Background
Endometriosis is an inflammatory condition characterised by the presence of tissue resembling endometrium in sites other than the uterine cavity
It is estimated that –10% of women, mainly of reproductive age, are
affected by the condition, with a reported higher prevalence in certain subgroups, such as those affected by infertility. Ovarian endometrioma(s) can be found in up to–44% of women with endometriosis and are often associated with the severe form of the disease
While the pathognomonic mechanisms of endometriosis per se
remain elusive, it is widely believed that most endometriotic lesions develop from retrograde menstruation and are possibly associated with immune dysfunction,which can interfere
with endometrial implant clearance
Endometriotic ovarian cysts (known as ‘endometriomas’) are mostly thought to occur through invagination of endometriotic tissue/cells through the ovarian serosa, for example, during remodelling of the ovarian cortex after ovulation
The presence of an endometrioma can often present a clinical dilemma during the course of fertility treatment.
For example, there can be uncertainty regarding the decision to operate or to manage conservatively, balancing
the potential detrimental effect of surgery on the ovarian reserve against the potential benefit that may be gained.
Current guidelines often rely on the evidence from either small and/or retrospective controlled studies. In particular,
for assisted reproductive treatment (ART) some of the referenced studies were conducted in the 1980s and 1990s.
Since then, in vitro fertilisation (IVF) success rates have significantly improved due to changes in stimulation protocols
and available drugs, as well as the introduction of laboratory techniques such as intracytoplasmic sperm injection and blastocyst culture.

Endometriomas and infertility
Fecundity rates may be reduced in women with endometriosis, potentially related to the severity of the disease(revised American Society  for Reproductive Medicine[rASRM] classification
The presence of ovarian endometriomas is usually associated with rASRM staging of moderate or severe disease.
A number of theories for endometriosis-related infertility have been proposed, including
chronic inflammation tuboperitoneal anatomic
distortion and reduced endometrial receptivity, leading to compromised oocyte and embryo quality, and ovarian reserve, but the precise mechanism has yet to be determined.

Chronic inflammatio
6
Endometriosis is associated with dysregulation of the immune system.6 Peritoneal fluid from women with endometriosis
has been found to contain increased numbers of immune cells, including macrophages, and mast, natural killer and
7
–9
T cells, as well as elevated levels of growth factors, chemokines and cytokines.
The enhanced inflammatory state can affect the quality of the oocytes and impair ovarian function, resulting in defective folliculogenesis and fertilisation.
As endometriomas and peritoneal disease often occur concomitantly and might be pathogenically linked, it is difficult to
establish which of these inflammatory clinical presentations of endometriosis affects fertility.

Oocyte and embryo quality
Endometriomas and associated pelvic endometriosis may affect oocyte and embryo quality adversely. While embryo 
development in women with endometriosis is slower compared to women with tubal disease,
women with moderate-to
severe disease receiving eggs from a donor without endometriosis have been shown to have similar pregnancy rates to other egg recipients.
An altered follicular environment, represented by elevated concentrations of progesterone and
interleukin-6 and decreased concentration of vascular endothelial growth factor, may be responsible for alterations within the
oocyte, leading to impaired fertilisation capacity of the oocytes and reduced embryo quality with low implantation potential.

Ovarian reserve
The presence of ovarian endometriomas, especially if bilateral, can affect the ovarian reserve, impacting the ovarian response to gonadotrophins during ART. A histological study
reported a significant reduction in the primordial follicle
cohort in affected ovaries. Follicle depletion may be secondary to damage induced by the endometriosis-associated inflammatory reaction and by increased tissue oxidative stress leading to fibrosi
A group of potentially toxic agents,
such as free iron, that can diffuse through the cyst wall of the endometrioma, as well as long-lasting mechanical stretching of ovarian cortex, can all have a detrimental impact on the ovarian reserve
Most importantly, however, is the negative
effect of ovarian surgery on ovarian reserve, especially if performed repeatedly .

Management options
While the options include expectant and surgical management, the recommended treatment should be guided by: the
woman’s symptoms; fertility prognostic factors, including age and ovarian reserve; previous treatment history with specific reference to past surgical interventions; nature of the cyst; and the wishes of the woman.
Treatment of incidental disease in otherwise asymptomatic women is currently not recommended, as the development and natural progression of endometriomas is not well understood.

Spontaneous conception
Conservative management for spontaneous conception
Young women with regular menstrual cycles and an incidental finding of an ovarian endometrioma without suspicion
of malignancy who wish to conceive should be encouraged to try natural conception before seeking fertility 15
treatment.
While the evidence of the impact of an endometrioma on spontaneous conception is limited, prospective observational stud
(n244) reported a 43% spontaneous pregnancy rate during the 6-month follow
up period in the presence of unilateral endometriomas of varying sizes (diameter 5.3
1.7 cm [mean SD]). The study also reported similar ovulation rates in the affected ovary to the healthy ovary (49.7% versus 50.3%), not
influenced by the laterality of the endometriomas, their number and size, or by the presence of deep endometriosis diagnosed by ultrasound. This finding contradicted previously reported data in a smaller prospective study (n 70) of reduced ovulation in the affected ovary (31% versus 69%). For women with a naturally or abnormally reduced
ovarian reserve, conservative management for fertility should be weighed against the potential benefits of surgery or
fertility treatment.

Surgical treatment for spontaneous conception
There is controversy regarding the surgical management of endometriomas in women undergoing treatment for
infertility. While surgical treatment may improve spontaneous pregnancy rates by restoring the pelvic anatomy, it
remains unclear as to whether surgical intervention on the ovary itself is beneficial as it may not reverse the inflammatory and biomolecular changes shown to influence fertilisation and implantation
Furthermore, there are
concerns regarding the safety of surgical treatments, with a reported reduction in the ovarian reserve
and the
small added risk of requiring an oophorectomy. In contrast, concerns have been raised about the effect of an
endometrioma on oocyte quantity and quality. This conflict suggests that management should be individualised and
based upon clinical factors, including pain symptoms, size of the cysts and concerns over potential malignancy.
Consideration should be given to surgical treatment being undertaken by a gynaecologist with specific expertise in
endometriosis and fertility, in order to minimise the impact on the ovarian reserve and provide a holistic assessment
regarding future fertility management.
When performing surgery, ovarian endometriomas are best managed by performing a cystectomy, as opposed to
drainage and coagulation, which is associated with an overall lower recurrence risk and higher spontaneous postoperative pregnancy rate, particularly if the cyst is 3 cm or more in diameter. Hart et al.
summarised two
randomised controlled trials (RCTs) which showed a beneficial effect of excisional surgery over drainage or ablation
1.92–
of an endometrioma in achieving a spontaneous pregnancy in subfertile women (OR 5.24, 95% CI
14.27;88; two trials). However, this can lead to a significant reduction in the number of ovarian follicles, especially in
women who have undergone previous ovarian surgery, and therefore, ovarian reserve, reflected by a sustained decrease in anti-M€ullerian hormone (AMH) levels. While data from observational controlled studies investigating ovarian endometrioma drainage and ablation using energy with minimal thermal spread, such as CO2 laser or plasma
energy, indicated good results; in terms of a satisfactory fertility outcome, reduced ovarian damage and reduced recurrence risks, RCTs are needed to be able to draw definitive conclusions.
Effect of endometriomas on IVF outcome
Evidence of the impact of an endometrioma on ovarian response during IVF is equivocal. Systematic reviews of
controlled studies have reported similar ovarian responses in women with endometriosis to controls with no evidence of endometriosis
and in women with a unilateral ovarian endometrioma compared to contralateral normal ovaries.
While most studies included in the latter systematic review evaluated women with small endometriomas, two studies
reported on the potential detrimental effect of the size of the endometrioma on ovarian response especially when this was 3 cm or more in diameter. In one systematic review
ovarian response was lower, with a lower number of oocytes retrieved (mean difference
0.23; 95% CI–0.1) and a higher cancellation rate (OR 2.83; 95% CI
6.06) in women with an endometrioma, although the total stimulation
0.71 dosage of gonadotrophin used was comparable. However, live birth (OR 0.98; 95% CI
–1.36), pregnancy (OR 1.17; 95% CI
–1.58) and miscarriage rates (OR 1.7; 95% CI
3.35) following IVF were similar in women with an endometrioma compared to women with no endometriosis
When compared to women with peritoneal
endometriosis in the absence of an endometrioma, IVF outcomes (live birth, pregnancy, miscarriage and cycle
cancellation rates, and mean number of oocytes retrieved) were similar in women with an endometrioma. No data
on adverse events, such as bleeding, infection or pain, were reported in these studies.
Basal follicle stimulating hormone levels were higher in women with an endometrioma compared with women with
=
no evidence of endometriosis (three studies; n
491), however, the antral follicle count was similar between the
33,34
=
two groups (two studies; n
433). Although equivocal, most studies
report that the observed reduced ovarian
response, especially in the presence of larger endometriomas, is related to an overall reduced ovarian reserve in
women with an endometrioma.
In contrast, an adverse impact of endometriomas and endometriosis on oocyte quality has been suggested by Simon
et al.
who reported on data from an oocyte donation programme in which women with endometriosis were
shown to have the same chance of implantation and pregnancy as other oocyte recipients, when the oocytes came
from donors without known endometriosis. However, the implantation rates were reduced in healthy recipients
when the oocytes came from donors with endometriosis, suggesting the condition had a negative effect on oocyte
quality. Nevertheless, as reviewed by the European Society of Human Reproduction and Embryology (ESHRE)
guideline for the management of endometriosis
no such differences have been demonstrated in large databases
that include more recent IVF cycles, such as the Human Fertilisation and Embryology Authority and the Society for Assisted Reproductive Technology.
Surgical treatment prior to IVF
Surgical treatment of endometriomas prior to IVF is widely practised,
although debatable on its effect and need. A systematic review
(five controlled studies; n
655) reported similar live birth (OR 0.9; 95% CI
–1.28), clinical pregnancy (OR 0.97; 95% CI
1.2) and miscarriage rates (OR 1.32; 95% CI
–2.65) following IVF treatment in
women with surgically-treated endometriomas compared to those with intact endometriomas. While the number of
oocytes retrieved and the cancellation rates were comparable, women with a surgically-treated endometrioma had a
lower antral follicle count and required higher doses of gonadotrophins for ovarian stimulation. Interestingly, women
who had undergone surgical management for a unilateral endometrioma had a lower number of oocytes retrieved from the surgically-treated ovary (mean difference
–2.59; 95% CI
–4.13 to1.05) when compared with the
contralateral normal ovary, indicating a reduction in the ovarian reserve following surgical intervention, as has been reported in several other studies
The potential physiological compensation by the normal ovary for the
compromised ovary, in conjunction with the higher follicle stimulating hormone doses required for ovarian
stimulation, may account for the similar IVF outcomes noted in women who have undergone surgical treatments for
their endometriomas.
A Cochrane review
incorporating two small RCTs has reported similar pregnancy rates for surgical (cystectomy or
aspiration) and expectant management. While no differences in pregnancy rates have been shown between a
cystectomy and aspiration of an endometrioma, a cystectomy is associated with a lower ovarian response following
controlled stimulation, with a lower number of mature oocytes retrieved, raising concern about the potential
adverse influence of a cystectomy on ovarian reserve. In contrast, a meta-analysi
incorporating three controlled