PATHOGENESIS OF INFERTILITY FROM ENDOMETRIOSIS — While endometriosis

is known to impair fertility [6-8], mechanisms of infertility associated with endometriosis

are uncertain and likely depend, in part, on the stage of disease [2]. Endometriosis is
surgically staged using the American Society of Reproductive Medicine staging system
(figure 1). The spectrum of disease ranges from minimal presence of ectopic tissue (eg,
1 to 5 mm implants on the pelvic peritoneum) to severe anatomic distortion (deep
ovarian endometriomas, major pelvic adhesions with obliteration of normal pelvic organ
relationships). Mild disease appears to incite inflammatory pathways while advanced
disease causes anatomic disruption in addition to the inflammatory response.

●Although Stage I (minimal) or II (mild) endometriosis (figure 1) may be identified

during an infertility evaluation, it is uncertain if early-stage disease is the cause of
infertility in these women. It is hypothesized that minimal/mild endometriosis is
associated with an inflammatory response that results from overproduction of
prostaglandins, metalloproteinases, cytokines, and chemokines [9], as well as
macrophages and natural killer cells [10]. The resultant inflammatory process
impairs ovarian, peritoneal, tubal, and endometrial function, and leads to defective
folliculogenesis, fertilization, and/or implantation [11].
Support for this theory comes from studies reporting that women with
endometriosis have increased numbers of macrophages and cytokines in their
peritoneal fluid [12-14], and that their peritoneal fluid inhibits both sperm [15] and
fallopian tube ciliary function in vitro [16]. In addition, eutopic endometrium may not
function normally in women with endometriosis, which could impair implantation
[17]. Progesterone resistance may also be involved and related to a reduction in
the concentration of progesterone receptors and progesterone coactivators (eg,
Hic-5) in the endometrium of women with endometriosis [18].
●Advanced endometriosis (Stage III or IV disease) (figure 1) is associated with
distorted pelvic anatomy and adhesions. These changes can impair oocyte release
or pick-up, alter sperm motility, cause disordered myometrial contractions, and
impair fertilization and embryo transport [8]. The chemical and immunologic
mechanisms discussed above for mild/moderate disease likely contribute as well.
In a study of monkeys with experimentally induced endometriosis, the pregnancy
rate was approximately 40 percent in normal controls, but only 12 percent in
animals with advanced endometriosis and 0 percent if ovarian adhesions were
present [19]. As a comparison, minimal endometriosis did not diminish the
pregnancy rate.
 Advanced endometriosis may also negatively impact the ovarian follicles.
Compared with women who have mild endometriosis or tubal factor infertility,
studies on women with advanced endometriosis have reported abnormal
folliculogenesis [20] and reduced fertilization potential of oocytes [21].

OUR APPROACH — Infertility may be caused by endometriosis alone or endometriosis

combined with other factors, both male and female. For women who present with
endometriosis and infertility, we proceed with an infertility evaluation (algorithm 1). We
then assess the need to perform primary surgery for staging and treatment of
endometriosis or repeat surgery to treat pain symptoms. Choice of infertility therapy is
based on the combination of findings from the infertility evaluation and surgical staging.

Perform infertility evaluation — We do not assume that endometriosis is the sole

cause of the infertility. Couples who present with infertility proceed with evaluation for
contributing male and female factors as reviewed in detail separately. (See "Evaluation
of female infertility" and "Evaluation of male infertility".)

Assess need for endometriosis surgery — Endometriosis is a chronic disease that

requires life-long management with the goal of maximizing medical treatment and
avoiding repeated surgery [22]. Primary laparoscopic surgery is indicated for staging
and treating of endometriosis, improving fertility, and reducing pain. Indications for
repeat surgical treatment are mainly severe recurrent pain symptoms that impair quality
of life or treatment of a symptomatic endometrioma. Repeat surgery does not improve
fertility.

A description of surgical techniques for treatment of endometriosis are found separately.

(See "Endometriosis: Surgical management of pelvic pain", section on 'Surgical
procedures'.)

Endometriosis symptoms — Women with symptoms suggestive of endometriosis (eg,

pain, dysmenorrhea, dyspareunia) who have not had primary surgical treatment are
candidates for primary surgical resection, typically with operative laparoscopy. Such
women may have had endometriosis diagnosed, but not treated, at a prior surgery or
may have imaging or examination findings that are highly suggestive of endometriosis.
(See "Endometriosis: Pathogenesis, clinical features, and diagnosis", section on
'Physical examination' and "Endometriosis: Pathogenesis, clinical features, and
diagnosis", section on 'Imaging'.)

For women with infertility and symptoms of endometriosis, primary surgery to resect or
ablate endometriosis increases postoperative pregnancy rates compared with
diagnostic laparoscopy only. A meta-analysis reported that operative laparoscopy nearly
doubled the live birth or ongoing pregnancy rates (57 verus 34 total live-births or
pregnancies over 382 surgeries, odds ratio 1.94, 95% CI 1.20-3.16) [23]. Surgical
treatment consists of both resection and ablation. A description of surgical techniques
for treatment of endometriosis is presented separately. (See "Endometriosis: Surgical
management of pelvic pain", section on 'Surgical procedures'.)

For women with continued severe pain and infertility after primary resection, repeat
surgery can reduce pain but does not treat infertility. The major fertility benefit of
surgical therapy is achieved shortly after the first procedure, and women who do not
conceive after initial surgical treatment typically have worse disease and their
pregnancy success is less, regardless of repeat surgical intervention. Clinicians must
balance the limited benefits of second and third operative procedures to treat pain or
other symptoms against the potential risks of major surgery and the lower likelihood of
improved birth rate compared with assisted reproductive technology (ART) [24].
(See "Complications of laparoscopic surgery".)

Analysis of three observational studies that included 313 women reported lower
pregnancy rates after repeat surgery compared with primary surgery for endometriosis
(odds ratio 0.44, 95% CI 0.28-0.68) [25]. In addition, the pregnancy rate for women
undergoing in vitro fertilization (IVF) was similar to women undergoing repeat surgery
(odds ratio 1.51, 95% CI 0.58-3.91). Thus, for women who have failed to conceive after
primary surgical resection of endometriosis, we proceed directly with infertility therapy
(See 'Infertility therapy' below.)

Endometrioma — Women with infertility and an asymptomatic endometrioma typically

proceed with ART [26-32]. Management of endometriomas is presented separately.
(See "Endometriosis: Management of ovarian endometriomas", section on 'Our
approach'.)

Exceptions to the above include women with an endometrioma that is limiting oocyte
retrieval during ART. Other indications for endometrioma resection are discussed
separately. (See "Endometriosis: Management of ovarian endometriomas".)

Asymptomatic women — Women with asymptomatic endometriosis do not require

surgical treatment, even if the endometriosis has not been previously surgically
removed. As the impact of asymptomatic endometriosis on fertility is not known, the
risks associated with surgical resection are not warranted [33].
Infertility therapy — Once the couple has completed an infertility evaluation and the
woman has undergone laparoscopic evaluation and treatment of endometriosis, if
indicated, the couple proceeds with infertility therapy. Infertility treatment is guided by
the type and number of infertility factors identified during the evaluation. For women with
no or reversible problems, reversible causes are treated when present and subsequent
therapy is guided by the stage of endometriosis. Women with non-reversible causes of
infertility proceed directly with ART.

No or reversible infertility factors identified — All potentially treatable infertility

factors are first addressed. (See "Treatments for female infertility" and "Treatment of
male infertility".)

If there are no identified causes or if the woman does not conceive after treatment of
reversible causes (eg, intrauterine polyps or fibroids), subsequent infertility treatment is
then based upon the surgical stage of endometriosis and patient age. Endometriosis is
surgically staged using the American Society of Reproductive Medicine staging system
(figure 1). Cost, treatment availability, and patient preference also play a major role in
the selection of treatment. (See "Unexplained infertility" and "Unexplained infertility",
section on 'Our approach'.)

Minimal or mild endometriosis — Women with Stage I/II endometriosis have the

options of natural conception, ovulation induction and intrauterine insemination, and
ART, which includes in vitro fertilization (IVF) and intracytoplasmic sperm injection.

There is no consensus as to the optimal approach. ART is more effective but more
costly and not always available or acceptable to the patient, while ovulation induction
and intrauterine insemination (IUI) is less expensive, but when ineffective delays
conception. While the selection of infertility treatment is based on medical indications,
factors such as patient age, patient preference, procedure risk, birth rate, insurance
coverage, and cost must also be considered. As an example, we would typically offer a
woman younger than age 35 clomiphene ovulation induction and IUI because of the low
risk of the treatment, low cost, and reasonable chance of conception. However, an
identical woman may prefer to go directly to IVF to maximize her chance of a live birth
despite the higher cost and invasive technique compared with ovulation induction and
IUI.

●For women younger than 35 years who desire a trial of natural conception, we
advise six months of timed intercourse. If conception does not occur within six
months, we then offer ovulation induction with clomiphene citrate and IUI.
 ●For women younger than 35 years who prefer infertility treatment (rather than a
trial of natural conception as above), or who do not conceive naturally, we advise
proceeding with ovulation induction with clomiphene citrate (CC) plus IUI. The
intent of ovulation induction plus IUI is to enhance follicular development, ovulation,
and luteal progesterone levels (to offset the associated progesterone resistance)
while placing a large number of motile sperm high in the reproductive tract (and
thus bypassing possible cervical factors) to facilitate fertilization.
Evidence from randomized trials shows that ovulation induction and IUI should be
used together [34], and that this combined therapy improves fecundability in
women with early stage endometriosis [33,35-37]. Women who do not conceive
after three cycles of CC/IUI are typically referred for ART. (See "Overview of
ovulation induction" and "Procedure for intrauterine insemination (IUI) using
processed sperm".)
CC has the advantages of being an oral agent, easy to use, low-cost, and less
likely to result in multiple gestation compared with gonadotropin ovulation induction
[38]. Cumulative pregnancy rates of nearly 40 percent have been reported with this
combination [39]. (See "Ovulation induction with clomiphene citrate".)
●For women ≥35 years of age, we typically proceed with ART but also
offer clomiphene if ART is not possible (eg, financial restraints). Advancing directly
to ART has been shown to shorten the time to pregnancy (median time to
pregnancy 8 and 11 months, respectively) [40]. In addition, ART offers the option of
freezing excess embryos for future use.
Historically, these women were offered gonadotropin ovulation induction and IUI
[36,41,42]. The use of gonadotropin/IUI has fallen out of favor because of the
increased rate of multiple gestations, including a rate of twin pregnancies of up to
20 percent [36]. During ART, the number of embryos transferred into the uterus is
controlled by the clinician.
For couples who do not desire or are unable to proceed with ART, we offer three to
five cycles of CC or an aromatase inhibitor such as letrozole, as clinically indicated,
with IUI. The use of aromatase inhibitors in infertility therapy is discussed
separately. (See "Overview of ovulation induction", section on 'Gonadotropin
therapy' and "Overview of ovulation induction", section on 'Aromatase inhibitors
(letrozole)'.)

In contrast to this sequential approach, some clinicians may proceed directly to ART
rather than attempt natural conception or ovulation induction, despite the higher cost,
because at least one study has reported ovulation induction does not perform better
than attempted natural conception. In this retrospective cohort study of 96 women who
underwent operative laparoscopy for endometriosis, 12-month cumulative pregnancy
rates did not statistically differ between natural and ovarian stimulation cycles (45
versus 42 percent for Stage I/II endometriosis and 20 and 10 percent for
stage III/IV endometriosis) [35]. (See 'Non-reversible infertility factors' below.)

Moderate to severe endometriosis — Women with surgically staged moderate (Stage

III) to severe (Stage IV) endometriosis, including those with endometriomas, benefit
from ART [24,43-45]. There does not appear to be a role for ovulation induction in these
women unless they are unable to access or decline ART [33,37]. Repeat surgery does
not improve fertility because even aggressive lysis of adhesions is accompanied by
adhesion re-formation that may block normal tubal function and ovum pickup. Repeat
surgery is only performed to treat persistent symptoms, such as severe pain.
(See 'Endometriosis symptoms' above.)

Non-reversible infertility factors — For couples with non-reversible infertility factors

(eg, significant male factor component, decreased ovarian reserve), we generally
proceed directly with ART rather than less invasive treatments, such as ovulation
induction and intrauterine insemination, because ART is more likely to result in
pregnancy. Other variables that impact this decision are the cost of treatment and
extent of fertility coverage.

IMPACT OF ENDOMETRIOSIS ON ART — The impact of endometriosis on assisted

reproductive technology (ART) outcomes is variable. Mild endometriosis (ie,
Stage I/II disease) does not appear to negatively impact ART outcomes [46,47]. While
an earlier meta-analysis of 22 studies reported worsened in vitro fertilization (IVF)
outcomes for women with mild endometriosis compared with other infertile women [48],
subsequent larger meta-analyses have consistently reported that women with minimal
to mild endometriosis have similar live birth rates after IVF compared with women
without endometriosis (relative risk [RR] 0.99, 95% CI 0.29-1.06 [49] and RR 0.94, 95%
CI 0.84-1.06 [50]). There was approximately 50 percent overlap in the included studies
[49,50]. (See "In vitro fertilization", section on 'Pregnancy and live birth rate'.)

In contrast to mild endometriosis, Stage III/IV disease appears to negatively impacts

ART outcomes. Three systematic reviews of 22 [48], 27 [51], and 36 [50] studies (with
approximately 50 percent overlap between two of the studies [50,51]) reported lower
oocyte retrieval, implantation, and pregnancy rates for women with advanced
endometriosis undergoing IVF compared with women with mild endometriosis. In
contrast, a much larger meta-analysis of 78 studies comprising over 20,000 women
reported no difference among women with Stage I/II endometriosis and
Stage III/IV endometriosis in live birth rate (RR 0.94, 95% CI 0.80 to 1.11) and clinical
pregnancy rate (RR 0.90, 95% CI 0.82 to 1.00) [49]. However, women with advanced
disease, particularly those with endometriomas, often have lower ovarian reserve and
produce fewer oocytes for recovery, which reduces ART success [47]. The impact of
diminished ovarian reserve becomes more pronounced in women of older age whose
declining egg quality is associated with greater embryo aneuploidy. In women with poor
ovarian reserve, such as those with advanced age and severe endometriosis, we
discuss the option to pursue ART with donor oocytes.

There is no evidence that ART increases the recurrence of endometriosis [33]. In

addition, the use of ART in women with endometriosis does not appear to increase the
risk of poor birth outcome, particularly preterm birth [52].

INEFFECTIVE THERAPY — Medical therapy, including hormonal suppression,

Chinese herbal medicine, nutritional supplements,
and complementary/alternative medicine have not been shown to improve pregnancy
rates in women with endometriosis-related infertility [33,53,54]. Randomized clinical
trials consistently report that hormone therapy with agents such as danazol or
gonadotropin-releasing hormone agonists for suppression of endometriosis does not
improve fertility or pregnancy rates [33,55-59]. The lack of improvement applies to
women treated with medical therapy alone, as well as those treated with combined
medical and surgical therapy versus surgery alone. In contrast, for women whose
treatment goal is pain reduction, hormonal suppression is an effective treatment.
(See "Endometriosis: Treatment of pelvic pain".)

FERTILITY PRESERVATION — As endometriosis can be associated with ovarian

depletion and infertility, fertility preservation therapies such as embryo, oocyte, and
ovarian tissue freezing have been proposed for women diagnosed with endometriosis
[60]. These technologies, especially embryo and oocyte freezing, have proven efficacy
for women planning treatment with gonadotoxic medications, such as chemotherapy.
(See "Fertility preservation in patients undergoing gonadotoxic treatment or gonadal
resection", section on 'Cryopreservation'.)

However, offering all women diagnosed with endometriosis additional fertility

preservation treatment would be extremely expensive and place a significant strain on
global health care costs without providing a clear advantage, as many of these women
will conceive with a combination of the treatments reviewed above. Women who may
benefit from this approach include those with bilateral endometriomas, prior ovarian
surgery, and young age at diagnosis. More data are needed before a recommendation
can be made regarding fertility preservation treatment in women with endometriosis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored

guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Endometriosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces
are written in plain language, at the 5th to 6th grade reading level, and they answer the
four or five key questions a patient might have about a given condition. These articles
are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated,
and more detailed. These articles are written at the 10th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you
to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on "patient info" and the keyword(s) of
interest.)

●Basics topic (see "Patient education: Endometriosis (The Basics)")

●Beyond the Basics topic (see "Patient education: Endometriosis (Beyond the
Basics)")

SUMMARY AND RECOMMENDATIONS

●The pathogenesis of infertility in women with endometriosis varies by the stage of

the disease, with mild disease inciting inflammatory pathways and advanced
disease involving anatomic disruption in addition to inflammation.
(See 'Pathogenesis of infertility from endometriosis' above.)
●For women who present with endometriosis and infertility, we proceed with an
infertility evaluation. We do not assume the endometriosis is the cause of infertility.
We then assess the need to perform primary endometriosis surgery. (See 'Our
approach' above.)
•For women with symptoms suggestive of endometriosis (eg, pain,
dysmenorrhea, dyspareunia) who have not had primary surgical treatment, we
recommend operative laparoscopy with ablation or excision of endometriosis
implants as the first step in management after the infertility evaluation is
 complete (Grade 1B). Operative treatment is associated with improved
pregnancy rates and reduced pain symptoms compared with diagnostic
surgery alone. (See 'Endometriosis symptoms' above.)
•For women who have previously undergone primary surgical treatment of
endometriosis, we suggest not repeating surgical removal of endometriosis for
the treatment of infertility (Grade 2C). Repeat surgery does not improve
fertility, although it can reduce pain. Thus, clinicians must balance the limited
benefits of second and third operative procedures to treat pain or other
symptoms against the potential risks of major surgery and the lower likelihood
of improved birth rate compared with assisted reproductive technology (ART).
(See 'Endometriosis symptoms' above.)
•For women with infertility and an asymptomatic presumed endometrioma, we
generally proceed with ART and observation of the endometrioma rather than
surgical removal. (See 'Endometrioma' above.)
•For women with endometriosis who have no symptoms other than infertility,
surgical treatment to improve fertility is not indicated, even if the endometriosis
has not been previously removed. As the impact of asymptomatic
endometriosis on fertility is not known, the risks associated with surgical
resection are not warranted. (See 'Asymptomatic women' above.)
●Infertility therapy is guided by the combination of findings from the infertility
evaluation and surgical staging of endometriosis as well as patient age. Cost and
patient preferences also play a major role in treatment decisions. (See 'Infertility
therapy' above.)
•Women with no or reversible infertility factors, minimal to mild endometriosis
(Stage I/II), and age younger than 35 years are usually offered a trial of natural
conception or continued infertility treatment with ovulation induction and
intrauterine insemination (IUI). For women ≥35 years of age with
Stage I/II endometriosis, we proceed directly with ART because of the
shortened time to pregnancy. (See 'Minimal or mild endometriosis' above.)
•Women with no or reversible infertility factors and/or those with advanced
endometriosis (Stage III/IV) are suggested to proceed directly with ART,
typically in vitro fertilization when available. (See 'Moderate to severe
endometriosis' above.)
•For women with non-reversible infertility factors (eg, significant male factor
component, decreased ovarian reserve), we generally proceed directly with
ART rather than less invasive treatments because ART is more likely to result
in pregnancy. (See 'Non-reversible infertility factors' above.)
 ●The impact of endometriosis on ART outcomes is variable. Mild endometriosis (ie,
Stage I/II disease) does not appear to negatively impact ART results. In contrast,
the body of evidence suggests Stage III/IV disease negatively impacts outcomes,
although the data are conflicting. The mechanism appears to be decreased ovarian
reserve. (See 'Impact of endometriosis on ART' above.)

Treatment for infertility

In women with endometriosis, infertility arises mostly as the consequence of chronic
pelvic inflammation.137 Adhesions secondary to this flogistic phenomenon may disrupt
pelvic anatomy, and inflammatory molecules can create a local milieu that is
unfavourable to conception. Interference has been hypothesized with the complex
mechanisms of ovulation, oocyte pick-up by the fallopian tubes, spermatozoa function,
fertilization process, tubal transport of the embryos and, possibly, embryo
implantation.137 On the basis of these pelvic inflammatory effects, two possible
therapeutic options can be envisaged, surgical ‘normalization’ of the altered anatomy or
bypass of the unfavourable pelvic environment. In the former case, adhesiolysis may re-
establish normal relationships between pelvic organs, and removal of endometriotic
lesions may discontinue the permanent inflammatory trigger. In the latter case, IVF can
be performed, thus overcoming problems with adhesions and tubal patency. Oocytes
are retrieved directly from the ovaries and embryos are replaced within the endometrial
cavity, thus avoiding direct exposure to the detrimental effects of the pelvic milieu.
However, this approach may not fully overcome the unfavourable effects of
endometriosis, given that both folliculogenesis and endometrial receptivity might at least
in part be influenced by the adjacent detrimental peritoneal milieu.137 A possible
therapeutic algorithm for endometriosis-related infertility is shown in Figure 3.
Hormonal medical treatment has no effect on infertility in women with endometriosis.
According to a Cochrane meta-analysis, the odds ratio of pregnancy following ovulation
suppression versus placebo or no treatment was 0.97 (95% CI 0.68–1.34) for all
women, and 1.02 (95% CI 0.70–1.52) for subfertile couples.138 These results fit with
the modern view of the disease. Both eutopic and ectopic endometrium have
outstanding capacity of remaining quiescent even for years under suppressive hormonal
therapy, but only until exposed again to gonadal activity. Even if the steady hormonal
condition obtained with ovary-suppressing agents improves the pelvic milieu by
reducing inflammation, the potential benefits are rapidly lost at drug discontinuation;
thus, the fertility potential remains unchanged. Overall, the effect of surgery for
endometriosis-associated infertility is supported by evidence of limited quality. A small
benefit has been demonstrated for early, peritoneal disease. A meta-analysis of the two
randomized controlled trials (RCT) conducted on women with stage I–II endometriosis,
documented an odds ratio for pregnancy of 1.64 (95% CI 1.05–2.57) in favour of
laparoscopic surgery.139 However, the cumulative pregnancy rate at 9–12 months
increased only from 18% to 26%, corresponding to a number of women needed to be
treated of 12. This finding means that, in real-world conditions, the number needed to
be treated is actually doubled at least, considering that the prevalence of early stage
endometriosis is between 30% to 50% in women with unexplained infertility, and that
peritoneal implants cannot be reliably diagnosed before surgery.140 On this basis, in
clinical practice, the value of diagnostic laparoscopy in women with unexplained
infertility is limited.141
Data regarding more advanced endometriosis, that is, stage III–IV disease, are less
robust, as no RCTs have investigated the benefit of surgery as a conception-enhancing
procedure in these women. Only case series have been published on the effect of
treatment of ovarian endometriotic cysts. Overall, the likelihood of pregnancy following
endometrioma excision has been estimated to be around 50%.137 However, this figure
is most probably an overestimate, considering the poor design of the available studies,
and the inclusion in some of them of women who were not infertile at the time of
surgery, as well as of those who achieved a conception through IVF.140 Indirect
evidence suggests that surgery may not be of major benefit for deep infiltrating
endometriosis.142 In a patient preference trial comparing women with rectovaginal
endometriosis opting for surgery (n = 44) with those choosing expectant management
(n = 61), the cumulative pregnancy rate was, respectively, 34% and 36%.143 On the
other hand, it has been shown that, even when bowel surgery was needed because of
infiltrative endometriosis, one-third of infertile women conceived spontaneously.117
Intrauterine insemination (IUI) is commonly advocated for infertile women with
endometriosis stage I–II who fail to become pregnant following surgery. This approach
is theoretically illogical, as the procedure does not overcome the negative effect of a
detrimental pelvic milieu. On the other hand, limited peritoneal endometriotic implants
may be unrelated to infertility in a considerable proportion of women. Endometriosis
stage I–II was observed in 19% of women undergoing tubal ligation and in 32% of those
with an azoospermic partner.144,145 Thus, minimal or mild endometriosis might be an
incidental finding in women with infertility. IUI, which is typically prescribed for
unexplained infertility, may thus be effective. Moreover, most studies involve IUI in
combination with controlled ovarian hyperstimulation, not IUI alone.146,147 Probably,
the combination of both modalities is the factor that increases pregnancy rates in
patients with tubal patency and the partner’s reasonable-quality sperm.

Endometriosis is a classic indication for IVF, as the tubes are bypassed, and oocytes as
well as spermatozoa are not directly exposed to the abnormal peritoneal environment.
Therefore, anatomical distortion and biochemical insults are mostly overcome.
Nonetheless, endometriosis seems to be associated with lower than normal chances of
success. According to a meta-analysis of available data published in 2002, the
pregnancy rate was significantly lower for patients with endometriosis (OR 0.56, 95% CI
0.44–0.70) compared with control individuals with infertility related to tubal factors.148
Moreover, pregnancy rates for women with severe endometriosis were significantly
lower than for women with mild disease (OR 0.60, 95% CI 0.42–0.87).148 A second,
adjourned meta-analysis confirmed the above findings, as the relative risk of pregnancy
in women with endometriosis stage I–II and III–IV undergoing IVF was 0.93 (95% CI
0.87–0.99) and 0.79 (96% CI 0.69–0.91), respectively.149

At least two main reasons explain this reduced performance. Firstly, as mentioned
above, the detrimental effects of chronic pelvic inflammation might act beyond the limits
of the peritoneal cavity. Follicular development may be altered and the quality of the
oocytes may be affected even if a direct exposure to the peritoneal fluid is avoided.
Furthermore, endometrial receptivity might also be negatively influenced. One
suggestion is that therapy with a GnRH agonist for 2–6 months before initiation of an
IVF cycle (ultralong protocol) ‘switches off’ the inflammation, thus improving the
chances of pregnancy. A meta-analysis of three small RCTs documented an odds ratio
of pregnancy of 4.28 (95% CI 2.00–9.15) in women allocated to the ultra-long protocol,
compared with women allocated to the normal protocol. 150 Interestingly, another
suggestion is that similar benefits may be obtained with oral contraceptives, but more
robust evidence is required.151 Finally, some evidence also indicates that, in women
with endometriosis failing to become pregnant with IVF, surgery enhances the chances
of both spontaneous or IVF-mediated pregnancy.152 It may be speculated that,
similarly to what is observed with medical ovarostatic treatments, surgery also reduces
the inflammatory-mediated detrimental effects of endometriosis, at least in the subgroup
of patients refractory to IVF treatments.

Secondly, endometriosis may affect ovarian reserve, a crucial factor for IVF success.
However, laparoscopic excision of endometriomas, rather than the disease itself, has
been shown to cause follicle loss,153–155 and women operated on for bilateral cysts
are at particularly increased risk.156,157 Potential mechanisms leading to damage
include accidental removal of adjacent healthy ovarian tissue, vascular injury, heat
damage consequent to diathermy-coagulation, and local inflammation.158 This poses a
clinical dilemma as, paradoxically, surgery can improve spontaneous pregnancy rate
while it can damage the gonads.111,137,140 Considering that the success rate of
surgery and IVF are similar, infertile women with ovarian endometriomas may be
scheduled directly to receive IVF without prior surgery. However, given the lack of
robust data, the decision between surgery and IVF must be discussed and shared with
the patient, also considering that IVF is associated with complications such as ovarian
hyperstimulation syndrome, haemorrhage, thrombosis, and twinning with increased risk
of preterm birth.159 Women should receive comprehensive information illustrating the
potential benefits and risks of both approaches. Additional factors to be taken into
consideration in the decision-making process are age, surgical history, cyst sonographic
appearance, cyst bilaterality, ultrasound detection of hydrosalpinx, results from tests of
ovarian reserve, and presence of pain symptoms. 158 Research is now aimed at
improving the surgical technique to preserve follicles while maintaining the benefits of
surgery.112,113 Some clinicians suggest that the injury to the ovarian reserve depends
on surgical skillfulness and that an accurate and faultless intervention could actually
prevent the damage.