(183). Side effects more frequently related to LNG-IUS were
bleeding and pain. On the other hand, with LNG the symptoms
of hypoestrogenic state were avoided and a better lipid profile
was observed in comparison with GnRH agonists (183).
The effectiveness of LNG-IUS and depot medroxyproges-
terone acetate (MPA) was compared in a prospective
547
VIEWS AND REVIEWS
randomized study in which 30 patients with endometriosis re-
ceived one of either medication for 3 years after conservative
surgery (187). Depot MPA, a 17-hydroxyprogesterone deriv-
ative with moderate androgenic activity, is administered
intramuscularly every 3 months (187, 188). Although
symptoms and recurrence were restricted by both therapies,
LNG-IUS was associated with better compliance. By the
end of the study, bone density gain was observed
among LNG-IUS users, while the opposite was seen in the
MPA group (187).
The efficacy and safety of depot MPA in the treatment of
endometriosis were compared with those of leuprolide acetate
(LA) in two large randomized trials with 274 and 300 patients,
respectively (135, 189). The treatments lasted for 6 months,
and the patients were observed until months 12 and 18,
respectively. Both therapies were statistically significantly
equivalent in decreasing endometriosis symptoms. After 6
months of treatment, the women who received MPA had
statistically significantly less bone density loss than those
who received LA, but at the end of the studies the scores
returned to baseline (135, 189). Regarding side effects, fewer
hypoestrogenic symptoms but more irregular bleeding were
found in women treated with MPA compared with LA (189).
An alternative way of delivering progestogens is the
single-rod etonogestrel-containing contraceptive implant
named Implanon (Organon). Because this long-term subder-
mal progestogen delivery system improves dysmenorrhea,
its effectiveness for endometriosis-related pain was evaluated
in a prospective, randomized, controlled clinical trial (190). A
total of 41 patients received either Implanon or MPA. During
the 1-year follow-up period, both treatments reduced pain in-
tensity in all control visits. At month 6, the mean decrease in
VAS score was 68% in the Implanon group and 53% in the
MPA group (difference not statistically significant). Treat-
ment withdrawal occurred in 4 out of 21 patients and in 7
out of 20 patients on the Implanon and MPA groups, respec-
tively. The main reason for dropping out of the study in the
Implanon group was spot-bleeding episodes. In the MPA
group, most relevant reported symptoms were severe depres-
sion, hot flashes, or persistent pelvic pain. The proportion of
women satisfied or very satisfied with treatment was 57%
and 58% in the Implanon and MPA groups, respectively.
Flavonoids
Isoflavones. Isoflavones, a major subclass of the phytoestro-
gen family, are plant-derived nonsteroidal compounds that
possess weak estrogen-like biologic activity. Structural simi-
larities allow isoflavones to bind to estrogen receptors, com-
peting with estradiol and having an antiestrogenic effect on
women of reproductive age with high estrogenic levels. These
compounds might thus be expected to have an impact on the
development and the severity of endometriosis. However, few
studies have investigated the effects of isoflavones on this
disease (97, 191, 192).
In vitro/animal models. Puerarin is an isoflavone derived from
the Chinese medicinal herb Radix Pueraria (193). Genistein is an
isoflavonic phytoestrogen found in high concentrations in soy
products, legumes and grains (98, 194). In vitro cultured hESCs
548
were shown to have their invasiveness and neovascularization
capacity reduced when exposed to puerarin (193). Both
isoflavones were tested in peritoneal endometriosis induced in
rats and were associated with significant reduction in lesions,
compared with controls in which lesions grew during the
study period (97, 98). With puerarin, this effect was dose-
dependent, but high doses of the compound also statistically
significantly reduced estrogen levels, leading to lower blood
calcium and osteoporosis (97). No effects of genistein on
reproductive function were described (98).
In opposition to the findings mentioned above, no
differences in the morphology or vascularity pattern of
endometriosis-like lesions were observed in the skinfold cham-
ber hamster model of endometriosis treated with genistein (99).
Humans. To date, a single study was published on the effect
of isoflavones on human endometriosis. Pycnogenol, an ex-
tract of French maritime pine bark with known anti-
inflammatory properties and an efficient suppressive effect
on menstrual pain, was compared with LA in a randomized
trial (195). Fifty-eight women with endometriosis, recurrent
dysmenorrhea, and pelvic pain were assigned to treatment
with 60 mg/kg daily of pycnogenol for 48 weeks (n ¼ 32) or
6 monthly doses of 3.75 mg of subcutaneous LA (n ¼ 26).
In both groups, the pain score improved. Improvement was
more significant in the LA group, but lasted longer in the pyc-
nogenol group. The same happened with the levels of CA-125,
with a more marked rebound effect in the LA group. Of clinical
relevance is the documentation of a lower incidence of side ef-
fects in the group treated with the flavonoid, in which no pa-
tient discontinued treatment. In addition, while treatment
with LA suppressed menstruation, pycnogenol had no influ-
ence on menstrual cycles. More extensive study is clearly
needed to determine the actual effect of pycnogenol on symp-
toms and disease progression.
Epigallocatechin-3-gallate (EGCG). The major chemical
component of green tea, epigallocatechin-3-gallate (EGCG),
is a flavonoid with high antioxidant, proapoptotic, and anti-
angiogenic capacity. In vitro in isolated hamster endometrial
cells, EGCG has been shown to suppress estradiol-stimulated
activation and proliferation, and VEGF expression (100).
In vivo in the dorsal skinfold chamber model of endometriosis
in the Syrian golden hamster, daily administration of EGCG
inhibited growth, angiogenesis, and blood perfusion of
endometriosis-like lesions without affecting ovarian follicle
physiology (100). In the mouse model, EGCG significantly in-
hibited lesion size and the length, area, number, and size of
microvessels (101, 102). Expression of VEGFC, VEGFA, and
VEGFR-2 protein were also statistically significantly reduced.
Apoptosis was more evident, and NF-kB mRNA expression
was statistically significantly reduced (101).
Histone Deacetylase Inhibitors
Accumulating evidence indicates that survival of endometri-
otic cells is mediated by down-regulation of genes involved in
apoptosis. Aberrant methylation seems to take part in this
process of gene silencing. Because demethylation agents
and histone deacetylase inhibitors (HDACI) can reactivate
the genes silenced by promoter hypermethylation, it has
VOL. 98 NO. 3 / SEPTEMBER 2012

been proposed that HDACI might be used for treating endo-
metriosis (196, 197).
In vitro/animal models. The exposure of hESCs and epithelial
endometriotic cell cultures to the HDACI romidepsin resulted
in inhibited cell proliferation, cell cycle arrest at the G0/G1 or
G2/M phases, and statistically significantly increased apopto-
sis (197, 198). Romidepsin was shown to specifically reduce
HDAC enzymatic activity (199). Reduced transcriptional
activity of VEGF and reduced VEGF release in culture
media were also documented, suggesting an antiangiogenic
role for this molecule (199).
Trichostatin A has been the most studied HDACI in the
treatment of experimental endometriosis. Cultures of epithe-
lial and hESCs to which this substance is added display atten-
uation of proliferative capacity and invasiveness. The
expression of E-cadherin, a key intercellular protein in the
formation of adherence junctions, is enhanced, and NF-kB
activation is suppressed (200, 201). Similarly, human
adenomyotic cells viability is inhibited by trichostatin A in
a concentration-dependent fashion through mechanisms of
both cytotoxicity and cell cycle arrest (202). Trichostatin
and valproic acid were capable of reducing lesion size and im-
proving response to hyperalgesia in the murine model of en-
dometriosis (103, 203).
Humans. Valproic acid was used in a pilot study of three pa-
tients with endometriosis and adenomyosis who had moder-
ate to severe dysmenorrhea (204). A dose of 1,000 mg/day
was used for 3 months. Complete relief of pain in all cases
and an average reduction of one-third in uterine size were re-
ported. Disappearance or reduction of palpable tender nodules
in the cul-de-sac was also reported. Obviously, any beneficial
effect of valproic acid must be confirmed by larger controlled
studies.
CONCLUSION
Clinical manifestations of endometriosis may be the result of
disease activity and/or anatomic distortions determined by
such activity (namely, adhesions). Pharmacologic therapy is
expected to be of greater use in the treatment of active lesions,
but symptomatic benefit may also be obtained via pain relief
of adhesions. The ideal pharmacologic agent must fulfill the
following criteria:
1. High effectiveness in blocking disease progression and
symptoms
2. Ability to inhibit and suppress established lesions
3. High specificity, not interfering with physiologic processes
in which the same molecules that are targeted in the treat-
ment are involved
4. Demonstrated safety for long-term use in humans
5. High lingering effect in the inhibition of endometriotic
lesions
To date, the most extensively used medications in the
treatment of endometriosis are sex steroid expression mod-
ulators, mainly OCPs and GnRH agonists. Their effectiveness
has been clearly established, but the inhibition of the
pituitary-gonadal axis typically generated impairs reproduc-
tive function and induces (in the case of GnRH agonists)
VOL. 98 NO. 3 / SEPTEMBER 2012
Fertility and Sterility®
bone density loss and worsening of metabolic parameters
such as the lipid profile. Also, recurrence of symptoms is
high within a few months after discontinuation of treat-
ment. The same is true for other options within this group,
such as non-OCP methods and progesterone delivery sys-
tems, which are also associated with frequent unscheduled
bleeding. It is still not clear whether the use of danazol in-
creases the risk of ovarian cancer or if any increase is related
solely to endometriosis itself. This is an issue that must be
clarified.
An interesting new modulator of sex steroid expression is
the selective estrogen receptor-b agonist ERB-041. Biologic
plausibility for a significant impact on the development of en-
dometriosis exists, and the single study performed in mice is
promising. This molecule must be further studied in animals,
and its safety profile must be defined.
Anti-inflammatory agents comprise the other group of
medications that have been used for decades in the treatment
of endometriosis with demonstrated effectiveness in pain re-
lief. However, no regression of the disease has been docu-
mented in humans with this treatment, no lingering effect
has been observed, and their chronic use has side effects.
Very little is known about specific anti-inflammatory agents
COX-2 inhibitors and peroxisome proliferator-activated re-
ceptor g-agonists. In humans, a single study was published
on rofecoxib, and more data are certainly required before de-
finitive conclusions can be reached.
With regard to other pharmacologic groups, TNF-
a blockers were shown to be effective in animals, and etaner-
cept is already used with few adverse effects in the treatment
of chronic inflammatory diseases in humans. Thus, it could
certainly be tested in the treatment of endometriosis. Other
TNF-a blockers such as the anti-TNF-a-monoclonal antibody
should be avoided because of their uncertain safety record in
studies on primates.
Information available about the use of statins and met-
formin in endometriosis comes from experimental studies
but, as in the case of etanercept, these molecules are exten-
sively used in humans for other indications. The preliminary
results with animals warrant clinical trials. Concurrent treat-
ment with statins and danazol is contraindicated.
Many of the other agents that have only been tested in
experimental models (NF-kB inhibitors, melatonin, MAPK
inhibitors, MMP inhibitors, and apoptotic agents) require
more extensive study of their safety profiles. For some
agents, such as MMP inhibitors and the apoptotic agent b-
HIVS, future use in humans seems far-fetched because
they interfere with ovarian and endometrial physiology. Im-
munomodulators are used in humans in other contexts, but
their known risks of severe side effects make their chronic
use in a condition such as endometriosis not recommended.
Temsirolimus therapy, for instance, has an increased inci-
dence of infections, noninfectious pneumonitis, and meta-
bolic disturbances.
Hyaluronic acid is a valid option to be considered during
surgery, as a preventive measure for the formation on endo-
metriotic lesions.
Among the pharmacologic groups already tested in hu-
mans for the treatment of endometriosis, antiangiogenic
549
VIEWS AND REVIEWS
agents deserve special attention. In animal models, VEGF-
blockers have been shown to be highly effective, and they
are currently used in humans for the treatment of oncologic
diseases, but the incidence and seriousness of their side effects
contraindicates their use for the treatment of endometriosis.
The same concern is true for the chronic use of VEGF inhibi-
tors such as rapamycin (also an immunosuppressor) and 2-
ME2. On the other hand, DAs were shown to be effective in
-animals and in the first pilot study in humans. The DA qui-
nagolide needs to be tested in a randomized fashion, and
nonoral routes may reduce its side effects. Other very interest-
ing VEGF inhibitors include endostatin, the nontoxic oral
form of TNP-470, and HBA. Endostatin has shown a marked
effect in in vitro and animal models and is now being studied
in phase 2 human cancer treatments. Nontoxic TNP-470 and
HBA deserve further studies in animals. Although gene-
therapy with angiostatin was highly effective in rodents, it
completely blocks ovarian estrous cycles and thus cannot
be used in humans.
Oxidative stress is clearly an important factor in the peri-
toneal environment of women with endometriosis. However,
there is no evidence to support a clinical benefit to the use
of antioxidants. The same is true for flavonoids and
pentoxifylline.
The single small pilot study of the HDAC inhibitor val-
proic acid in humans has shown interesting results. The med-
ication must be tested in a randomized fashion.
In summary, among the plethora of pharmacologic
agents experimentally tested in the treatment of endometri-
osis, a few constitute realistic alternatives to conventional
therapy and can be promptly studied in the clinical setting
by well-designed, randomized trials.
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