Endometriosis and Infertility
Table of Contents
Does endometriosis cause infertility?
How can someone tell if she has endometriosis?
Assisted reproductive technology
Introduction
Infertility Treatment affects around 30–50 per cent of
people with endometriosis. Endometriosis lesions can cause inflammation in the
area and may form scar tissue, as well as stick different organs together. They
also bleed, similarly to the regular uterine lining, in response to hormones
What is endometriosis?
Endometriosis is when tissue is found outside the uterus
that appears similar to the lining of the uterus (endometrium). Endometriosis
may grow on the outside of your uterus, ovaries, and tubes and even on your
bladder or intestines. This tissue can irritate structures that it touches,
causing pain and adhesions (scar tissue) on this organ
Does endometriosis cause infertility?
If you have endometriosis, it may be more difficult for you
to become pregnant. Up to 30% to 50% of women with endometriosis may experience
infertility. Endometriosis can influence fertility in several ways: distorted
anatomy of the pelvis, adhesions, scarred fallopian tubes, inflammation of the
pelvic structures, altered immune system functioning, changes in the hormonal the environment of the eggs, impaired implantation of a pregnancy, and altered egg
quality.
At the time of surgery, your doctor may evaluate the amount,
location, and depth of endometriosis and give you a “score.” This score
determines whether your endometriosis is considered minimal (Stage 1), mild
(Stage 2), moderate (Stage 3), or severe (Stage 4). This scoring system
correlates with pregnancy success. Women with severe (Stage 4)
endometriosis, which causes considerable scarring, blocked fallopian tubes, and
damaged ovaries, experience the most difficulty becoming pregnant and often
require advanced fertility treatment.
How is endometriosis treated?
Endometriosis needs the female hormone estrogen to develop
and grow. Birth control pills and other drugs that lower or block estrogen can
be effective in improving pain symptoms. For patients who wish to become
pregnant, medical therapy may be considered prior to attempts at conception,
but this treatment usually does not improve pregnancy rates.
The Endometriosis is a chronic inflammatory disease in women
of reproductive age and can cause both pain and infertility. The reference
standard for diagnosing endometriosis is Laparoscopy, preferably
including histological verification by biopsy of suspected lesions. As surgery
is invasive and costly, the true prevalence of endometriosis in women of
reproductive age remains uncertain. The estimated overall prevalence of
endometriosis in population‐based studies varies from 0.8% to 6% 1-3; however,
in subfertile women the prevalence seems to be considerably higher, ranging
from 20% to 50%, but with significant variation overtime periods and the age
of patients. In a large cohort study on women of reproductive age, the risk of
infertility was increased two‐fold in women <35 years with endometriosis
compared with women without endometriosis. Endometriosis is, therefore, a frequent cause of infertility, either by itself or in conjunction with other
fertility‐reducing factors
If endometriosis is seen at the time of surgery, your doctor will surgically destroy or remove the endometriosis and remove the scar tissue. This treatment will restore your normal anatomy and will allow your reproductive organs to function more normally. Your chances of becoming pregnant are improved after surgical treatment, especially if your endometriosis is in the moderate or severe range. The combination of surgical and medical therapy may be beneficial in patients attempting to conceive through in vitro fertilization (IVF). Overall, treatment is highly individualized for each patient.
How can someone tell if she has endometriosis?
Many women with endometriosis have pelvic or abdominal pain,
particularly with their menstrual bleeding or with sex. Some women have no
symptoms. Endometriosis can make it difficult to become pregnant. In fact, 30%
to 50% of infertile women have endometriosis. Sometimes, endometriosis can grow
inside your ovary and form a cyst (endometrioma). This usually can be seen on
ultrasound, unlike other endometriotic tissue
Etiology/Pathogenesis
It may be initiated by retrograde menstrual flux through the
Fallopian tubes. Epithelial progenitor cells derived from the shedding of
endometrial tissue can implant on the peritoneum, ovaries, or in the
rectovaginal pouch. Once established, these hormone‐responsive and cyclically
active endometriotic lesions drive acute then chronic inflammatory reactions and lead to pelvic adhesions, pain, and infertility. Individual susceptibility
to endometriosis, however, is influenced by genetic, anatomical, endocrine, and
environmental factors.
Clinical experience suggests that, at least in some women
with established endometriosis, the disease is progressive and brings about
increasingly worsened pain and subfertility. There seems to be an association
between the extent of disease and the degree of reduced spontaneous fertility
in endometriosis, although the strength of this association is variable. Among
women with minimal/mild endometriosis, approximately 50% will be able to
conceive without treatment, whereas in women with moderate disease, only 25%
will conceive spontaneously, and few spontaneous conceptions occur in the case
of severe disease. Indeed, the rate of spontaneous pregnancy is comparable
among women with minimal/mild endometriosis and women with unexplained
infertility, indicating that minimal/mild endometriosis may have just a modest
effect on fertility. Nonetheless, superficial peritoneal lesions are more
closely associated with infertility than endometrioma and deeply infiltrating
endometriosis 16. Extensive disease with pelvic adhesions and obliteration of
the cul‐de‐sac, however, may result in infertility due to occlusion of the
tubal ostium compromising sperm passage, further aggravated by the embedding of
the ovaries in adhesions. Nonetheless, in the absence of major mechanical
distortions in moderate endometriosis, alternative pathomechanisms of
endometriosis‐associated infertility must be considered (Table 1).
Table 1. Possible
causes for reduced fertility in women with endometriosis
·
Adhesions
·
Chronic intraperitoneal inflammation
·
Disturbed folliculogenesis
·
Luteinized unruptured follicle
·
Luteal phase defects
·
Progesterone resistance
·
Detrimental effects on spermatozoa
·
Anti‐endometrial antibodies
·
Dysfunctional uterotubal motility
Chronic
intraperitoneal inflammation is a characteristic feature of endometriosis. According
to a likely disease model, endometriotic peritoneal implants induce an acute
inflammatory reaction, which is associated with recruitment and activation of T
helper and regulatory T (Treg) cell subsets. After resolution of the acute
phase, monocytes/macrophages maintain a chronic inflammation, which contributes
to peritoneal adhesion formation and angiogenesis. In women, most data support
an increased presence of inflammatory mediators (cytokines, chemokines, and
prostaglandins) in the peritoneal fluid in endometriosis. The concentration of
peripheral Treg cells is reduced, whereas intraperitoneal Treg cells are increased.
Intraperitoneal Treg cells may suppress effector T cells and promote
proliferation and invasion of endometrial stromal cells. The macrophages in the
ectopic lesions are typically polarized towards M2, however, there is a bias
towards M1 among macrophages of the eutopic endometrium in women with
endometriosis notably, and a recent paper identified an endometriosis‐related
cytokine profile, which could be linked to macrophage activation.
Chronic inflammation in endometriosis may impair fertility
by several pathways. The increased concentration of interleukin‐1β (IL‐1β), IL‐8,
IL‐10 and tumour necrosis factor‐α in follicles adjacent to endometriomas is
associated with reduced ovarian response. The level of IL‐6 in peritoneal fluid
from women with endometriosis is elevated and this cytokine may inhibit sperm motility,
and inflammatory mediators of the peritoneal fluid may also contribute to sperm
DNA damage. In addition, oxidative stress, prostaglandins and cytokines may
interfere with oocyte–sperm interactions, impair embryo development, and hinder
implantation.
Dysfunction of the hypothalamic-pituitary-ovarian axis may
contribute to infertility in patients presenting with a prolonged follicular
phase, low serum estradiol levels, and reduced peak luteinizing hormone concentration.
Pituitary dysfunction in endometriosis would predict disturbed
folliculogenesis, reduced oocyte quality, and/or a reduced endometrial
receptivity. Indeed, these abnormalities have been demonstrated in some
studies, but the findings are equivocal
Normal secretion of progesterone and responsiveness of
endometrium to its effect during the luteal phase is mandatory for the
transition of the endometrium from a proliferative to a secretory and receptive
stage. In endometriosis, reduced expression of progesterone receptors in the endometrium
may cause progesterone resistance. Furthermore, progesterone induces the
expression of 17β‐hydroxysteroid dehydrogenase type 2 (HSD17B2), which
metabolizes the biologically potent estradiol to the less potent estrone. In
women with endometriosis and progesterone resistance, the endometrial function may
be afflicted by increased estrogenic bioactivity upon loss of HSD17B2 activity.
Indeed, an increased estrogenic milieu induces inflammatory responses in the
endometriotic tissue, characterized by elevated levels of many inflammatory cytokines.
Oocyte donation is an instructive clinical model to dissect
the effects of endometrial receptivity from oocyte competence in
endometriosis‐associated infertility. A recent review of oocyte donation
studies found that patients receiving oocytes from donors with endometriosis
achieve lower implantation and pregnancy rates, whereas the status of the
recipient does not influence treatment outcome 38. This suggests that a reduced
fertility potential in women with endometriosis may be the result of poor
oocyte quality rather than a defective endometrium. Nevertheless, elevated
levels of anti‐endometrial antibodies have been detected in serum from women
with endometriosis, and binding of such antibodies to endometrial antigens may
cause implantation failure.
Infertile women, the dominant follicle will rupture and
release the oocyte–cumulus complex within 38 h after the luteinizing hormone
surge. Occasionally, the follicle undergoes luteinization but fails to rupture
and release the ovum, a condition termed luteinized unruptured follicle
syndrome (LUF). LUF syndrome cannot be diagnosed by hormonal assays, only by
repeated ultrasound scans demonstrating the presence of unruptured follicles.
Women with endometriosis have a higher prevalence of LUF syndrome than women
without endometriosis. In addition, nonsteroidal anti‐inflammatory drugs that
are often prescribed for dysmenorrhea have been shown to increase the risk of
LUF syndrome. Nonsteroidal anti‐inflammatory drugs inhibit cyclooxygenase with
a resulting low prostaglandin production in the ovaries, inhibition of matrix
metalloproteinases, and loss of follicle rupture.
In the uterus, coordinated muscular contractions enhance
sperm transport to the Fallopian tubes where spermatozoa undergo capacitation
and hyperactivation in order to reach the ampullary part of the tube and
fertilize the ovum. After fertilization, the embryo is passively transported
through the Fallopian tube to the uterine cavity. In endometriosis, uterotubal
dysperistalsis may contribute to infertility because of disturbed transport of
gametes and embryos.
Treatment
Treatment of endometriosis‐associated infertility has been
based on three modalities: medical treatment, surgery, and assisted
reproduction.
Medical treatment
Medical treatment of endometriosis‐associated infertility
has followed two strategies: suppression of follicle growth with the aim of
inducing amenorrhea and thereby suppressing the development and growth of
endometriotic lesions with the aim of increasing subsequent fertility; and
stimulation of follicle growth and ovulation. Suppression of ovulation with
gonadotropin‐releasing hormone agonists, progestins, danazol, or oral
contraceptives have all been shown not to improve fertility in women with
endometriosis; indeed, such treatments seem rather postpone pregnancy and
imply side‐effects. For stimulation of follicle growth and ovulation,
clomiphene citrate has most commonly been prescribed, either alone or in
combination with gonadotropins. More recently, aromatase inhibitors have also
been used for follicle stimulation. However, these studies most often tested
combinations of various treatments, and therefore the efficacy of ovarian
stimulation isolated from other procedures in endometriosis‐associated
infertility remains to be documented.
Surgery
Surgery has previously played an important role in the
treatment of endometriosis‐associated infertility. When considering the
efficacy of surgical treatment, the disease stage (minimal/mild, moderate/severe,
and endometriomas) and outcomes compared with alternative treatment modalities
must be taken into account.
In minimal/mild
endometriosis without disruptive anatomy, the objective of surgery is to
destroy or remove all or most of the endometriotic implants. In such women, two
meta‐analyses published in 2014 concluded that removal or destruction of
endometriosis improves fertility. In one of the studies, summarizing data from
two randomized trials, clinical pregnancy rate improved by a risk ratio of
1.44, 95% results indicate a superiority of laparoscopic surgery compared with
diagnostic laparoscopy, one may question whether a 30% cumulative probability
of becoming pregnant during 36 weeks of justifies surgical treatment, when one
single IVF‐attempt will usually have a similar success rate.
Nonetheless, one should also consider the age of the patient, the costs, and
reimbursement, when recommending treatment alternatives.
In moderate/severe endometriosis, the goal of surgery is to
restore the normal anatomy of the pelvis and remove large endometriomas.
Unfortunately, there are no randomized controlled trials on the effect of
surgery in women with moderate/severe endometriosis-associated infertility vs.
medical or no treatment, Intrauterine insemination
Intrauterine insemination with partner sperm is a simple procedure that has been subject to many studies looking for optimal treatment
of couples with minimal/mild endometriosis and normal semen quality.
Unfortunately, several of these studies have methodological weaknesses, like
combination of IUI with ovarian stimulation, not reporting the stage of
endometriosis, or performing ablative surgery just before the IUI treatment.
Hence, the effect of IUI per se remains unclear. Assisted reproduction
Assisted reproductive technology comprises
several treatment modalities that combine some kind of hormonal follicle
stimulation with preparation and handling of gametes to bypass pathological
barriers of reproduction. In principle, ART can be divided into in vivo or in
vitro procedures depending on whether or not oocytes have been extracted from
the ovaries, fertilized and cultured in a laboratory before transfer back into
the uterus or in some cases the Fallopian tubes Intrauterine insemination
Intrauterine insemination
with partner or donor sperm is a simple procedure that has been subject to many
studies looking for optimal treatment of couples with minimal/mild
endometriosis and normal semen quality. Unfortunately, several of these studies
have methodological weaknesses, like a combination of IUI with ovarian
stimulation, not reporting the stage of endometriosis, or performing ablative
surgery just before the IUI treatment. Hence, the effect of IUI per se remains
unclear.
In vitro fertilization in a now classical meta‐analysis, it was
shown that infertile women with endometriosis had substantially lower success
with IVF compared with tubal factor infertility, including lower ovarian
response reduced implantation rate and pregnancy rate. In addition, a more
advanced disease was related to an increasingly inferior outcome 64. In two more
recent meta‐analyses on the outcome of IVF in endometriosis, the live birth rate was
found to be similar in minimal/mild endometriosis and other indications for
IVF, whereas in patients with moderate/severe endometriosis, the results were
inferior, including fewer oocytes retrieved, lower implantation rate, and lower
birth rate
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