Peritoneal fluid environment in endometriosis
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2476-M.GIN./Review MINERVA GINECOL 2003;55:000-000
Peritoneal fluid environment in endometriosis
Clinicopathological implications
M. A. BEDAIWY, T. FALCONE
Endometriosis is a puzzling disorder with Department of Gynecology and Obstetrics,
obscure pathogenesis. The objective of this The Cleveland Clinic Foundation,
review was to evaluate the complex role of per- Cleveland, OH, USA
itoneal fluid in the etiopathogenesis of endome-
triosis. Several studies suggest that peritoneal
fluid is a key inflammatory environment asso-
ciated with endometriosis. Many active sub-
stances (cytokines, growth factors, hormones a huge number of clinical and basic science
and oxidative stress parameters) have been researches, endometriosis remains a puzzling
identified in endometriosis patients at different disorder and its exact pathogenesis has not
stages of the disease. Inflammatory mediators never been established yet.
may be involved in the endometriosis associat- The current consensus is that endometrio-
ed-infertility and possibly pain. Furthermore,
these mediators may represent a non surgical sis is a local pelvic inflammatory process with
method for diagnosing endometriosis. Better altered function of immune-related cells in
understanding of the mechanism of cytokines, the peritoneal environment. Supporting this
growth factor and reactive oxygen species pro- concept are recent studies suggesting that
duction and detoxification and further investi- the peritoneal fluid of women with endome-
gation of their effects on the peritoneal fluid triosis contains an increased number of acti-
environment are essential to obtain new insight vated macrophages that secrete various local
into this disease and eventually develop novel
diagnostic and therapeutic remedies.
products, such as growth factors, cytokines
and possibly free oxygen radicals.1-16
Key words: Endometriosis, etiology - Peritoneal
fluid - Cytokines - Reactive oxygen species.
Studies have reported elevated levels of
several cytokines in the peritoneal fluid of
women with endometriosis, thus implicating
these cytokines in the development and pro-
E ndometriosis is characterized by the pres-
ence and growth of endometrial tissue
outside the uterus. It is a common disease
gression of endometriosis and endometriosis-
associated infertility. Reactive oxygen spe-
cies (ROS) are also produced by peritoneal
among women of reproductive age. The wide fluid mononuclear leucocytes in endometri-
range of symptoms associated with endome- osis patients.17 Production of ROS is known
triosis jeopardize the quality of life. Despite to increase after activation of immune cells,
especially polymorphonuclear leukocytes
Address reprint requests to: T. Falcone, Department of and macrophages. Consequently, ROS appear
Obstetrics and Gynecology, The Cleveland Clinic Founda- to be an important mediator in the etiopath-
tion, 9500 Euclid Avenue A81, Cleveland, OH 44195, USA.
E-mail: falcont@ccf.org ogenesis of endometriosis.
Vol. 55, N. MINERVA GINECOLOGICA 1BEDAIWY PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS
Once endometrium reaches the peritoneal Peritoneal fluid is rich with variable cellu-
cavity, its growth must be stimulated and lar components including macrophages, mes-
maintained to initiate the disease process. othelial cells, lymphocytes, eosinophils, and
Critical to this mechanism is the establish- mast cells. The normal concentration of per-
ment of a novel blood supply. Angiogenic itoneal fluid leukocytes is 0.5 to 2.0×106/mL,
factors figure prominently in the pathogene- of which approximately 85% are macrophag-
sis of endometriosis. Failure of initiation, es.19, 20 It has been 1 hypothesized that peri-
growth and maintenance may hamper the toneal macrophage 1 activation is a pivotal
development of endometriosis. Endometri- step in the disease initiation and progression.
otic tissue usually behaves like euotopic Activated macrophages in the peritoneal cav-
endometrium in their hormonal responsive- ity of women with endometriosis are potent
ness. Frequently, endometriotic tissues often producers of cytokines. Thus, peritoneal fluid
behave in an aberrant way. contains a rich mixture of cytokines. Iron
Such data suggest that a combination of overload was also observed in the cellular
factors, including the hormonal milieu and and peritoneal fluid compartments of the per-
the number and secretory capacity of cells itoneal cavity of endometriosis patients sug-
residing in the peritoneal cavity, might be gesting a role in its pathogenesis.21 Oxida-
required to sustain the growth of ectopic tive stress is also a commonly observed pro-
endometrium and thus induce clinical endo- cess identified in the peritoneal fluid of endo-
metriosis. In this review, the current under- metriosis patients.22, 23
standing of the role of the peritoneal fluid
environment in the pathogenesis of endo-
metriosis and endometriosis-associated infer-
tility is evaluated. Peritoneal fluid immunological factors
and endometriosis
Significant role of the immune system in
Peritoneal fluid
the pathogenesis of endometriosis has been
recently documented.24 Based on these recent
Peritoneal fluid is often seen in the vesicou-
terine cavity or the cul-de-sac during gyneco- findings, there is an emerging concept of
logic surgery and bathes the pelvic cavity, treating endometriosis as an autoimmune dis-
uterus, fallopian tubes, and ovaries. It is ease.25 Accumulating evidence suggests that
believed to be a major factor controlling the systemic T cell activity influences the patho-
peritoneal microenvironment that influences genesis of endometriosis.26, 27 Altered T-help-
the development and progression of endome- er to T-suppressor ratio and concentration
triosis and endometriosis-associated infertil- of both cells respectively have been report-
ity. Peritoneal fluid is formed in part by the ed in serum, peritoneal fluid (PF) 28 and endo-
contribution of the follicular activity, corpus metriotic tissue 29 in endometriosis patients.
luteum vascularity, and hormonal produc- Moreover, such differences could be detect-
tion. The volume of peritoneal fluid is dynam- ed between eutopic endometrium from wom-
ic and phase dependent peaking at the time en with and without the disease. There is
of ovulation.18 The peritoneal fluid ingre- lack of consistency regarding the alterations
dients are variable in normal menstrual cycles in T-cells and their role in the pathophysio-
and different pathologic entities.19, 20 It has logy of endometriosis.
been found that women with endometriosis Natural killer (NK) cells are also altered in
had a greater peritoneal fluid volume than endometriosis. Both peripheral and perito-
fertile controls, patients with tubal disease, or neal fluid NK cells from women with endo-
those with unexplained infertility. Moreover, metriosis showed different characteristics
an increased volume of peritoneal fluid may compared with those of the controls.30 Addi-
be commonly associated not only with endo- tionally, NK cell cytotoxicity has been shown
metriosis but also with idiopathic infertility. to be inversely correlated with the stages of
2 MINERVA GINECOLOGICA Mese 2003PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS BEDAIWY
the disease.31 Consequently, altered NK cyto- ger pathways via specific high-affinity recep-
toxicity to endometrial tissue may be respon- tors on target cell membranes. The cytokine
sible in part for the initiation, propagation nomenclature reflects the historical descrip-
and establishment of pelvic endometriosis. tion of these biological activities.
Sera and PF from women with endometrio-
sis have been shown to reduce NK cell activ- Cytokines: sources
ity.32 This is probably caused by monocyte or
macrophage activity through their secretions The main source of cytokines is macro-
that modulate immune and non-immune phages, which originate in bone marrow, cir-
cells. culate as monocytes, and migrate to various
Besides the alterations of T cell functions, body cavities. Chemoattractant cytokines par-
many recent findings have shown alterations ticularly RANTES, and IL-8, facilitate macro-
in B-cell function in endometriosis patients as phages recruitment into the peritoneal cavity.
evidenced by abnormal antigen-antibody The second major source of cytokines is T
reaction and increased B-cell function. lymphocytes. Helper -T cells can be classified
Decreased C3 deposition in the endometrium into 2 subsets: type 1 (Th1) and type 2 (Th2).
and a corresponding reduction in the serum Th1 cells produce IL-2, IL-12, and interfer-
total complement levels has been shown in on-γ, which are potent inducers of cell-medi-
endometriosis patients.33 Antiendometrial ated immunity. Th2 cells produce mainly IL-
antibodies particularly IgG and IgA have been 4, IL-5, IL-10, and IL-13, which are involved
detected in sera, vaginal, and cervical secre- in suppression of cell-mediated immunity.
tions of endometriosis patients.34 The pres- There is alteration of cytokines secreted by
ence of antiphospholipids and antihistones of Th1 and Th2 in endometriosis patients partic-
IgG, IgM, and IgA have been documented ularly in the balance of Th1 and Th2 cells
by some investigators 35 and questioned by toward the Th2. This may—in part—be
others.36 The exact correlation between the responsible for the impaired immunologic
stage of endometriosis and autoantibodies defense in endometriosis.3
ranges from positive 37 to negative 38 to no Tsudo et al. hypothesized that cytokines
relationship at all.39 These observations of are not only produced by immune competent
immune alterations have lead investigators cells but by endometriotic implants as well.40
to believe that markers of immune reactivity, They demonstrated that endometriotic cells
particularly cytokines, may be potentially constitutively express IL-6 messenger RNA
used as diagnostic aid for endometriosis. and produce IL-6 protein and that adding
TNF-α stimulated IL-6 gene and protein
Cytokines: chemistry expression in a dose-dependent manner. On
comparing IL-6 production by macrophages
Cytokines are polypeptides or glycopro- and endometriotic stromal cells in-patients
teins secreted into the extracellular compart- with endometriosis, they found that similar
ment mainly by leukocytes. Upon secretion, levels of IL-6 were produced in stromal cells
they exert autocrine, paracrine and some- derived from an endometrioma and by mac-
times endocrine effects. Moreover, cytokines rophages under basal- and TNF-α-stimulated
may exist in cell-membrane-associated forms conditions. This finding supports the hypoth-
where they exert juxtacrine activity on adja- esis that endometriotic tissue is another
cent cells. They are essential mediators of important source of cytokines.40
cell-cell communication in the immune
system. They affect a wide variety of target
cells exerting proliferative, cytostatic, chem- Peritoneal fluid cytokines
oattractant, or differentiative effects. Their Peritoneal fluid is rich with variable cellu-
biological activities are mediated by coupling lar components including macrophages, mes-
to intracellular signaling and second-messen- othelial cells, lymphocytes, eosinophils, and
Vol. 55, N. MINERVA GINECOLOGICA 3BEDAIWY PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS
mast cells. The normal concentration of PF concentration in the PF of endometriosis
leukocytes is 0.5 to 2.0×106/mL, of which patients is variable. Some in vitro studies sug-
approximately 85% are macrophages.19, 20 It gest that peritoneal macrophages 44 and
has been 1 hypothesized that peritoneal mac- peripheral blood monocytes 45 from these
rophage activation is a pivotal step in the patients have up-regulated TNF-α protein
disease initiation and progression. Activated secretion. Activated macrophages play a crit-
macrophages in the peritoneal cavity of wom- ical role in the pathogenesis of endometrio-
en with endometriosis are potent producers sis. The secreted TNF-α may play an impor-
of cytokines.23 Thus, PF contains a rich mix- tant role in the local and the systemic mani-
ture of cytokines. Iron overload was also festations of the disease. Because of its impor-
observed in the cellular and PF compartments tance in other inflammatory processes, it is
of the peritoneal cavity of endometriosis likely that this cytokine plays a central role in
patients suggesting a role in its pathogene- the pathogenesis of endometriosis.46 More-
sis.21 over, its level in the PF can be used as a foun-
dation for non-surgical diagnosis of endo-
Individual cytokines metriosis as well.23 Recently, the concept of
Tumor necrosis factors using TNF-α blockers in treating endometri-
osis is gaining popularity.25
The tumor necrosis factors (TNF) are pleio-
tropic cytokines that exerts an essential role Interleukin-6
in the inflammatory process. It is believed to
be seminal in many physiological and path- IL-6 is a regulator of inflammation and
ological reproductive processes. The spec- immunity, which may be a physiologic link
trum of its effects is very wide with beneficial between the endocrine and the immune
and hazardous effects. The quantity of TNF systems. It also modulates secretion of other
produced is the main factor that controls its cytokines, promotes T-cell activation and B-
role in the disease process. The main TNF is cell differentiation, and inhibits growth of
TNF-α, which is produced by neutrophils, various human cell lines.25 Monocytes, mac-
activated lymphocytes, macrophages, NK rophages, fibroblasts, endothelial cells, vas-
cells, and several non-hematopoietic cells. cular smooth-muscle cells, and endometrial
Little is known about TNF-α, which is pro- epithelial, stromal cells and several endo-
duced by lymphocytes. The primary func- crine glands, including the pituitary and the
tion of TNFs is their ability to initiate the cas- pancreas are all production sites for IL-6.47
cade of cytokines and other factors associat- The role of IL-6 in the pathogenesis of
ed with inflammatory responses. TNF-α helps endometriosis was extensively studied. IL-6
to activate helper T cells. response in the peritoneal macrophages,48
In the human endometrium, TNF-α is a endometrial stromal cells,49 and peripheral
factor in the normal physiology of endome- macrophages 45 was dysregulated in patients
trial proliferation and shedding. TNF-α is with endometriosis. The level of IL-6 detect-
expressed mostly in epithelial cells particular- ed in the PF of patients with endometriosis
ly in the secretory phase.41 Stromal cells stain was inconsistent. Some investigators have
for TNF-α mostly in the proliferative phase of demonstrated elevated concentrations,4, 5
the cycle. These data suggest a hormonal whereas others have found no elevation.10
control of this cytokine.42 Some studies failed to demonstrate statisti-
Peritoneal fluid TNF-α concentrations are cally significant differences in IL-6 levels
elevated in patients with endometriosis, and between controls and endometriosis pa-
some studies show higher concentrations tients.50 These inconsistent findings likely are
correlate with the stage of the disease.43 Our related to antibody specificity of the assay. In
study did not observe any relationship our recent study, we found that there is sig-
between levels of TNF-α and stage of the nificant elevation of IL-6 in the sera of endo-
disease.23 The source of the elevated TNF- metriosis patients but not in the PF as com-
4 MINERVA GINECOLOGICA Mese 2003PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS BEDAIWY
pared to patients with unexplained infertility secretion of RANTES by endometrioma-
and tubal ligation/re-anastomosis.23 derived stromal-cell cultures is significantly
greater than in eutopic endometrium. In this
Vascular endothelial growth factor way, PF concentrations of RANTES may be
Many studies focused on the proliferation increased in patients with endometriosis.11
and neovascularization of the endometriotic
implants. Vascular endothelial growth factor Interleukin-1
(VEGF) is one of the most potent and specif- Interleukin-1 (IL-1) is a key cytokine in the
ic angiogenic factors. The main biochemical regulation of inflammation and immune
activity of VEGF when it binds to its targeted responses. IL-1 affects the activation of T-
receptor is that VEGF-receptor activation lymphocytes and the differentiation of B-lym-
leads to a rapid increase in intracellular Ca2+ phocytes. There are 2 receptors for IL-1,
and inositol triphosphate concentrations in namely IL-1α and IL-1β sharing only 18-26%
endothelial cells.51, 52 The basic physiological amino acid homology. Both receptors are
function of VEGF is that VEGF-induced angio- encoded by different genes but have similar
genesis allows repair of the endometrium biological activities. It was found that suc-
following menstruation. It also modulates the cessful implantation in mice was blocked by
characters of the newly formed vessels by the administration of exogenous IL-1 recep-
controlling the microvascular permeability, tor antagonist. This illustates its important
permitting the formation of a fibrin matrix role in the implantation of the ectopic endo-
for endothelial migration and proliferation.53 metrium.59 IL-1 has been isolated from the
This may be responsible for the local endo- PF of patients with endometriosis. Results
metrial edema which help to prepare the have been inconsistent, with some investi-
endometrium for embryo implantation.54 gators demonstrating elevated concentrations
In endometriosis patients, VEGF was local- in patients with endometriosis 60 and others
ized in the epithelium of endometriotic finding no elevation.2, 23, 44
implants,55 particularly in hemorrhagic red
implants.56 Moreover, there are increased con- Other cytokines
centrations of VEGF in PF of endometriosis
patients. The exact cellular sources of VEGF A highly sensitive ELISA kits have made it
in PF have not been precisely defined yet. easy to measure the entire battery of cyto-
Although evidence exists to suggest that endo- kines in the serum and PF of endometriosis
metriotic lesions themselves produce this fac- patients. Other cytokines have been identified
tor,55 activated peritoneal macrophages also and include IL-4 3; IL-5 4; IL-8 6, 23; IL-10 7; IL-
have the capacity to synthesize and secrete 12 8, 23; IL-13 9; interferon-γ 10; monocyte
VEGF.16 Similar to the concept of using TNF- chemotactic protein-1 (MCP-1) 12; macro-
α blockers, antiangiogenic drugs are potential phage colony stimulating factor (MCSF) 13
therapeutic agents in endometriosis. and transforming growth factor (TGF)-α 14. All
these cytokines may regulate the actions of
RANTES leukocytes or may act directly on ectopic
endometrium, where they may play various
RANTES (Regulated on Activation, Normal roles in the pathogenesis and pathophysiolo-
T-Cell Expressed and Secreted) belongs to gy of endometriosis. However, their exact
the or “C-C” chemokine family. It attracts for role needs further investigation.
monocytes and memory T-cells. RANTES is a
secretory product of hematopoietic cells, epi-
Role of peritoneal fluid cytokines and growth
thelial and mesenchymal cells and a media-
factors in endometriosis
tor in both acute and chronic inflammation.57
RANTES protein distribution in ectopic The role of peritoneal fluid cytokines and
ectopic endometrium is similar to that found growth factors in the pathophysiology of
in a eutopic endometrium.58 However, in vitro endometriosis has been investigated exten-
Vol. 55, N. MINERVA GINECOLOGICA 5BEDAIWY PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS
TABLE I.—The role of peritoneal fluid cytokines and Autoantibodies
growth factors in the pathophysiology of endome-
triosis. A variety of autoantibodies have been
detected in endometriosis patients. The most
I Endometrial cells implantation 63
commonly reported types are antiendome-
II Endometrial cell proliferation 61, 62
trial antibodies 33, 67 and autoantibodies
III Endometrial tissue remodeling 64
against oxidative stress parameters.68
IV Angiogenesis and neovascularization 50
Antiendometrial antibodies
The antigens used to induce antiendome-
sively in the past decade. The hypothesized trial antibodies included sonicated endome-
roles of cytokines in the pathogenesis of trium of women with normal menstrual
endometriosis are summarized in Table I.50, 61- cycles, endometrial tissue of patients with
64 They are probably responsible for endome- endometriosis, endometriosis tissue, human
trial cell proliferation 61, 62 and implantation of endometrial carcinoma cells line, epithelial
endometrial cells or tissue.63 Moreover, cyto- monolayers or endometrial glands and stro-
kines increased tissue remodeling through mal cells. Moreover, the exact antigen is not
their effects on the matrix metalloproteinas- known, consequently there is no simple anti-
es.64 Increased angiogenesis of the ectopic gen-antibody assay as yet.38
endometrial tissue and neovasculariztion of Serum antiendometrial antibodies.—Anti-
the affected region is probably the most endometrial antibodies have been postulated
important effect of cytokines on ectopic endo- to be a probable cause of infertility in endo-
metrial tissue. metriosis patients as shown by some investi-
Another variable is the role of growth fac- gators 33, 67 but not by others.69 Besides the
tors. In rodents, epidermal growth factor inconsistency of the assay techniques used,70
(EGF), transforming growth factor α, and EGF the nature of the antigens used to illicit
receptors have been demonstrated in both immune response are inconsistent as well.
eutopic and ectopic endometrium.65 EGF, The sensitivity and the specificity of serum
insulin-like growth factor I and growth hor- anti-endometrial antibodies screening were
mone all stimulate the growth of human endo- reported by some investigators to be 0.84
metrial stromal cells in vitro. Platelet-derived and 1.00, respectively.34 On comparing infer-
growth factor has been shown to lead to the tile women with endometriosis with unex-
proliferation of human endometrial stromal plained infertility, Wild and Shiver found a
cells in a dose-dependent fashion. Addition- sensitivity of 0.71 and a specificity of 1.00. 39
ally, macrophage-derived growth factor Similarly, Meek et al.36 found a sensitivity of
(MDGF) enhances endometrial stromal-cell 0.75 and a specificity of 0.90 while in another
proliferation 66 with maximal stimulation of study the values were 0.85 and 0.67, respec-
growth when MDGF and estrogen are both tively.71 Although serum antiendometrial anti-
present in the culture medium. As such, acti- bodies matches CA 125 regarding both sen-
vated macrophages, through the liberation of sitivity and specificity, it does not satisfy the
cytokines and growth factors, could poten- criteria of an ideal screening test. Despite
tially contribute to the early establishment as this limitation, anti-endometrial antibody was
well as the progression of endometriosis. proposed not only as a screening marker but
Cytokines play a major role in the initiation, as a follow-up marker of treatment results
propagation, and regulation of immune and and recurrence as well.72
inflammatory responses. Immune cell acti-
vation results in a burst and cascade of inflam- Peritoneal fluid antiendometrial antibod-
matory cytokines. These cytokines have pleio- ies.—Although antiendometrial antibodies
tropic and redundant activities that culmi- were found in the PF of endometriosis
nate in recruitment of numerous cell types to patients, their sensitivity and specificity are
the site of inflammation. variable. Halme and Mthur found a sensitiv-
6 MINERVA GINECOLOGICA Mese 2003PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS BEDAIWY
ity of 0.23 and a specificity of 0.96 using a TABLE II.—Mechanisms of endometriosis associated
passive haemagglutination assay 73 while the infertility.
results were 0.75 and 0.90 using Ouchterlo- I Ovarian causes
ny immune diffusion.36 1. Impaired folliculogenesis
2. Defective granulosa cell steroidogenesis
3. Luteinized unruptured follicle syndrome
Autoantibodies to markers of oxidative stress 4. Reduced oocyte quality
There is increasing evidence of oxidative 5. Luteal phase defects
stress in the PF of women with endometrio- II Tubal causes
1. Tubal distortion
sis and showed that oxidatively modified lip- 2. Tubal obstruction
id proteins exist in the PF.22, 23, 74 In addition, 3. Tubal dysfunction
oxidation-specific epitopes and macro-phag- III Immunological causes
es are present in the endometrium and in 1. Autoimmunity
endometriosis.68 Lipid peroxides interact with 2. Antiendometrial antibody
3. Antiphospholipid antibody
proteins, resulting in several types of altera-
tions, and such oxidatively modified proteins IV Hyperprolactinaemia
are themselves antigenic. Antigenicity is attrib- V Local peritoneal factors affecting gametes and early
embryos
uted to specific modified epitopes and not to 1. Cytokines
the protein backbone. 2. Prostaglandins
In a study to measure autoantibodies to 3. Macrophages
oxidatively modified proteins in the sera of VI Defective implantation
women with surgically proven endometriosis,
Murphy et al., included women undergoing
surgery for endometriosis or tubal ligation.68 increased in endometriosis. Large amounts
They measured serum and PF autoantibody of ROS were released after chronic stimula-
titers to malondialdehyde-modified low-den-
tion of peritoneal fluid macrophages in wom-
sity lipoprotein, oxidized low-density lipo-
en with endometriosis. Production of ROS is
protein, and lipid peroxide-modified rabbit
known to increase after activation of immune
serum albumin determined by ELISA. They
cells, especially polymorphonuclear leuko-
correlated the autoantibody titers with the
disease stage, symptoms, and morphologic cytes and macrophages.17
type of endometriosis. However, further studies based on direct
They found that autoantibodies to markers measurement of reactive oxygen species pro-
of oxidative stress were significantly increased duction failed to show an obvious oxidant
in women with endometriosis without any or antioxidant imbalance in the peritoneal
correlation with the stage, symptoms, or mor- cavity of patients with endometriosis. Our
phologic type of the disease. Peritoneal fluid group 22 found similar levels of ROS detect-
did not contain autoantibodies to any of the ed by enhanced chemiluminescence assay
3 antigens. Given the fact that autoantibodies using luminol as a probe in the peritoneal
to Ox-LDL have been long considered as a fluid of patients with endometriosis and dis-
screening tool for atherosclerosis,75 a similar ease-free controls. The same results were
role might be claimed in endometriosis. confirmed in a later study with large number
of cases.23 Furthermore, the total antioxidant
status was not increased in endometriosis,76
a finding confirmed recently by Polak et al.77
Peritoneal fluid oxidative stress Expression of xanthine oxidase, an enzyme
and endometriosis which produces ROS, in ectopic and eutop-
ic endometrium remained high throughout
Peritoneal fluid reactive oxygen species
the menstrual cycle in women with endome-
The production of ROS by peritoneal fluid triosis; in contrast, cyclic variations in its
mononuclear cells was long reported to be expression were seen in controls.78 This
Vol. 55, N. MINERVA GINECOLOGICA 7BEDAIWY PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS
TABLE III.—Possible negative effects of cytokine rich per- er, others 83 found no relation between lev-
itoneal fluid on gamete function and embryonic
development. els of malondialdehyde in peritoneal fluid
and severity of endometriosis. Higher levels
I Spermatozoa of lysophosphatidyl choline, another indica-
1. Impairment of acrosome reaction tor of lipoprotein peroxidation, were found
2. Impairment of sperm motility
in the peritoneal fluid of patients with endo-
II Oocyte
1. Impaired folliculogenesis
metriosis as well.74 Murphy et al. demonstrat-
2. Impaired oocyte quality ed increased modified lipidprotein complex-
III Sperm-oocyte interaction impairment es at the level of the endometrium as well.68
IV Impaired embryonic development Ectopic endometrial cells were also immu-
1-2. Cell stage block nostained with antibodies to oxidatively mod-
2. Decreased blastulation ified proteins.
Peritoneal fluid antioxidants
apparent discrepancy between results may Several recent studies appear to show that
be due to the fact that only persistent mark- in women with endometriosis, the endome-
ers of oxidative stress, such as enzymes or trium shows altered expression of enzymes
stable by-products of oxidative reactions, can involved in defense against oxidative stress
still be detected when endometriosis is diag- such as manganese and copper/zinc super-
nosed. Another possible explanation is that oxide dismutase 84 and glutathione peroxi-
oxidative stress occurs only locally—for dase.85 Expression of manganese superox-
example, at the site of bleeding—and does ide dismutase and glutathione peroxidase,
not result in an increase in total peritoneal which are induced during increased release
fluid concentrations.79 of reactive oxygen species, can be consid-
Contrary to ROS, no evidence of increased ered as an indicator of oxidative stress.84 It has
nitric oxide (NO) metabolism was found in been suggested that eutopic endometrium
the peritoneal fluid of women with and with- undergoes oxidative stress even in patients
out endometriosis.76 However, generation of who do not develop endometriosis,81 but
peroxynitrite by ectopic endometrium was probably to a lesser extent.
recently demonstrated in patients with ade- Vitamin E plays an important role in pro-
nomyosis.80 Expression of endothelial and tecting biological membranes by preventing
inducible nitric oxide synthase and peroxy- peroxidation. It may also play a role in pre-
nitrite generation were markedly reduced
venting activation of redox-sensitive path-
after GnRH agonist therapy, supporting their
ways, which have been implicated in abnor-
potential role in the pathophysiology of ade-
mal cell proliferation and inflammatory
nomyosis.80
response. Vitamin E levels were found to be
significantly lower in the peritoneal fluid of
Peritoneal fluid oxidized low-density lipop- women with endometriosis, perhaps due to
roteins: their consumption during oxidation reactions.
74, 81
In contrast, Murphy et al.81 found increased
oxidation of low-density lipoprotein in A decrease in antioxidant capacity may
patients with pelvic endometriosis and explain why low-density lipoproteins in the
increased concentrations of oxidized low- peritoneal fluid of patients with endometrio-
density lipoproteins in the peritoneal fluid sis are more readily oxidized than are low-
of women in whom the disease was develop- density lipoproteins from control patients.74
ing.81, 82 Oxidative modification of these mole- In conclusion, these findings indicate that
cules involves peroxidation of the lipid com- oxidative stress related mechanisms in the
ponent, which leads to release of aldehydes, peritoneal cavity of women with endometri-
such as malondialdehyde (MDA), and reac- osis are contributing to the etiopathogene-
tion with lysine residues of proteins. Howev- sis of the disease.
8 MINERVA GINECOLOGICA Mese 2003PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS BEDAIWY
Reproductive implications of the endometrium but also on the devel-
of peritoneal fluid opment of the oocyte and embryo, which
in endometriosis patients might be due to local peritoneal fluid effects.93
Gleicher et al. noted that a significant pro-
Endometriosis is frequently associated with portion of endometriosis patients has elevat-
infertility, even if affected women are ovula- ed autoantibody titers. Autoantibodies have
tory or have mechanical patency of the fallo- been reported to interfere with various pro-
pian tubes. An approximate estimate sug- cesses during human reproduction, including
gests that about 20% to 25% of infertile wom- sperm function, fertilization, and normal
en have endometriosis, compared with 2% progress of pregnancy.94
to 5% of women undergoing tubal ligation.86 Since the ovaries and fallopian tubes are
Endometriosis has been associated with infer- immersed in the peritoneal fluid, cytokines
tility even in its early stages, before adhesion among other active chemicals present in per-
or anatomic distortion take place. The exact itoneal fluid may jeopardize tubal motility,
mechanism of endometriosis-associated infer- ovum pick-up, or ovulation. Given the fact
tility is not fully understood, although many that oocytes are exposed to the peritoneal
possible causes have been suggested (Table environment even after they are captured by
II). the fimbriae, and spermatozoa are present
Ovulatory dysfunction has been proposed in the peritoneal fluid after intercourse, gam-
as the main cause of infertility in women with etes and early embryos are exposed to cyto-
minimal endometriosis. The association kine rich peritoneal fluid, which may influ-
between the luteinized unruptured follicle ence early reproductive process.
(LUF) syndrome and endometriosis was
described in endometriosis patients as well.87
In women with the LUF syndrome, steroid The potential mechanisms by which
hormone concentrations in peritoneal fluid the peritoneal fluid affects fertility
are much lower after the ovulatory cycle.88 It in endometriosis
was suggested that this lower steroid environ-
ment is a contributory factor in the develop-
ment of endometriosis. Hyperprolactinemia
and luteal phase defects have also been also Sperm phagocytosis
suggested as a possible cause of endometri- Peritoneal fluid contains many phagocytic
osis-associated infertility.89 cells (macrophages). They are responsible
Impaired follicular development in endo- for phagocytosis of cellular debris, including
metriosis patients undergoing IVF/ICSI was sperm, in the pelvis. It has been demonstrat-
observed in IVF data published everywhere.90, ed that peritoneal macrophages phagocy-
91 Defective granulosa cell steroidogenesis,92
tosed sperm in vitro and that macrophages
reduced pregnancy rates in IVF cycles in from women with endometriosis were more
women with minimal and mild endometrio- active than those from women without the
sis,90 impaired oocyte quality 90 and defects in disease. Peritoneal fluid flushing the tubal
implantation 90 were all proposed as etiolog- and endometrial environment may affect
ical factors for poor IVF outcome in endo- sperm and their interaction with the oocyte.95
metriosis patients. In a recent meta-analysis, However most indicators of sperm function
it was found that patients with endometriosis- have been hown to be normal after expo-
associated infertility undergoing IVF respond sure to peritoneal fluid of endometriosis
with significantly decreased levels of all mark- patients (Table III).96
ers of a good reproductive outcome, resulting
in a pregnancy rate that is almost one half
Sperm egg interaction
that of women with other indications for IVF.
These data suggest that the effect of endo- Studies showed that the peritoneal fluid
metriosis is not exclusively on the receptivity of patients with endometriosis jeopardizes
Vol. 55, N. MINERVA GINECOLOGICA 9BEDAIWY PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS
sperm function. Sperm motility acrosome these abnormalities identified are the result or
reaction, gamete interaction, and ovum pick the cause of the disease. However, recent
up by tubal fimbriae have been shown to be animal data suggests that altering these cyto-
affected by peritoneal fluid.97-99 Aeby et al., kine levels particularly TNF may have a ben-
using a hamster penetration assay, recently eficial effect on endometriotic growth. The
showed that peritoneal fluid from patients mechanism by which the abnormal perito-
with endometriosis impaired gamete inter- neal environment causes infertility or chron-
action. In their study, the mean number of ic pelvic pain is speculative. Future research
eggs penetrated by sperm mixed with perito- into the peritoneal fluid environment can
neal fluid from patients with endometriosis lead to more insight into the pathogenesis
was significantly less than that observed in of endometriosis as well as to potential non-
controls. These data propose that chemicals surgical diagnostic and treatment modalities.
in the peritoneal fluid of patients with endo-
metriosis contribute to infertility by impairing
sperm egg interaction.100 Riassunto
Preimplantation embryonic development Composizione del liquido peritoneale nell’endome-
triosi: implicazioni clinico-patologiche
Peritoneal fluid effect on preimplantation L’endometriosi rappresenta una patologia enig-
murine embryo development has also been matica, la cui patogenesi è ancora oscura. L’obiettivo
studied. There are contradictory conclusions di questa review è la valutazione del complesso ruo-
regarding the effect of peritoneal fluid lo svolto dal liquido peritoneale nell’eziopatogenesi
obtained from patients with endometriosis dell’endometriosi. Diversi studi suggeriscono che il
liquido peritoneale costituisce un bacino infiamma-
on embryonic development in vitro. Some torio di cruciale importanza per lo sviluppo dell’en-
studies suggested a negative effect,101 and dometriosi. Nei pazienti affetti da endometriosi è sta-
others have found that peritoneal fluid had no ta rinvenuta la presenza, a diversi stadi della malattia,
adverse effects at all.102 However, peritoneal di molteplici sostanze dotate di attività infiammatoria
fluid from patients with endometriosis has (citochine, fattori di crescita, ormoni e parametri di
frequently been shown to be toxic to the pre- stress ossidativo). Questi mediatori del processo
infiammatorio possono essere coinvolti nell’inferti-
implantation embryo. Medical treatment of lità associata all’endometriosi e verosimilmente nel
endometriosis was found to reverse the dolore. Inoltre, questi mediatori possono rappresen-
embryotoxicity of the peritoneal fluid.2 More- tare una metodica non chirurgica per la diagnosi del-
over, the levels of IL-1 and TNF-α were mark- l’endometriosi.
edly reduced in the peritoneal fluid of wom- Una migliore comprensione del meccanismo di
produzione delle citochine, dei fattori di crescita e
en who received medical treatment for endo- delle specie reattive dell’ossigeno e della loro detos-
metriosis. sificazione, insieme a indagini più approfondite cir-
ca i loro effetti sulla composizione del liquido peri-
toneale, costituirebbero un passo fondamentale ver-
Conclusions so la chiarificazione della patogenesi di questa malat-
tia e, in ultima analisi, verso lo sviluppo di nuove
strategie diagnostiche e terapeutiche.
Randomized clinical trial on the use of sur- Parole chiave: Endometriosi, eziologia – Liquido peri-
gery for infertility or pain associated with toneale - Citochine - Specie reattive dell’ossigeno.
endometriosis have shown a clear benefit.103
This clearly shows that the peritoneal environ-
ment is a critical part of the pathogenesis and References
treatment of the disease. Most research on
the peritoneal fluid environment has been 1. Halme J, Becker S, Wing R. Accentuated cyclic activa-
tion of peritoneal macrophages in patients with endo-
observational. These studies have reported a metriosis. Am J Obstet Gynecol 1984;148:85-90.
variety of inflammatory cytokines and growth 2. Taketani Y, Kuo TM, Mizuno M. Comparison of cyto-
kine levels and embryo toxicity in peritoneal fluid in
factors that are abnormally elevated in infertile women with untreated or treated endometri-
patients with endometriosis. It is unclear if osis. Am J Obstet Gynecol 1992;167:265-70.
10 MINERVA GINECOLOGICA Mese 2003PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS BEDAIWY
3. Hsu CC, Yang BC, Wu MH, Huang KE. Enhanced inter- 20. Syrop CH, Halme J. Cyclic changes of peritoneal fluid
leukin-4 expression in patients with endometriosis. parameters in normal and infertile patients. Obstet
Fertil Steril 1997;67:1059-64. Gynecol 1987;69:416-8.
4. Koyama N, Matsuura K, Okamura H. Cytokines in the 21. Van Langendonckt A, Casanas-Roux F, Donnez J. Iron
peritoneal fluid of patients with endometriosis. Int J overload in the peritoneal cavity of women with pel-
Gynaecol Obstet 1993;43:45-50. vic endometriosis. Fertil Steril 2002;78:712-8.
5. Harada T, Yoshioka H, Yoshida S, Wabe T, Onohara Y, 22. Wang Y, Sharma RK, Falcone T, Goldberg J, Agarwal A.
Tanikawa M et al. Increased interleukin-6 levels in per- Importance of reactive oxygen species in the peritoneal
itoneal fluid of infertile patients with active endometri- fluid of women with endometriosis or idiopathic infer-
osis. Am J Obstet Gynecol 1997;176:593-7. tility. Fertil Steril 1997;68:826-30.
6. Iwabe T, Harada T, Tsudo T, Tanikawa M, Onohara Y, 23. Bedaiwy MA, Falcone T, Sharma RK, Golberg JM, Atta-
Terakawa N. Pathogenetic significance of increased ran M, Nelson DR et al. Prediction of endometriosis
levels of interleukin-8 in the peritoneal fluid of patients with serum and peritoneal fluid markers: a prospective
with endometriosis. Fertil Steril 1998;69:924-30. controlled trial. Hum Reprod 2002;17:426-31.
7. Ho HN, Wu MY, Chao KH, Chen CD, Chen SU, Yang 24. Lebovic DI, Mueller MD, Taylor RN. Immunobiology of
YS. Peritoneal interleukin-10 increases with decrease in endometriosis. Fertil Steril 2001;75:1-10.
activated CD4+ T lymphocytes in women with endo- 25. Nothnick WB. Treating endometriosis as an autoim-
metriosis. Hum Reprod 1997;12:2528-33. mune disease. Fertil Steril 2001;76:223-31.
8. Mazzeo D, Vigano P, Di Blasio AM, Sinigaglia F, Vigna- 26. Steele RW, Dmowski WP, Marmer DJ. Immunologic
li M, Panina-Bordignon P. Interleukin-12 and its free p40 aspects of human endometriosis. Am J Reprod Immu-
subunit regulate immune recognition of endometrial nol 1984;6:33-6.
cells: potential role in endometriosis. J Clin Endocrin- 27. Badawy SZ, Cuenca V, Stitzel A, Tice D. Immune
ol Metab 1998;83:911-6. rosettes of T and B lymphocytes in infertile women
9. McLaren J, Dealtry G, Prentice A, Charnock-Jones DS, with endometriosis. J Reprod Med 1987;32:194-7.
Smith SK. Decreased levels of the potent regulator of 28. Dmowski WP, Gebel HM, Braun DP. The role of cell-
monocyte/macrophage activation, interleukin-13, in mediated immunity in pathogenesis of endometriosis.
the peritoneal fluid of patients with endometriosis. Acta Obstet Gynecol Scand Suppl 1994;159:7-14.
Hum Reprod 1997;12:1307-10. 29. Witz CA, Montoya IA, Dey TD, Schenken RS. Charac-
10. Keenan JA, Chen TT, Chadwell NL, Torry DS, Caudle terization of lymphocyte subpopulations and T cell
MR. Interferon-gamma (IFN-gamma) and interleukin- activation in endometriosis. Am J Reprod Immunol
6 (IL-6) in peritoneal fluid and macrophage-condi- 1994;32:173-9.
tioned media of women with endometriosis. Am J 30. Wilson TJ, Hertzog PJ, Angus D, Munnery L, Wood
Reprod Immunol 1994;32:180-3. EC, Kola I. Decreased natural killer cell activity in
11. Khorram O, Taylor RN, Ryan IP, Schall TJ, Landers DV. endometriosis patients: relationship to disease patho-
Peritoneal fluid concentrations of the cytokine RANTES genesis. Fertil Steril 1994;62:1086-8.
correlate with the severity of endometriosis. Am J 31. Ho HN, Chao KH, Chen HF, Wu MY, Yang YS, Lee TY.
Obstet Gynecol 1993;169:1545-9. Peritoneal natural killer cytotoxicity and CD25+ CD3+
12. Arici A, Oral E, Attar E, Tazuke SI, Olive DL. Monocyte lymphocyte subpopulation are decreased in women
chemotactic protein-1 concentration in peritoneal fluid with stage III-IV endometriosis. Hum Reprod 1995;
of women with endometriosis and its modulation of 10:2671-5.
expression in mesothelial cells. Fertil Steril 1997; 32. Kanzaki H, Wang HS, Kariya M, Mori T. Suppression of
67:1065-72. natural killer cell activity by sera from patients with
13. Fukaya T, Sugawara J, Yoshida H, Yajima A. The role endometriosis. Am J Obstet Gynecol 1992;167:257-61.
of macrophage colony stimulating factor in the perito- 33. Weed JC, Arquembourg PC. Endometriosis: can it pro-
neal fluid in infertile patients with endometriosis. Toho- duce an autoimmune response resulting in infertility?
ku J Exp Med 1994;172:221-6. Clin Obstet Gynecol 1980;23:885-93.
14. Oosterlynck DJ, Meuleman C, Waer M, Koninckx PR. 34. Mathur S, Peress MR, Williamson HO, Youmans CD,
Transforming growth factor-beta activity is increased in Maney SA, Garvin AJ et al. Autoimmunity to endome-
peritoneal fluid from women with endometriosis. trium and ovary in endometriosis. Clin Exp Immunol
Obstet Gynecol 1994;83:287-92. 1982;50:259-66.
15. McLaren J, Prentice A, Charnock-Jones DS, Millican 35. Gleicher N, Adelsberg BR, Liu TL, Cederqvist LL, Phil-
SA, Muller KH, Sharkey AM et al. Vascular endothelial lips RN, Siegel I. Immune complexes in pregnancy.
growth factor is produced by peritoneal fluid macro- III. Immune complexes in immune complex-associat-
phages in endometriosis and is regulated by ovarian ed conditions. Am J Obstet Gynecol 1982;142:1011-5.
steroids. J Clin Invest 1996;98:482-9. 36. Meek SC, Hodge DD, Musich JR. Autoimmunity in
16. McLaren J, Prentice A, Charnock-Jones DS, Smith SK. infertile patients with endometriosis. Am J Obstet Gyne-
Vascular endothelial growth factor (VEGF) concentra- col 1988;158:1365-73.
tions are elevated in peritoneal fluid of women with 37. Taylor PV, Maloney MD, Campbell JM, Skerrow SM,
endometriosis. Hum Reprod 1996;11:220-3. Nip MM, Parnar R et al. Autoreactivity in women with
17. Zeller JM, Henig I, Radwanska E, Dmowski WP. endometriosis. Br J Obstet Gynaecol 1991;98:680-4.
Enhancement of human monocyte and peritoneal mac- 38. Evers JL, Dunselman GA, Van der Linden PJ. Markers
rophage chemiluminescence activities in women with for endometriosis. Baillieres Clin Obstet Gynaecol 1993;
endometriosis. Am J Reprod Immunol Microbiol 7:715-39.
1987;13:78-82. 39. Wild RA, Shivers CA. Antiendometrial antibodies in
18. Maathuis JB, Van Look PF, Michie EA. Changes in vol- patients with endometriosis. Am J Reprod Immunol
ume, total protein and ovarian steroid concentrations Microbiol 1985;8:84-6.
of peritoneal fluid throughout the human menstrual 40. Tsudo T, Harada T, Iwabe T, Tanikawa M, Nagano Y,
cycle. J Endocrinol 1978;76:123-33. Ito M et al. Altered gene expression and secretion of
19. Syrop CH, Halme J. Peritoneal fluid environment and interleukin-6 in stromal cells derived from endometri-
infertility. Fertil Steril 1987;48:1-9. otic tissues. Fertil Steril 2000;73:205-11.
Vol. 55, N. MINERVA GINECOLOGICA 11BEDAIWY PERITONEAL FLUID ENVIRONMENT IN ENDOMETRIOSIS
41. Philippeaux MM, Piguet PF. Expression of tumor necro- metriosis tissues and cells. J Clin Endocrinol Metab
sis factor-alpha and its mRNA in the endometrial muco- 1997;82:1621-8.
sa during the menstrual cycle. Am J Pathol 1993; 59. Simon C, Frances A, Piquette GN, el Danasouri I,
143:480-6. Zurawski G, Dang W et al. Embryonic implantation in
42. Hunt JS, Chen HL, Hu XL, Tabibzadeh S. Tumor necro- mice is blocked by interleukin-1 receptor antagonist.
sis factor-alpha messenger ribonucleic acid and protein Endocrinology 1994;134:521-8.
in human endometrium. Biol Reprod 1992;47:141-7. 60. Fakih H, Baggett B, Holtz G, Tsang KY, Lee JC, William-
43. Eisermann J, Gast MJ, Pineda J, Odem RR, Collins JL. son HO. Interleukin-1: a possible role in the infertility
Tumor necrosis factor in peritoneal fluid of women associated with endometriosis. Fertil Steril 1987;47:
undergoing laparoscopic surgery. Fertil Steril 1988; 213-7.
50:573-9. 61. Hammond MG, Oh ST, Anners J, Surrey ES, Halme J.
44. Keenan JA, Chen TT, Chadwell NL, Torry DS, Caudle The effect of growth factors on the proliferation of
MR. IL-1 beta, TNF-alpha, and IL-2 in peritoneal fluid human endometrial stromal cells in culture. Am J Obstet
and macrophage-conditioned media of women with Gynecol 1993;168:1131-6; discussion 1136-8.
endometriosis. Am J Reprod Immunol 1995;34:381-5. 62. Iwabe T, Harada T, Tsudo T, Nagano Y, Yoshida S,
45. Braun DP, Gebel H, House R, Rana N, Dmowski NP. Tanikawa M et al. Tumor necrosis factor-alpha pro-
Spontaneous and induced synthesis of cytokines by motes proliferation of endometriotic stromal cells by
peripheral blood monocytes in patients with endome- inducing interleukin-8 gene and protein expression. J
triosis. Fertil Steril 1996;65:1125-9. Clin Endocrinol Metab 2000;85:824-9.
46. Braun DP, Ding J, Dmowski WP. Peritoneal fluid-medi- 63. Zhang RJ, Wild RA, Ojago JM. Effect of tumor necrosis
ated enhancement of eutopic and ectopic endometri- factor-alpha on adhesion of human endometrial stro-
al cell proliferation is dependent on tumor necrosis mal cells to peritoneal mesothelial cells: an in vitro
factor-alpha in women with endometriosis. Fertil Ster- system. Fertil Steril 1993;59:1196-201.
il 2002;78:727-32. 64. Osteen KG, Keller NR, Feltus FA, Melner MH. Para-
47. Laird SM, Li TC, Bolton AE. The production of placen- crine regulation of matrix metalloproteinase expres-
tal protein 14 and interleukin 6 by human endometri- sion in the normal human endometrium. Gynecol
al cells in culture. Hum Reprod 1993;8:793-8. Obstet Invest 1999;48:2-13.
48. Rier SE, Parsons AK, Becker JL. Altered interleukin-6 65. Melega C, Balducci M, Bulletti C, Galassi A, Jasonni
production by peritoneal leukocytes from patients with VM, Flamigni C. Tissue factors influencing growth and
endometriosis. Fertil Steril 1994; 61:294-9. maintenance of endometriosis. Ann N Y Acad Sci 1991;
49. Tseng JF, Ryan IP, Milam TD, Murai JT, Schriock ED, 622:256-65.
Larders DN et al. Interleukin-6 secretion in vitro is up- 66. Olive DL, Montoya I, Riehl RM, Schenken RS. Macro-
regulated in ectopic and eutopic endometrial stromal phage-conditioned media enhance endometrial stromal
cells from women with endometriosis. J Clin Endo- cell proliferation in vitro. Am J Obstet Gynecol
crinol Metab 1996; 81:1118-22. 1991;164:953-8.
50. Taylor RN, Ryan IP, Moore ES, Hornung D, Shifren JL, 67. Badawy SZ, Cuenca V, Stitzel A, Jacobs RD, Tomar RH.
Tseng JF. Angiogenesis and macrophage activation in Autoimmune phenomena in infertile patients with
endometriosis. Ann N Y Acad Sci 1997;828:194-207. endometriosis. Obstet Gynecol 1984;63:271-5.
51. Lebovic DI, Mueller MD, Taylor RN. Vascular endo- 68. Murphy AA, Palinski W, Rankin S, Morales AJ, Partha-
thelial growth factor in reproductive biology. Curr Opin sarathy S. Evidence for oxidatively modified lipid-pro-
Obstet Gynecol 1999;11:255-60. tein complexes in endometrium and endometriosis.
52. D'Angelo G, Struman I, Martial J, Weiner RI. Activa- Fertil Steril 1998;69:1092-4.
tion of mitogen-activated protein kinases by vascular 69. Dunselman GA, Bouckaert PX, Evers JL. The acute-
endothelial growth factor and basic fibroblast growth phase response in endometriosis of women. J Reprod
factor in capillary endothelial cells is inhibited by the Fertil 1988;83:803-8.
antiangiogenic factor 16-kDa N-terminal fragment of 70. Wild RA, Shivers CA, Medders D. Detection of antien-
prolactin. Proc Natl Acad Sci U S A 1995;92:6374-8. dometrial antibodies in patients with endometriosis:
53. Dvorak HN, Senger DR, Dvorak AM, Harvey VS, McDo- methodological issues. Fertil Steril 1992;58:518-21.
nagh J. Regulation of extravascular coagulation by 71. Wild RA, Hirisave V, Podczaski ES, Coulam C, Shivers
microvascular permeability. Science 1985;227:1059-61. CA, Satyaswaroop PG. Autoantibodies associated with
54. Hornung D, Lebovic DI, Shifren JL, Vigne JL, Taylor RN. endometriosis: can their detection predict presence of
Vectorial secretion of vascular endothelial growth fac- the disease? Obstet Gynecol 1991;77:927-31.
tor by polarized human endometrial epithelial cells. 72. Kennedy SH, Starkey PM, Sargent IL, Hicks BR, Barlow
Fertil Steril 1998;69:909-15. DH. Antiendometrial antibodies in endometriosis meas-
55. Shifren JL, Tseng JF, Zaloudek CJ, Ryan IP, Meng YG, ured by an enzyme-linked immunosorbent assay before
Ferrara N et al. Ovarian steroid regulation of vascular and after treatment with danazol and nafarelin. Obstet
endothelial growth factor in the human endometrium: Gynecol 1990;75:914-8.
implications for angiogenesis during the menstrual 73. Halme J, Mathur S. Local autoimmunity in mild endo-
cycle and in the pathogenesis of endometriosis. J Clin metriosis. Int J Fertil 1987;32:309-11.
Endocrinol Metab 1996;81:3112-8. 74. Murphy AA, Santanam N, Morales AJ, Parthasarathy S.
56. Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle Lysophosphatidyl choline, a chemotactic factor for
M. Vascular endothelial growth factor (VEGF) in endo- monocytes/T- lymphocytes is elevated in endometrio-
metriosis. Hum Reprod 1998;13:1686-90. sis. J Clin Endocrinol Metab 1998;83:2110-3.
57. Ortiz BD, Krensky AM, Nelson PJ. Kinetics of tran- 75. Salonen JT, Yla-Herttuala S, Yamamoto R, Butler S,
scription factors regulating the RANTES chemokine Korpela H, Salonen R et al. Autoantibody against oxid-
gene reveal a developmental switch in nuclear events ised LDL and progression of carotid atherosclerosis.
during T-lymphocyte maturation. Mol Cell Biol 1996; Lancet 1992;339:883-7.
16:202-10. 76. Ho HN, Wu MY, Chen SU, Chao KH, Chen CD, Yang
58. Hornung D, Ryan IP, Chao VA, Vigne JL, Schriock ED, YS. Total antioxidant status and nitric oxide do not
Taylor RN. Immunolocalization and regulation of the increase in peritoneal fluids from women with endo-
chemokine RANTES in human endometrial and endo- metriosis. Hum Reprod 1997;12:2810-5.
12 MINERVA GINECOLOGICA Mese 2003AGGIORNAMENTO IN TEMA DI DIAGNOSI PRENATALE DI ERNIA DIAFRAMMATICA CONGENITA SPINA
77. Polak G, Koziol-Montewka M, Gogacz M, Blaszkows- 91. Pagidas K, Falcone T, Hemmings R, Miron P. Compar-
ka I, Kotarski J. Total antioxidant status of peritoneal ison of reoperation for moderate (stage III) and severe
fluid in infertile women. Eur J Obstet Gynecol Reprod (stage IV) endometriosis-related infertility with in vitro
Biol 2001;94:261-3. fertilization-embryo transfer. Fertil Steril 1996;65:791-5.
78. Ota H, Igarashi S, Tanaka T. Xanthine oxidase in eutop- 92. Harlow CR, Cahill DJ, Maile LA, Talbot WM, Mars J,
ic and ectopic endometrium in endometriosis and ade- Wardle PG et al. Reduced preovulatory granulosa cell
nomyosis. Fertil Steril 2001;75:785-90. steroidogenesis in women with endometriosis. J Clin
79. Van Langendonckt A, Casanas-Roux F, Donnez J. Oxi- Endocrinol Metab 1996;81:426-9.
dative stress and peritoneal endometriosis. Fertil Ster- 93. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of
il 2002;77:861-70. endometriosis on in vitro fertilization. Fertil Steril
80. Kamada Y, Nakatsuka M, Asagiri K, Noguchi S, Haba- 2002;77:1148-55.
ra T, Takata M et al. GnRH agonist-suppressed expres- 94. Gleicher N, el-Roeiy A, Confino E, Friberg J. Is endo-
sion of nitric oxide synthases and generation of peroxy- metriosis an autoimmune disease? Obstet Gynecol
nitrite in adenomyosis. Hum Reprod 2000;15:2512-9. 1987;70:115-22.
81. Murphy AA, Santanam N, Parthasarathy S. Endometri- 95. Muscato JJ, Haney AF, Weinberg JB. Sperm phagocy-
osis: a disease of oxidative stress? Semin Reprod Endo- tosis by human peritoneal macrophages: a possible
crinol 1998;16:263-73. cause of infertility in endometriosis. Am J Obstet
82. Murphy AA, Palinski W, Rankin S, Morales AJ, Partha- Gynecol 1982;144:503-10.
sarathy S. Macrophage scavenger receptor(s) and oxi- 96. Sharma RK, Wang Y, Falcone T, Goldberg J, Agarwal
datively modified proteins in endometriosis. Fertil Ster- A. Effect of peritoneal fluid from endometriosis
il 1998;69:1085-91. patients on sperm motion characteristics and acro-
83. Arumugam K, Dip YC. Endometriosis and infertility: the some reaction. Int J Fertil Womens Med 1999;44:31-7.
role of exogenous lipid peroxides in the peritoneal 97. Drudy L, Lewis SE, Barry-Kinsella C, Harrison RF,
fluid. Fertil Steril 1995;63:198-9. Thompson W. The influence of peritoneal fluid from
patients with minimal stage or treated endometriosis
84. Ota H, Igarashi S, Hatazawa J, Tanaka T. Immunohis- on sperm motility parameters using computer-assist-
tochemical assessment of superoxide dismutase expres- ed semen analysis. Hum Reprod 1994;9:2418-23.
sion in the endometrium in endometriosis and ade- 98. Arumugam K. Endometriosis and infertility: raised iron
nomyosis. Fertil Steril 1999;72:129-34. concentration in the peritoneal fluid and its effect on
85. Ota H, Igarashi S, Kato N, Tanaka T. Aberrant expres- the acrosome reaction. Hum Reprod 1994;9:1153-7.
sion of glutathione peroxidase in eutopic and ectopic 99. Coddington CC, Oehninger S, Cunningham DS, Han-
endometrium in endometriosis and adenomyosis. Fer- sen K, Sueldo CE, Hodgen GD. Peritoneal fluid from
til Steril 2000;74:313-8. patients with endometriosis decreases sperm bind-
86. Strathy JH, Molgaard CA, Coulam CB, Melton LJ, 3rd. ing to the zona pellucida in the hemizona assay: a pre-
Endometriosis and infertility: a laparoscopic study of liminary report. Fertil Steril 1992;57:783-6.
endometriosis among fertile and infertile women. Fer- 100. Aeby TC, Huang T, Nakayama RT. The effect of per-
til Steril 1982;38:667-72. itoneal fluid from patients with endometriosis on
87. Koninckx PR, Oosterlynck D, D'Hooghe T, Meuleman human sperm function in vitro. Am J Obstet Gynecol
C. Deeply infiltrating endometriosis is a disease where- 1996; 174:1779-83; discussion 1783-5.
as mild endometriosis could be considered a non-dis- 101. Martinez-Roman S, Balasch J, Creus M, Fabregues F,
ease. Ann N Y Acad Sci 1994;734:333-41. Carmona F, Viella R et al. Immunological factors in
88. Koninckx PR, Meuleman C, Oosterlynck D, Cornillie FJ. endometriosis-associated reproductive failure: studies
Diagnosis of deep endometriosis by clinical examina- in fertile and infertile women with and without endo-
tion during menstruation and plasma CA-125 concen- metriosis. Hum Reprod 1997;12:1794-9.
tration. Fertil Steril 1996;65:280-7. 102. Awadalla SG, Friedman CI, Haq AU, Roh SI, Chin
89. Balasch J, Vanrell JA. Mild endometriosis and luteal NW, Kim MH. Local peritoneal factors: their role in
function. Int J Fertil 1985;30:4-6. infertility associated with endometriosis. Am J Obstet
90. Arici A, Oral E, Bukulmez O, Duleba A, Olive DL, Gynecol 1987;157:1207-14.
Jones EE. The effect of endometriosis on implantation: 103. Marcoux S, Maheux R, Berube S. Laparoscopic surgery
results from the Yale University in vitro fertilization in infertile women with minimal or mild endometri-
and embryo transfer program. Fertil Steril 1996;65: osis. Canadian Collaborative Group on Endometrio-
603-7. sis. N Engl J Med 1997;337:217-22.
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