Review

Endometriosis: an update on
management
Lia A Bernardi1 & Mary Ellen Pavone*2
Endometriosis is an inflammatory disease that commonly occurs in women of reproductive age
and is associated with pain and infertility. This disease can be challenging to manage given its
propensity to progress and recur despite treatment. Although medical therapy is beneficial for
controlling pain due to endometriosis, medical management has not proven to be effective in
treating infertility resulting from endometriosis. Surgery has historically been performed to both
improve pain and treat infertility in women with endometriosis. However, the optimal management
of endometriosis in asymptomatic women who desire fertility is unclear. Intrauterine insemination
with superovulation and IVF are other treatments that have proven to be effective in assisting
women with endometriosis to conceive. As the underlying molecular mechanisms of this disease
become better understood, promising new therapies for the treatment of endometriosis continue
to be investigated.

Endometriosis is a benign, inflammatory dis- and infertility in women with endometriosis

ease defined by the presence of extrauterine
endo­metrial tissue that is dependent upon
estrogen [1] . It occurs frequently among women
in the general population, with an estimated
prevalence of 6–10% [1] . The most common
symptoms of endometriosis include infertility,
dyspareunia and chronic pelvic pain, and it is
typically present on the pelvic peritoneum, the
recto­vaginal septum or the ovaries [1,2] . Although
clinical findings and symptoms may suggest
that a woman has endometriosis, a definitive
diagnosis can only be made pathologically after
surgery has been performed [3] .
Various theories of pathogenesis have his-
torically been used to explain how endome-
triosis develops. These include retrograde men-
struation leading to implantation of refluxed
endometrial tissue, the development of endo-
metrial tissue from coelomic mesothelial cells
that undergo metaplasia and lymphatic or
hematogenous dissemination of endometrial
cells [4] . Despite research efforts, the definite
mechanisms responsible for the development
of endometriosis have not been completely
elucidated.
Advancements have suggested that endo-
metriosis is not simply a local disease, but
rather a chronic, multifaceted process [2] . As
a result, its management can be challenging.
Although traditional medical, surgical and
infertility treatments continue to be employed
in women with endometriosis, more recent
research has focused on using therapies that
target the disease at a molecular level [1,4] . This
review will focus on the management of pain
and will discuss the evidence behind various
treatment strategies.
Pain
The most common symptom associated with
endometriosis is pain. It is believed that endo-
metriosis-related pain results from the effects of
inflammatory cytokines within the peritoneal
cavity, bleeding from endometriotic implants
and the invasion and irritation of pelvic floor
nerves [5,6] . Women with endometriosis may
suffer from dyspareunia, dysmenorrhea or
general cyclic or noncyclic pelvic pain. Both
medical and surgical treatments are utilized to 1
Department of Obstetrics &
control the pain associated with endometriosis. Gynecology, University of Illinois at
Chicago, IL, USA
2
Department of Obstetrics &
Medical treatment for pain Gynecology, Division of Reproductive
The goals with medical therapy are to mini- Endocrinology & Infertility & Division
of Reproductive Biology, Feinberg
mize the production and action of estradiol, School of Medicine at Northwestern
limit inflammation, inhibit the production of University, 303 Superior Street,
Suite 4-123, Chicago, IL 60611, USA
cyclic hormones from the ovaries and reduce *Author for correspondence:
menses [7] . The retrograde menstruation theory Tel.: +1 312 503 0520
and the notion that endometriotic implants Fax: +1 312 503 0095
mpavone@nmff.org
behave similarly to the normal endometrium
have led to the use of medications that decrease
cyclic menstruation while limiting the growth Keywords
of the endometrial tissue [5] . Thus, combined
• dysmenorrhea • dyspareunia
oral contraceptives (COCs), progestogens,
• endometrioma • endometriosis
gonadotropin-releasing hormone (GnRH) ago- • infertility • IVF • medical
nists and danazol, a synthetic androgen, have treatment • pelvic pain • surgery
historically been used to control symptoms. As
endometriosis has become better understood
at the molecular level, other medical therapies
have also been studied to evaluate their effec-
tiveness in treating endometriosis-associated part of

10.2217/WHE.13.24 © 2013 Future Medicine Ltd Women's Health (2013) 9(3), 233–250 ISSN 1745-5057 233
Review – Bernardi & Pavone
pain. Ultimately, individual aspects of these
medications, such as effectiveness, cost, side
effects and long-term safety, influence which
therapy is used.
Estrogen–progestogen contraceptives
COCs, used cyclically or continuously, are
commonly prescribed as a first-line treatment
for women suffering from mild endometriosis-
related pain, although their mechanism of action
is not completely understood. It has been pro-
posed that by inducing a pseudopregnancy state,
COCs cause decidualization and subsequent
atrophy of the endometrium [8] . Other studies
have suggested that alternative mechanisms may
be responsible for improving the pain associated
with endometriosis [9–11] .
An early randomized trial by Vercellini et al.
compared the effectiveness of a cyclic low-dose
COC with a GnRH agonist in 57 women with
moderate or severe endometriosis-related pelvic
pain. At the completion of 6 months of treat-
ment, there was a significant improvement in
nonmenstrual pain in both groups of women,
with no difference between the COC or GnRH
agonist groups. There was also a significant
decrease in deep dyspareunia in both groups,
although the GnRH agonist group had more
significantly improved pain scores compared
with the COC group. In addition, there was a
significant improvement in dysmenorrhea in the
COC group. However, at the 6-month follow-
up, symptoms recurred in both groups, with no
significant difference between the groups [12] .
In recent years, additional studies have been
published evaluating the effectiveness of COCs
in treating pain secondary to endometriosis.
A double-blind, placebo-controlled, random-
ized trial of 100 women by Harada et al. com-
pared a cyclic monophasic COC with placebo
for the treatment of endometriosis-associated
dysmenorrhea. The majority of women in this
study only had radiologic evidence of endome-
triosis. After four cyclic treatments, dysmenor-
rhea scores were significantly decreased in both
groups, but dysmenorrhea was significantly
milder in the COC group compared with the
placebo group [13] . More recently, in a prospec-
tive, randomized, double-blind controlled trial
of 47 women, Guzick et al. compared a GnRH
agonist with hormonal add-back with a continu-
ous monophasic COC. Both treatments, admin-
istered for 48 weeks, significantly reduced pain
from the baseline, but there was not a significant
difference in pain improvement between the two
treatment arms [14] .
234 www.futuremedicine.com
These studies suggest that COCs are as effec-
tive as GnRH agonists, and better than placebo,
at treating endometriosis-associated pain. Their
relatively low cost and long-term usability make
these medications an attractive first-line therapy.
However, COCs are contraindicated in certain
women with coexisting medical disorders, and
side effects may limit their use. To assist in
determining when COCs should be avoided, the
CDC adapted the WHO’s Medical Eligibility
Criteria for Contraceptive Use and published
guidelines, which are summarized in Box 1 [101] .
Progestogens
Progestogens are commonly prescribed to treat
endometriosis-associated pain and are an option
for women with contraindications to estrogen
use. Although it has been postulated that these
compounds are effective because they suppress
endometrial estrogen receptors, which leads
to the decidualization and subsequent atrophy
of endometrial tissue [8] , other studies have
proposed alternate mechanisms of action that
may improve endometriosis-related pain [9–11] .
Suppression of matrix metalloproteinases in
the endometrium may also contribute to their
effectiveness [8] . Various progestogens are avail-
able for clinical use, including medroxypro-
gesterone acetate (MPA) and norethindrone, a
19-nortestosterone derivative [5] .
The effectiveness of MPA in treating endo-
metriosis-related pain was evaluated in a pro-
spective, double-blind, placebo-controlled trial
by Telimaa et al. A total of 59 women with
mild–moderate endometriosis were randomized
to continuous therapy with oral MPA, danazol
or placebo for 6 months. Both MPA and dan-
azol led to significant reductions in pelvic pain,
lower back pain and pain with defecation when
compared with placebo. Laparoscopy performed
6 months after treatment to evaluate peritoneal
implants demonstrated partial or total resolu-
tion in 63% of the women who received MPA
versus only 18% resolution in the placebo group,
suggesting that MPA was superior to placebo
in treating endometriosis [15] . Later, in a pro-
spective, randomized, double-blind, placebo-
controlled trial, Harrison and Barry-Kinsella
also investigated the efficacy of MPA in treat-
ing endometriosis. A total of 100 women with
infertility were surgically diagnosed with endo-
metriosis and were randomized to receive either
MPA or placebo for 3 months. Both groups had
significant decreases in their revised American
Fertility Society stages and scores at second-
look laparoscopy, but there were no differences
future science group
 Endometriosis: an update on management – review

Box 1. Contraindications to the initiation of estrogen–progestogen contraceptives.

Unacceptable health risks
• Current breast cancer
• History of DVT/PE with high risk for recurrent VTE
• Acute DVT/PE
• History of DVT/PE after major surgery with prolonged immobilization
• Known thrombogenic mutation
• Diabetic retinopathy/nephropathy/neuropathy†
• Diabetes with other vascular disease or of longer than 20 years duration†
• Migraine with aura at any age
• History of cerebrovascular accident
• Multiple risk factors for arterial cardiovascular disease†
• Hypertension that is poorly controlled or with presence of vascular disease
• History of, or current, ischemic heart disease
• Peripartum cardiomyopathy that occurred within previous 6 months or that has led to moderately
or severely impaired cardiac function
• Complicated valvular heart disease
• Smoking:
– ≥35 years of age
– ≥15 cigarettes daily
• Complicated solid organ transplant
• Systemic lupus erythematosus with positive or unknown antiphospholipid antibodies
• Acute or flare of viral hepatitis†
• Severe cirrhosis
• Hepatocellular adenoma
• Malignant liver tumor
Theoretical or proven risks usually outweigh benefits of use
• Past history of breast cancer without evidence of current disease for 5 years
• Less than 3 weeks postpartum and not breastfeeding
• Less than 1 month postpartum and breastfeeding
• History of DVT/PE with lower risk for recurrent VTE
• Hyperlipidemia†
• Migraine without aura in women ≥35 years
• Adequately controlled hypertension
• Peripartum cardiomyopathy more than 6 months ago
• Smoking:
– ≥35 years of age
– <15 cigarettes daily
• Inflammatory bowel disease with increased risk of VTE
• Medically treated or current symptomatic gallbladder disease
• Past COC-related history of cholestasis
• On retroviral therapy with ritonavir-boosted protesase inhibitors
• Use of certain anticonvulsants
• Use of rifampicin or rifabutin therapy
• History of bariatric surgery with malabsorptive procedures
†
Assess according to the severity of the condition.
COC: Combined oral contraceptive; DVT: Deep vein thrombosis; PE: Pulmonary embolism; VTE: Venous thromboembolism.
Data taken from [101].

between the groups. However, there was a greater
improvement in wellbeing in the women who
received MPA when compared with the placebo
group [16] .
Depot MPA (DMPA) has also been employed
for the treatment of pain from endometriosis.
Vercellini et al. randomized 80 women with
moderate or severe pelvic pain to 1 year of treat-
ment with DMPA or cyclic COCs plus low-
dose danazol. After 12 months, both groups of
women had significantly reduced deep dyspa-
reunia and nonmenstrual pain scores with no

future science group Women's Health (2013) 9(3) 235

Review – Bernardi & Pavone
significant differences noted between the groups.
Dysmenorrhea was significantly reduced in both
groups, but more significantly reduced in the
DMPA group. Patient satisfaction was nonsignif-
icantly higher in the DMPA group (72.5%) than
in the COC plus danazol group (57.5%) [17] . In
another randomized controlled trial, Schlaff
et al. compared DMPA with a GnRH agonist
in 274 women for 6 months. At the end of
treatment, both therapies significantly reduced
pain scores, and there were no significant differ­
ences between the therapies in reducing four of
five pain-related symptoms. Over 60% of the
women in each group had improvement in pain
compared with baseline 12 months after treat-
ment was complete, and there was no difference
between groups for all five of the pain-associated
symptoms [18] .
The levonorgestrel-releasing intrauterine sys-
tem (LNG-IUS), a derivative of 19-nortestoster-
one, is a newer therapy that is gaining popular-
ity for the treatment of endometriosis-related
pain. Through local release of hormone, endo-
metrial tissue becomes atrophic and inactive [19] .
In a pilot study by Vercellini et al., 40 women
with moderate or severe dysmenorrhea were
randomized to immediate LNG-IUS insertion
or expectant management following opera-
tive laparoscopy for endometriosis. Moderate
or severe dysmenorrhea recurred significantly
less frequently in the women who received
the LNG-IUS (10%) versus the expectantly
managed women (45%). Of the women who
received the LNG-IUS, 75% were satisfied or
very satisfied after 1 year of treatment versus
50% of the women who did not [19] . Since then,
studies have compared more traditional treat-
ments with the LNG-IUS and have confirmed
that it is a useful treatment modality [20–22] .
Consequently, the LNG-IUS has become more
commonly used for endometriosis-related pain,
although it is not currently approved by the US
FDA for this use.
Although progestogens are effective in
controlling endometriosis-related pain for
some women, the side effects of treatment
can limit their use. Irregular bleeding, weight
gain, bloating, fluid retention, breast tender-
ness, headaches, nausea and mood changes
are among the reported side effects [23] . How-
ever, advantages, including less bone mineral
density loss compared with GnRH agonists
[18] , improved compliance with the LNG-IUS
[21] and lower cost, make progestogens an
attractive option for certain women with
endometriosis-associated pain.
236 www.futuremedicine.com
Gonadotropin-releasing hormone
agonists
GnRH agonists are similar to native GnRH,
but are modified to remain bound to pituitary
GnRH receptors for longer. The altered struc-
ture of these agonists prevents the stimulation
from GnRH that normally occurs in a pulsatile
fashion. This nonpulsatile binding results in an
ultimate downregulation of the pituitary–ovar-
ian axis. A hypoestrogenic state ensues leading
to amenorrhea and endometrial atrophy [6,8] .
GnRH agonists are approved by the FDA for
the management of endometriosis, as they have
proven to be effective in the treatment of pain
due to the hypogonadotropic–hypogonadal state
that is produced. GnRH agonists used in clini-
cal practice include leuprolide, nafarelin, gosere-
lin, buserelin and triptorelin [5] . These can be
administered subcutaneously, intra­muscularly
or intranasally at various time intervals.
Many studies have evaluated the use of GnRH
agonists for the treatment of endometriosis-asso-
ciated pain. In a meta-analysis by Brown et al.
that included 41 trials of 4935 women, the use of
GnRH agonists for endometriosis-related pain
was compared with various other strategies. One
study compared GnRH agonists with no treat-
ment and found that dysmenorrhea was signifi-
cantly relieved in the treatment group (risk ratio:
3.93; 95% CI: 1.37–11.28; p = 0.01). Two addi-
tional studies compared GnRH agonists with
placebo. There was a significant relief in pelvic
tenderness in the GnRH agonist group (risk
ratio: 4.17; 95% CI: 1.62–10.68; p = 0.003),
but no significant difference in dyspareunia or
defecation pressure between the two groups.
There was also a significant temporary increase
in symptom severity score during the stimula-
tory phase of therapy in the treatment group
(mean difference: 2.90; 95% CI: 2.11–3.69;
p < 0.001) [24] .
Overall, GnRH agonists appear to improve
endometriosis-related pain. However, side
effects, including bone mineral depletion and
vasomotor symptoms, which are related to the
hypoestrogenic environment [6] , limit the long-
term use of these medications. The ‘estrogen
threshold’ theory suggests that the amount of
estrogen necessary to prevent these side effects
is less than the amount needed to support endo-
metriosis [25] . Therefore ‘add-back’ therapy using
estrogen and progestogen or progestogen alone
is commonly administered to help reduce these
side effects and allow for longer-term use of
GnRH agonists [6,8] . Hormonal add-back has
proven to be effective in protecting against bone
future science group

loss and suppressing vasomotor symptoms while
continuing to control pain from endometriosis
[26,27] . Although the usability of GnRH agonists
for endometriosis is improved by add-back ther-
apy, their universal use remains limited by their
high cost and contraceptive properties.
Other treatments
Various other medical treatments have been,
and continue to be, evaluated for the treatment
of endometriosis-associated pain. However,
due to undesirable side effects or unconfirmed
effectiveness, current clinical use remains limited.
Danazol was the first drug approved by the
FDA for the treatment of endometriosis. It is an
isoxazol derivative of 17 a-ethinyltestosterone
that creates a state of anovulation by inhibiting
the LH surge [8] . Danazol also increases free
testosterone and inhibits enzymes involved
in steroidogenesis [8] . These effects lead to a
hypoestrogenic, hyperandrogenic environ-
ment that limits growth of endometriosis [5] .
A Cochrane review of five studies concluded
that when compared with placebo, 6 months of
danazol use resulted in significantly improved
pain relief from endometriosis. However, side
effects including muscle cramps, acne, edema
and weight gain were more common in women
using danazol [28] . These undesirable side effects
result from the low estrogen, high androgen
state produced by danazol and have limited
its use.
Newer treatments to control pain, such
as aromatase inhibitors (AIs), target specific
molecular differences present in women with
endometriosis. Aromatase is responsible for cata-
lyzing the creation of estrogen in various tis-
sues, including in endometriotic lesions where it
serves to synthesize estradiol locally [2,29] . Given
the essential role that estrogen plays in stimulat-
ing endometriosis, the goal of AIs is to eliminate
its creation [29] . As aromatase is involved in the
final step of biosynthesis of estradiol, it is a good
target for inhibition [30] . The commonly used
third-generation AIs are letrozole, anastrazole
and examestande [30] . In premenopausal women,
as AIs block extraovarian estrogen production,
increases in FSH lead to the development of
ovarian follicles. Therefore, additional treat-
ments must be used in combination with AIs
to downregulate the ovaries [30] . Studies that
have examined the use of AIs for the treat-
ment of endometriosis-related pain have dem-
onstrated promising results [31–33] . Although a
recent review has suggested that AIs are well
tolerated overall [30] and a previous study has
future science group Women's Health (2013) 9(3)
Endometriosis: an update on management – review
shown that AIs are safe for ovulation induction
[34] ,
additional trials are necessary to further
confirm the efficacy and safety of these medi-
cations. In the future, these medications may
have a more prominent role in the treatment of
endometriosis-associated pain.
Investigational drugs that target molecular
mechanisms are also being studied for the treat-
ment of endometriosis-related pain. As the cyto-
kine TNF-a is believed to be elevated in women
with endometriosis, and likely plays a role in the
increase in peritoneal macrophages that occur in
this disease [8] , the use of TNF-a inhibitors have
been investigated. Pentoxifylline is an immuno-
modulator that has also been evaluated for the
treatment of endometriosis-associated pain [8] .
Thus far, studies that have examined the effec-
tiveness of these drugs in treating pain from
endometriosis do not provide enough evidence
to support their routine use [35–37] .
Surgical treatment
In certain women with endometriosis-related
pain, medical treatment fails, side effects from
medications become unbearable or fertility is
desired. In these individuals, endometriosis is
surgically managed. The goal with operative
management is to restore normal anatomy,
destroy visible disease and minimize recur-
rence [5] . Possible procedures include ablation,
excision or drainage of endometriomas, lysis of
adhesions, destruction of peritoneal implants
through ablation and fulguration or excision [7] .
Management of endometriosis
Previous trials have examined whether surgery
is effective in treating women with pain from
endometriosis. In a prospective, randomized,
double-blind study by Sutton et al., laser abla-
tion of minimal to moderate endometriosis was
compared with diagnostic laparoscopy alone in
63 women. 6 months after surgery, there was
significantly improved pain relief in women
who underwent laser ablation (62.5%) when
compared with those who had only diagnostic
laparoscopy performed (22.6%) [38] . A follow-
up study of these patients demonstrated that
90% of women whose pain was improved at
6 months had continued pain relief at 1 year
[39] . After the randomization code was broken,
24 women who had originally been expectantly
managed underwent laparoscopic laser ablation.
Overall, a total of 56 women had laser ablation
performed, and Jones et al. described longer term
outcomes in 38 of these individuals. At a mean
of 73 months after surgery, 73.7% of the women
237
Review – Bernardi & Pavone
reported recurrence of pain, which occurred at a
median time of 19.7 months. However, 55.3% of
the women had satisfactory symptom relief [40] .
The initial study by Sutton et al. was included
in a meta-analysis of five studies that evaluated
the efficacy of operative laparoscopy in the treat-
ment of endometriosis-associated pelvic pain and
found that it was beneficial when compared with
diagnostic laparoscopy alone [41] .
These findings suggest that operative manage-
ment of endometriosis is effective in treating pain,
but that recurrence is common. Although studies
have confirmed that there is a role for surgery, the
optimal surgical approach remains unclear [42] .
Postoperative medical treatment
Some clinicians believe that postoperative medical
therapy eliminates remaining disease or micro-
scopic endometriosis that is unable to be removed
surgically [7] and will treat women who suffer
from more severe endometriosis-related pain with
adjuvant medications. Furness et al. performed a
meta-analysis to determine if postoperative medi-
cal treatment with GnRH agonists, danazol, pro-
gestogens and COCs improved endometriosis-
associated pain and reduced disease recurrence.
The studies suggest that post­operative medical
therapy improves painful symptoms in women
who are not interested in conceiving immediately
after surgery, but given that medical treatments do
not seem to alleviate pain after 1 year, long-term
use may not be beneficial [43] .
Management of endometriomas
The decision to proceed with surgical manage-
ment of an endometrioma often depends on
whether a woman has associated pain. If pain-
ful symptoms are present, surgery is warranted,
as medical treatment is unlikely to completely
resolve cysts [6] . The optimal surgical strategy for
the treatment of endometriomas has been evalu-
ated. In studies that have examined whether lapa-
roscopic cystectomy or drainage and coagulation
resulted in differences in pain relief and disease
recurrence, cystectomy was the more effective
surgical strategy. Pain and recurrence rates were
lower after laparoscopic cystectomy when com-
pared with other procedures [44,45] . However, the
impact of cystectomy on fertility must also be
considered. This subject will be discussed later
in the review.
Management of deep infiltrating
endometriosis
Although previous reviews have discussed
the surgical management of deep infiltrating
238 www.futuremedicine.com
endometriosis in detail [46,47] , this topic is
beyond the scope of this review.
Infertility
Although a definite causal relationship has not
been confirmed, endometriosis is associated with
infertility. Endometriosis is found in 20–40%
of infertile women, and it is suspected that mul-
tiple mechanisms contribute to decreased fertil-
ity in these women. Ovum transport may be
impaired as a result of distorted pelvic anatomy.
It is also theorized that the chronic inflamma-
tion that results from endometriosis may affect
the receptivity of the uterus, folliculogenesis of
the ovaries and proper functioning of the fal-
lopian tubes [5] . Advanced endometriosis may
impact fertility more significantly, as data sug-
gest that an inverse relationship exists between
disease severity and monthly fecundity rate [48] .
Both medical therapies and surgical strategies
have been employed in the treatment of endo-
metriosis-related infertility. Other treatments,
such as intrauterine insemination (IUI) and
IVF, have also been used in infertile women
with endometriosis.
Medical treatment
As medical therapy appears to be beneficial in
controlling pain due to endometriosis, the use of
medications to treat endometriosis-related infer-
tility has also been investigated. A meta-analysis
of 25 trials studied whether ovulation suppres-
sion agents improved pregnancy outcomes in
women with infertility. When suppression with
MPA, COCs, GnRH agonists, danazol or gestri-
none was compared with placebo or no treat-
ment, the odds ratio (OR) for pregnancy among
infertile women or those trying to conceive was
1.02 (95% CI: 0.69–1.50; p = 0.22). There-
fore, pregnancy outcomes did not significantly
improve when women with endometriosis-related
infertility were treated with ovulation suppres-
sion. In addition, as these medications inhibit
pregnancy, their use actually delays a woman’s
ability to conceive. Thus, there is no role for
medications as the sole therapy in the treatment
of endometriosis-associated infertility [49] .
Although other medical therapies such as
AIs, progesterone antagonists, selective proges-
terone receptor modulators and selective estrogen
receptor modulators have also been considered
for the management of infertility, a recent com-
mittee opinion from the American Society for
Reproductive Medicine explains that there is not
enough evidence at this time to determine their
efficacy [50] .
future science group

Superovulation & IUI
Other strategies to treat infertility, including
superovulation and IUI, have also been evalu-
ated in women with endometriosis. In a random-
ized, prospective trial, Deaton et al. compared
four cycles of clomiphene citrate and IUI with
periovulatory intercourse in 51 women with sur-
gically corrected endometriosis or unexplained
infertility. There was a significantly higher per
cycle fecundity in the women treated with clo-
miphene citrate plus IUI (0.095) than in women
who did not receive the treatment (0.033) [51] .
Tummon et al. later performed a randomized
trial comparing superovulation with IUI to
expectant management in 103 women with
minimal or mild endometriosis. The women
who underwent superovulation and IUI for
four cycles had higher live-birth rates (11%) than
those who were expectantly managed (2%). The
OR of live birth was 5.6 (95% CI: 1.8–17.4),
favoring treatment [52] .
Later, a randomized controlled study of
932 infertile women, including individuals
with stage I and II endometriosis, was per-
formed to compare four cycles of intra­cervical
insemination, IUI, superovulation with intra-
cervical insemination and superovulation
with IUI. The pregnancy rate was 33% in the
superovulation/IUI group, 19% in the super­
ovulation/intracervical insemination group,
18% in the IUI alone group and 10% in the
intracervical insemination group [53] . Given
these findings, superovulation with IUI can be
used as one of the first-line therapies in younger
infertile women with stage I/II endometriosis.
In older women, superovulation or IVF may be
considered [50] .
IVF
Although it is not routine practice worldwide,
throughout the USA, IVF is commonly per-
formed in infertile women with endometriosis.
According to data from the Society for Assisted
Reproductive Technology, endometriosis was the
indication for IVF in 4% of all cycles performed
in 2011 [102] .
The data from Society for Assisted Reproduc-
tive Technology suggest that IVF is an effective
treatment for women with endometriosis-asso-
ciated infertility. In women with endometriosis,
36% of retrievals resulted in live birth compared
with 32% in women undergoing IVF for all indi-
cations [102] . These findings contrast results from
a meta-analysis of 22 studies by Barnhart et al.,
which examined outcomes in women with endo-
metriosis who underwent IVF. When women
future science group
Endometriosis: an update on management – review
with endometriosis were compared with women
with tubal factor infertility, the chance of preg-
nancy was significantly lower in the endometriosis
group (OR: 0.56; 95% CI: 0.44–0.70). When
pregnancy rates were compared between women
with mild and severe endometriosis, they were
significantly lower in those with severe disease
(OR: 0.60; 95% CI: 0.42–0.87). Overall, the
pregnancy rate in women with endometriosis who
underwent IVF was 25% [54] . Despite the fact
that this study demonstrated that pregnancy rates
were lower in women with endometriosis than in
women without endometriosis, IVF is the most
successful assisted reproductive technology (ART)
option that can be offered to women with this dis-
ease [54] . As it is believed that per cycle pregnancy
rates in individuals with endometriosis are maxi-
mized with IVF [50] , it continues to be one of the
main treatment options for this group of women.
Some clinicians use medical therapy to treat
endometriosis before a patient undergoes IVF.
This practice has been studied to determine
whether pregnancy outcomes are improved.
Sallam et al. performed a meta-analysis of three
randomized controlled trials of 165 women to
investigate whether the use of a GnRH agonist for
3–6 months before IVF or intracytoplasmic sperm
injection in women with various stages of endo-
metriosis improved pregnancy rates. The clinical
pregnancy rate per woman was significantly higher
in those who received treatment when compared
with those who did not (OR: 4.28; 95% CI:
2.00–9.15). The live-birth rate per woman, as
reported in one study, was also significantly higher
in those who received a GnRH agonist when com-
pared with those who did not (OR: 9.19; 95%
CI: 1.08–79.22) [55] . Given these results, medical
pretreatment with a GnRH agonist may be war-
ranted in women with endometriosis who will be
undergoing IVF.
As IVF has developed into a more commonly
performed procedure, not all women with endo-
metriosis are surgically managed before undergo-
ing IVF. Therefore, there may be a role for surgery
in these women if they fail to become pregnant.
In a retrospective case series, Littman et al. inves-
tigated whether women with endometriosis who
were unsuccessful in achieving pregnancy with
IVF were able to conceive after operative lapa-
roscopy was performed. There were 29 women
who opted to undergo laparoscopic treatment of
endometriosis after an average of 2.2 failed IVF
cycles. In this group of women, 76% conceived,
with 59% of the conceptions being spontane-
ous. The rates of conception were highest in the
women with stage I disease and lowest in stage IV
Women's Health (2013) 9(3) 239
Review – Bernardi & Pavone

Table 1. Summary of studies examining endometriosis-related pain.

Study (year) Study Sample Indication for Intervention Time Outcome Ref.
type size treatment
Medical treatments
Combined oral contraceptives
Vercellini et al. RCT 57 Moderate or COC vs GnRH 6 months of Both with improvement in nonmenstrual [12]
(1993) severe pelvic agonist treatment pain and deep dyspareunia
pain Improved dysmenorrhea in COC group
Symptoms recurred in both groups at
6-month follow-up
Harada et al. RCT 100 Dysmenorrhea COC vs Four Dysmenorrhea scores significantly milder [13]
(2008) placebo treatment and endometrioma volume significantly
cycles decreased in COC group
Guzick et al. RCT 47 Pelvic pain GnRH agonist 48 weeks of Both groups with significantly reduced [14]
(2011) plus add-back treatment pain
vs COC
Progestogens
Telimaa et al. RCT 59 Mild–moderate MPA vs 6 months of Both treatment groups with significantly [15]
(1987) endometriosis danazol vs treatment reduced pelvic pain and increased
placebo resolution of disease
Harrison and RCT 90 Surgically MPA vs 3 months of Both groups with significantly reduced [16]
Barry-Kinsella diagnosed placebo treatment revised American Fertility Society stages
(2000) endometriosis and scores at second-look laparoscopy
MPA more effectively improved overall
wellbeing
Vercellini et al. RCT 80 Moderate– DMPA vs cyclic 1 year of Both groups with significantly reduced [17]
(1996) severe pelvic COC plus low treatment symptoms
pain dose danazol Dysmenorrhea more significantly
reduced in DMPA group at 1 year
Schlaff et al. RCT 274 Persistent pain DMPA vs 6 months of After 12 months of follow-up, both [18]
(2006) after surgery GnRH agonist treatment groups equivalent in reducing pain
symptoms
Vercellini et al. RCT 40 Moderate or LNG-IUS vs Followed-up Moderate or severe dysmenorrhea [19]
(2003) severe expectant at 12 months significantly less common in LNG-IUS
dysmenorrhea management group
after surgery
Petta et al. RCT 82 Endometriosis, LNG-IUS vs 6 months of Both groups with significantly decreased [20]
(2005) dysmenorrhea GnRH agonist treatment pain scores during treatment
and CPP
Wong et al. RCT 30 Moderate or LNG-IUS vs 36 months Pain scores reduced in both groups [21]
(2010) severe DMPA after of treatment LNG-IUS users with better compliance
endometriosis conservative
surgery
Tanmahasamut RCT 55 Moderate-to- LNG-IUS vs 12 months LNG-IUS users with significantly lower [22]
et al. (2012) severe expectant of treatment dysmenorrhea and noncyclic pelvic pain
dysmenorrhea management scores, and less likely to have recurrent
after surgery dysmenorrhea
GnRH agonists
Brown et al. Meta- 41 Symptoms of GnRH agonist Varied by GnRH agonists with better symptom [24]
(2010) analysis studies endometriosis vs placebo, no study from relief than placebo or no treatment
treatment or 4 weeks to No difference in pain relief between
other 9 months of GnRH agonists vs danazol or between
medications treatment GnRH agonists vs levonorgestrel
AI: Aromatase inhibitor; COC: Combined oral contraceptive; CPP: Chronic pelvic pain; DMPA: Depot medroxyprogesterone acetate; GnRH: Gonadotropin-releasing
hormone; LNG-IUS: Levonorgestrel-releasing intrauterine system; MPA: Medroxyprogesterone acetate; RCT: Randomized controlled trial.

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 Endometriosis: an update on management – review

Table 1. Summary of studies examining endometriosis-related pain (cont.).

Study (year) Study Sample Indication for Intervention Time Outcome Ref.
type size treatment
Medical treatments (cont.)
Other treatments
Farquhar et al. Meta- Five Surgically Danazol vs 3–6 months Danazol significantly improved pain, but [28]
(2007) analysis studies confirmed placebo of treatment side effects more common
endometriosis
Ailawadi et al. Prospective 10 Refractory AI plus 6 months of Pelvic pain scores and visible disease [31]
(2004) pelvic pain norethindrone treatment significantly decreased
acetate
Soysal et al. RCT 80 Severe AI plus GnRH 6 months of Significantly increased time to [32]
(2004) endometriosis agonist vs treatment recurrence and lower rates of recurrence
after GnRH agonist in AI group
conservative
surgery
Amsterdam Prospective 15 Refractory AI plus COC 6 months of 14 women with significant improvement [33]
et al. (2005) endometriosis treatment in pain
and CPP
Kamencic and RCT 34 Mild–moderate Pentoxifylline 3 months of Both groups with improvement in pain [35]
Thiel (2008) endometriosis vs expectant treatment score, but significantly improved scores
and CPP management in pentoxifylline group at 2- and
refractory to after 3-month follow-up
medical therapy conservative
surgery
Alborzi et al. RCT 88 Infertile women Pentoxifylline 6 months of No significant difference in recurrence [36]
(2007) with vs placebo treatment rates at 1-year follow-up
dysmenorrhea, after
dyspareunia or conservative
pelvic pain surgery
Koninckx et al. RCT 21 Severe pain and Anti-TNF-a 12 weeks of Pain significantly decreased in both [37]
(2008) rectovaginal monoclonal treatment groups
nodules antibody vs
placebo
Surgical treatments
Endometriosis
Sutton et al. RCT 63 Minimal-to- Laser ablation Followed-up Significant improvement in pain relief in [38]
(1994) moderate vs diagnostic at 3 and laser ablation group at 6 months
endometriosis laparoscopy 6 months
and pain
Sutton et al. Follow-up 20 Underwent Continued Followed-up Of those with initial improvement, 90% [39]
(1997) from RCT laser surgery pain relief vs at 1 year with continued pain relief
(Sutton for recurrence
et al. 1994 endometriosis
[38] )

Jones et al. Long-term 38 Underwent Continued Mean of Painful symptoms recurred in 73.7% of [40]
(2001) follow-up laser surgery pain relief vs 73 months women, but satisfactory symptom relief
from RCT for recurrence of follow-up in 55.3%
(Sutton endometriosis since surgery
et al. 1994
[38] )

Jacobson et al. Meta- Five Endometriosis- Operative vs Followed-up Operative laparoscopy resulted in [41]
(2009) analysis studies associated diagnostic at improved pain
symptoms laparoscopy 6–12 months
AI: Aromatase inhibitor; COC: Combined oral contraceptive; CPP: Chronic pelvic pain; DMPA: Depot medroxyprogesterone acetate; GnRH: Gonadotropin-releasing
hormone; LNG-IUS: Levonorgestrel-releasing intrauterine system; MPA: Medroxyprogesterone acetate; RCT: Randomized controlled trial.

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Table 1. Summary of studies examining endometriosis-related pain (cont.).

Study (year) Study Sample Indication for Intervention Time Outcome Ref.
type size treatment
Surgical treatments (cont.)
Endometriosis (cont.)
Healey et al. RCT 178 Pelvic pain Laparoscopic Followed-up No significant difference in reduction in [42]
(2010) ablation vs at 3, 6, 9 pain scores at 12 months
excision of and
disease 12 months
Postoperative medical treatment
Furness et al. Meta- 12 studies Endometriosis Postoperative 3–6 months Postoperative medical treatment not [43]
(2004) analysis medical of treatment beneficial in improving pain or disease
treatment vs recurrence
placebo or
surgery alone
Endometriomas
Beretta et al. RCT 64 Endometriotic Laparoscopic Followed-up At 24 months, significantly lower pain [44]
(1998) cysts ≥3 cm cystectomy vs at 3, 6, 12 recurrence and longer length to
drainage and and recurrence in cystectomy group
coagulation 24 months
Alborzi et al. RCT 100 Endometriomas Laparoscopic Followed-up At 24 months, recurrence of symptoms [45]
(2004) ≥3 cm cystectomy vs at 3, 6, 9, and reoperation rates significantly lower
fenestration 12, 18 and in cystectomy group
and 24 months
coagulation
AI: Aromatase inhibitor; COC: Combined oral contraceptive; CPP: Chronic pelvic pain; DMPA: Depot medroxyprogesterone acetate; GnRH: Gonadotropin-releasing
hormone; LNG-IUS: Levonorgestrel-releasing intrauterine system; MPA: Medroxyprogesterone acetate; RCT: Randomized controlled trial.

disease. Pregnancy rates of these patients were sig-
nificantly higher than the 37% conception rates of
similarly matched women who failed to become
pregnant through an average of 2.4 IVF cycles but
declined surgical treatment of their endometriosis.
In addition, the rates of spontaneous pregnancy
were significantly higher in the surgically treated
women than in the nonsurgically treated women
(15%) [56] . These data suggest that surgery may
increase the likelihood of conception in women
with endometriosis who fail to become pregnant
through IVF.
Surgical treatment
Outcomes of women who have undergone sur-
gical management of endometriosis have been
studied to determine whether fertility is improved
postoperatively. The role of surgery in women
with early and advanced stage disease has been
evaluated. The impact of reoperation and post-
operative medical therapy, as well as the benefits
and risks of endometrioma removal, have also
been examined.
Management of endometriosis
Two randomized controlled trials assessed
whether laparoscopic surgery in infertile women
with minimal-to-mild endometriosis improved
pregnancy outcomes. Marcoux et al. randomized
341 women to resection or ablation of endometri-
osis or diagnostic laparoscopy and followed them
for 36 weeks. Of the women who had their endo­
metriosis treated surgically, significantly more
carried pregnancies to at least 20 weeks (30.7%)
compared with the women who only underwent
diagnostic laparoscopy (17.7%) [57] . In another
trial by the Gruppo Italiano, 101 women were
randomized to resection or ablation of endome-
triosis or diagnostic laparoscopy and followed
for 1 year postoperatively. There was no signifi-
cant difference in pregnancy rates between the
two groups, as 24% in the surgically treated
group and 29% in the laparoscopy only group
conceived [58] . Despite the fact that the studies
reported different outcomes, a meta-analysis of
these two trials determined that laparoscopic
surgery was significantly beneficial in terms of
live-birth rate and ongoing pregnancy rate after
20 weeks when compared with diagnostic lapa-
roscopy in infertile women with endometriosis
(OR: 1.64; 95% CI: 1.05–2.57). There was
also a benefit to laparoscopic surgery for clinical
pregnancy rates when compared with diagnostic
laparoscopy (OR: 1.66; 95% CI: 1.09–2.51) [59] .

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 Endometriosis: an update on management – review

Table 2. Summary of studies examining endometriosis-related infertility.

Study (year) Study type Sample Indication for Intervention Time Outcome Ref.
size treatment
Medical treatments
Hughes et al. Meta-analysis 25 Infertility and Danazol, MPA, 8–24 weeks No improvement in [49]
(2007) studies surgically gestrinone, COC, of treatment, pregnancy outcomes
confirmed GnRH agonists or 3–60 months with ovulation
endometriosis placebo of follow-up suppression
Superovulation & IUI
Deaton et al. RCT 51 Surgically CC plus IUI vs Four Improved fecundity in [51]
(1990) corrected periovulatory treatment or CC/IUI group
endometriosis or intercourse control cycles
unexplained
infertility
Tummon et al. RCT 103 Infertility and Superovulation with Four Higher live-birth rates [52]
(1997) minimal or mild IUI vs expectant treatment or in superovulation/IUI
endometriosis management control cycles group
Guzick et al. (1999) RCT 932 Infertility, some IUI vs IUI/ Four Pregnancy rates [53]
with stage I or II superovulation vs treatment highest in
endometriosis intracervical cycles superovulation/IUI
insemination vs group
intracervical
insemination/
superovulation
IVF
Barnhart et al. Meta-analysis 22 Infertility and IVF outcomes for Not applicable Lower pregnancy rates [54]
(2002) studies undergoing IVF endometriosis vs other in endometriosis vs
causes of infertility, other indications for
and for different IVF and in severe vs
stages of mild endometriosis
endometriosis
Sallam et al. Meta-analysis Three Undergoing ART GnRH agonists prior to 3–6 months Clinical pregnancy [55]
(2006) studies IVF or ICSI vs control of treatment rates significantly
higher in GnRH agonist
group
Littman et al. Retrospective 64 Failed IVF Operative laparoscopy 2.2–2.4 IVF Pregnancy and [56]
(2005) case series vs expectant cycles spontaneous
management conception rates
significantly higher in
operative laparoscopy
group
Surgical treatments
Endometriosis
Marcoux et al. RCT 341 Infertility and Resection or ablation Followed for Enhanced fecundity in [57]
(1997) minimal or mild vs diagnostic 36 weeks surgically managed
endometriosis laparoscopy group
Parazzini et al. RCT 101 Infertility and Resection or ablation Followed for No significant [58]
(1999) minimal or mild vs diagnostic 1 year difference in pregnancy
endometriosis laparoscopy rates
Jacobson et al. Meta-analysis Two Infertility and Operative laparoscopy Followed for Laparoscopic surgery [59]
(2010) studies minimal or mild vs diagnostic 36 weeks to significantly beneficial
endometriosis laparoscopy 1 year in terms of pregnancy
rates
AFC: Antral folic count; AMH: Anti-Müllerian hormone; ART: Assisted reproductive technology; CC: Clomiphene citrate; COC: Combined oral contraceptive;
GnRH: Gonadotropin-releasing hormone; ICSI: Intracytoplasmic sperm injection; IUI: Intrauterine insemination; MPA: Medroxyprogesterone acetate;
RCT: Randomized controlled trial.

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Table 2. Summary of studies examining endometriosis-related infertility (cont.).

Study (year) Study type Sample Indication for Intervention Time Outcome Ref.
size treatment
Surgical treatments (cont.)
Endometriosis (cont.)
Crosignani et al. Nonrandomized 92 Infertility and Laparotomy vs Followed for Cumulative pregnancy [60]
(1996) historical severe laparoscopy 24 months rates not significantly
surgical series endometriosis different
Postoperative medical treatment
Furness et al. Meta-analysis Eight Endometriosis Postoperative medical Followed-up No difference in [43]
(2004) studies treatment vs placebo for 5 years pregnancy rates
or no treatment between groups
Reoperation
Vercellini et al. Systematic Three Endometriosis Primary surgery vs Followed-up Pregnancy rates almost [63]
(2009) review studies and some with repeat surgery and IVF for 60 months halved after repeat
infertility vs repeat surgery surgery vs primary
surgery
No improvement in
pregnancy rates after
repeat surgery vs IVF
for recurrent
endometriosis
Endometriomas
Beretta et al. RCT 64 Endometriotic Laparoscopic Followed-up Cumulative pregnancy [44]
(1998) cysts ≥3 cm cystectomy vs for 3, 6, 12 rates significantly
drainage and and higher in cystectomy
coagulation 24 months group
Alborzi et al. RCT 62 Infertility and Laparoscopic Followed-up Significantly higher [45]
(2004) endometriomas cystectomy vs at 1 year pregnancy rates in
≥3 cm fenestration and cystectomy group
coagulation
Somigliana et al. Observational 36 Unilateral Compared response of Median of Reduced response to [66]
(2006) unoperated ovary with 10 months gonadotropins in
endometrioma endometrioma to between ovaries with
and undergoing intact ovary diagnosis of endometriomas
IVF-ICSI cyst and
IVF-ICSI cycle
Almog et al. (2011) Retrospective 81 Unilateral Compared ovary with Not applicable No significant [67]
case–control unoperated endometrioma to difference in number
endometrioma contralateral ovary of oocytes retrieved or
and undergoing antral follicles in
first IVF cycle ovaries with
endometriomas
Benaglia et al. Retrospective 84 Unilateral Compared response in Not applicable No difference in [68]
(2011) unoperated ovary with responsiveness to
endometrioma endometrioma to hyperstimulation in
and undergoing contralateral ovary ovaries with
IVF endometriomas
Benschop et al. Meta-analysis Three Endometriomas Surgery vs expectant Follow-up No difference for [69]
(2010) trials and undergoing management and varied by surgical vs expectant
ART ablation vs cystectomy study from management or
two cycles to ablation vs cystectomy
1 year or more on clinical pregnancy
rates
AFC: Antral folic count; AMH: Anti-Müllerian hormone; ART: Assisted reproductive technology; CC: Clomiphene citrate; COC: Combined oral contraceptive;
GnRH: Gonadotropin-releasing hormone; ICSI: Intracytoplasmic sperm injection; IUI: Intrauterine insemination; MPA: Medroxyprogesterone acetate;
RCT: Randomized controlled trial.

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 Endometriosis: an update on management – review

Table 2. Summary of studies examining endometriosis-related infertility (cont.).

Study (year) Study type Sample Indication for Intervention Time Outcome Ref.
size treatment
Surgical treatments (cont.)
Endometriomas (cont.)
Tsolakidis et al. RCT 20 Endometriomas Laparoscopic Followed-up Significant difference in [71]
(2010) ≥3 cm cystectomy vs at 6 and the decrease in AMH
three-step procedure 12 months and AFC in cystectomy
group
Somigliana et al. Systematic 11 Endometriomas Laparoscopic stripping Followed-up Nine studies with [72]
(2012) review studies for significantly reduced
1–9 months AMH after surgery
Raffi et al. (2012) Meta-analysis Eight Endometriomas Cyst excision Followed-up Significantly decreased [73]
studies for AMH after cystectomy
1–9 months
AFC: Antral folic count; AMH: Anti-Müllerian hormone; ART: Assisted reproductive technology; CC: Clomiphene citrate; COC: Combined oral contraceptive;
GnRH: Gonadotropin-releasing hormone; ICSI: Intracytoplasmic sperm injection; IUI: Intrauterine insemination; MPA: Medroxyprogesterone acetate;
RCT: Randomized controlled trial.

There are no randomized controlled trials Reoperation

that have assessed whether operative manage-
ment of advanced endometriosis in infertile
women improves fecundity. However, obser-
vational data suggest that these women may
benefit from surgery [50] . One study by Cro-
signani et al. reported pregnancy rates in 92
infertile women with severe endometriosis
who actively attempted to become pregnant
after undergoing surgical treatment with
laparotomy or laparoscopy. After surgery, the
24-month cumulative pregnancy rates were
44.9% in the laparoscopy group and 62.7%
in the laparotomy group [60] .
Therefore, surgical management of endome-
triosis appears to benefit infertile women with
earlier stage disease. Limited data suggest that
there is also a role for surgery in women with
more advanced disease.
Postoperative medical treatment
Postoperative medical therapy has also been
evaluated to determine whether adjuvant treat-
ment improves pregnancy rates in women with
endometriosis. A meta-analysis of eight studies
demonstrated that when postoperative medi-
cal treatment with GnRH agonists, MPA and
danazol was compared with placebo or no
treatment, there were no differences in preg-
nancy rates between the groups (risk ratio:
0.84; 95% CI: 0.59–1.18) [43] . Use of medical
therapy also delays a woman’s ability to con-
ceive in the immediate postoperative period.
Therefore, there does not appear to be a role
for adjuvant medical therapy in women with
endometriosis who are attempting pregnancy.
Recurrence of endometriosis is common, with
up to a 15% rate of annual recurrence [61] and
a 40–50% rate after 5 years [62] . Therefore, the
fertility benefits of repeat surgery for recurrent
endometriosis have been evaluated. A system-
atic review by Vercellini et al. reported that
the pregnancy rates in women who underwent
repeat surgery for recurrent endometriosis were
lower than the rates in women who had pri-
mary surgery for endometriosis [63] . Therefore,
the role of repetitive surgery for recurrent dis-
ease appears to be limited. In addition, evidence
has suggested that IVF may be a more effec-
tive treatment strategy than a second surgery in
women with recurrent endometriosis attempting
to conceive [63] .
Management of endometriomas
The optimal treatment strategy for women
with endometriomas who desire fertility is con-
troversial. Asymptomatic individuals may be
expectantly or surgically managed, but there
are concerns with both options. In addition, if
surgery is performed, the preferred strategy for
endometrioma removal is debatable.
The procedure resulting in the best sponta-
neous pregnancy outcomes was evaluated in a
study by Beretta et al. In this trial, 64 women
were randomized to undergo cystectomy or
drainage and coagulation of endometrio-
mas that were at least 3 cm in diameter. The
cumulative pregnancy rates after 24 months
were significantly higher in the cystectomy
group (66.7%) than the drainage group
(23.5%) [44] . Alborzi et al. also performed a

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Review – Bernardi & Pavone
Endometriosis
Symptoms
Pain Infertility
No contraindications
to COC
COC
Early referral to specialist in
reproductive endocrinology and
Treatment infertility for likely superovulation/IUI
failure or
contraindication
to COC
Refer to
gynecologist
Figure 1. Initial management of endometriosis.
COC: Combined oral contraceptive; IUI: Intrauterine insemination.
prospective, randomized trial that included
62 infertile women to determine whether
laparoscopic cystectomy or fenestration and
coagulation of endometriomas 3 cm or greater
in size resulted in different rates of spontaneous
pregnancy. After 1 year of follow-up, women
who underwent cystectomy had significantly
higher cumulative pregnancy rates (59.4%)
than the women who underwent fenestration
and coagulation (23.3%) [45] .
The most appropriate management for
women with endometriomas who require
ART is also highly debated. Possible difficul-
ties in performing IVF in women with endo-
metriomas include challenges with ultrasound
monitoring, access issues or accidental drain-
age during oocyte retrieval, which may predis-
pose patients to a pelvic infection and growth
or spontaneous rupture of the endometrioma
[64,65] . If endometriomas are not removed,
there are also concerns about impaired fertil-
ity. An observational study by Somigliana et al.
reported that women with endometriomas had
a decreased ovarian response to gonado­t ropins
[66] . However, other studies have failed to dem-
onstrate this finding [67,68] , suggesting that
expectant management may not alter fertility.
This was further supported by a meta-analysis
by Benschop et al. that included three random-
ized trials that examined the effectiveness of
various treatments for endometriomas before
ART cycles. This study found that there was
246 www.futuremedicine.com
no benefit of surgical management compared
with expectant management in terms of clini-
cal pregnancy rates (aspiration vs expectant:
Peto OR: 1.29; 95% CI: 0.45–3.64; cystec-
tomy vs expectant: Peto OR: 1.15; 95% CI:
0.52–2.55) [69] .
If operative management of an endome-
trioma is performed, the fertility risks should
be considered. It has been hypothesized that
surgery may be detrimental to ovarian func-
tion due to the removal of viable ovarian tissue.
Subsequent inflammatory changes, as well as
postoperative alterations in vascularity, may
also contribute to ovarian damage [70] . Sur-
rogate markers of ovarian function have been
investigated postoperatively to evaluate the
impact of surgical management. In a prospec-
tive, randomized trial, Tsolakidis et al. com-
pared ovarian reserve damage in 20 women
with endometriomas who underwent laparo-
scopic cystectomy or a ‘three-step procedure’.
This ‘three-step procedure’ included an ini-
tial laparoscopy where the endometrioma was
drained, irrigated, inspected and biopsied.
Afterwards, a GnRH agonist was given for
3 months, and then a second laparoscopy was
performed, where the internal wall of the cyst
was vaporized with a CO2 laser. There was a
significant difference in the decrease in mean
anti-Müllerian hormone and the antral folic
count, both markers of ovarian reserve, in the
cystectomy group compared with the ‘three-
step procedure’ group [71] . A systematic review
by Somigliana et al. and a meta-analysis by
Raffi et al. also examined the impact of sur-
gical removal of endometriomas on ovarian
reserve and demonstrated a significant decline
in anti-Müllerian hormone after cystectomy
[72,73] . However, when clinical outcomes in
women undergoing ART were evaluated in
a meta-analysis by Benschop et al., there was
no difference in clinical pregnancy rate (Peto
OR: 0.72; 95% CI: 0.25–2.08) or the number
of mature oocytes retrieved (Peto OR: 0.60;
95% CI: -1.32–0.12) when endometriomas
were managed with cystectomy or fenestration
and coagulation [69] .
Evidence from these studies suggests that
women with endometriomas who are attempt-
ing spontaneous conception have the highest
pregnancy rates when cystectomy is performed
over ablation. In women undergoing ART, there
is no proven benefit for endometrioma removal
in terms of pregnancy outcomes. In fact, surgery
may actually impair ovarian function. Therefore,
the risks and benefits of endometrioma removal
future science group
 Endometriosis: an update on management – review

must be considered before an asymptomatic historical therapies or even replace them. As

woman undergoes surgery.
Conclusion & future perspective
The studies reviewed here have demonstrated that
there are various medical, surgical and infertility
treatments available for women with endome-
triosis (Tables 1 & 2) . The initial treatment choice
depends on the severity of a woman’s symptoms
and her desire for fertility, as well as the clini-
cian experience. Referral to a specialist may be
warranted in more advanced and refractory cases
(Figure 1) .
Although conventional strategies will con-
tinue to be employed for the treatment of endo-
metriosis, new therapies will likely be introduced
in the coming years. Innovative strategies that
target the disease at the molecular level continue
to be developed and studied. Eventually, these
newer treatments may be used adjunctively with
interest in endometriosis research continues, it is
also likely that the optimal surgical management
of endometriomas will be further investigated.
Given that endometriosis is common amongst
women of reproductive age, it is imperative that
quality research continues to be performed so
that this disease may be better understood and
optimally treated.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan-
cial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.

Executive summary
Medical treatments for pain
• The traditional medications used to treat endometriosis-related pain, including combined oral contraceptives, progestogens,
gonadotropin-releasing hormone agonists and danazol, are effective in controlling symptoms. Side-effect profiles and cost commonly
dictate which therapy is used. In women with no contraindications to estrogen and progesterone therapy, combined oral
contraceptives should be the first-line treatment strategy.
• Women who fail oral contraceptive therapy or who have contraindications to hormonal therapy should be referred to a gynecologist for
treatment.
• Promising new compounds that target molecular mechanisms involved in endometriosis are actively being investigated.
Surgical management of pain
• Surgical management of endometriosis improves pain postoperatively, although disease commonly recurs. Postoperative medical
treatment has limited use since it may improve short-term symptoms, but does not impact disease recurrence or long-term pain control.
• In women with pain from endometriomas, laparoscopic cystectomy is the most successful surgical strategy in terms of pain relief and
recurrence.
Medical treatments for infertility
• There is no role for traditional medical therapy in women with endometriosis-related infertility.
• Women with a history of endometriosis warrant early evaluation by a reproductive specialist.
• Superovulation with intrauterine insemination is an effective first-line strategy for infertile women with early-stage endometriosis.
IVF
• Some evidence suggests that women with endometriosis have decreased IVF pregnancy rates compared with other infertile individuals.
However, IVF is widely used in women with endometriosis and is effective in helping these individuals conceive.
• Pregnancy rates are improved when women with endometriosis use gonadotropin-releasing hormone agonists before undergoing IVF.
Surgical management of infertility
• Surgery improves fertility in women with earlier stage endometriosis. Limited data suggest that there is also a role for operative
management of more advanced disease.
• Postoperative medical treatment of endometriosis does not improve pregnancy rates in women attempting spontaneous conception
and delays their ability to conceive.
• In women with endometriomas, cystectomy results in improved spontaneous pregnancy rates when compared with cyst drainage.
• The optimal treatment strategy for women with endometriomas who are undergoing IVF is unclear. Pregnancy rates are not
significantly improved in women who have surgery compared with expectant management. Although data have suggested that
ovarian reserves may decrease after cystectomy, other studies have shown that clinical pregnancy rates in women who have
cystectomies performed do not differ from those who undergo fenestration and coagulation.
• Repeat surgery provides limited benefits in infertile women with recurrent endometriosis. IVF is often a better option for women who
wish to conceive.

future science group Women's Health (2013) 9(3) 247

Review – Bernardi & Pavone
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