1 Introduction
Endometriosis is a chronic disease characterized by the presence of endometrium-like tissue outside the uterine cavity, affecting women of reproductive age with pelvic pain and infertility [
1]. The prevalence ranges between 2 and 10% of women in reproductive age, 30–50% among infertile women, and 5 to 21% among women with severe pelvic pain [
2]. However, the true prevalence is uncertain, because estimates vary widely among population samples and diagnostic approaches [
3].
The pathophysiology of endometriosis is still a matter of investigation, but endocrine and inflammatory backgrounds are well characterized, recognizing an estrogen-dependency [
4] and a progesterone-resistance [
5]. The main mechanisms involved in the ectopic location of endometrial cells include retrograde menstruation, vascular and lymphatic spread and/or metaplasia/stem cells. The most accepted theory is the retrograde menstruation, according to which menstrual endometrial fragments migrate through the fallopian tubes to the peritoneal cavity, where they implant, proliferate and invade pelvic peritoneum. The back flow of endometrial cells into the pelvis is physiologic, resulting apoptosis/autophagy and cell-mediated immunity the scavenger system for eliminating these cells, while in endometriotic patients hormonal influences and genetic/epigenetic factors determine an impairment of these mechanisms, promoting cell survival, proliferation and peritoneal invasion. [
6]. Increased estrogen receptors activity, estrogen production in endometriotic lesions and progesterone-resistance are the determinants of impaired apoptosis, reduced immune function and increased inflammation [
7‐
9]. Thus, endometriotic cells attach, penetrate and invade the peritoneum, determining growth of lesions which undergo cyclic bleeding with repeated tissue injury and repair [
10], neoangiogenesis [
11] and neurogenesis [
12]. Fibroblast–myofibroblast transdifferentiation contributes to collagen production and fibrogenesis [
13], with entrapment of nerve fibers which, associated with chronic inflammation, explain pain symptoms.
According to the location of the lesions three phenotypes of endometriosis are recognized: ovarian endometriomas (OMA) (the most common, characterized by typical chocolate cysts) superficial peritoneal endometriosis (SUP) and deep infiltrating endometriosis (DIE) (the most severe forms developing deeper than 5 mm under the peritoneal surface also infiltrating the muscularis propria of bladder or bowel) [
1]. In addition, extraperitoneal locations are described, i.e. pleura, diaphragm or umbilicus [
14] and 30% of cases endometriosis are associated to adenomyosis (infiltration by endometrial stroma and glands into the myometrium) [
15,
16].
The most common symptoms of endometriosis are menstruation-related pain, i.e. dysmenorrhea, dyspareunia, dysuria and dyschezia, and noncyclic pelvic pain may also occurs in these patients. Since these symptoms are not specific to endometriosis and may be signs of other gynecological or non-gynecological conditions, misdiagnosis or a significant delay in endometriosis identification is frequently reported [
17].
Painful symptoms and infertility are also associated with psychological stress, low self-esteem, and depression impairing physical, mental, and social well-being [
18] and reducing quality of life (QoL) [
19]. Therefore, these patients, other than hypothalamus-pituitary-ovary axis (HPO) changes, show also an impairment of hypothalamus–pituitary–adrenal axis (HPA) and thyroid function, and comorbidities associated with inflammation and immune dysfunction.
In the last two decades an increased diagnosis/incidence of endometriosis has been observed and its chronic and progressive nature determines a relevant impact in a lifelong perspective among these patients. In the past, surgery was considered the definitive treatment, but recent evidences showed that it does not solve the pathogenetic mechanisms and patients need a long-term management. Treatment goals are pain control and fertility improvement maximizing the use of medical treatment, but also postsurgical prevention of symptoms and lesions recurrence, in order to avoid repeated surgical procedures [
20,
21]. In fact, surgery in women with endometriosis is associated with the risk of urological, intestinal, vascular and neurological complications and pain may recur or persist in case of incomplete excision of endometriosis lesions [
22,
23]. Presently, the medical therapy is considered the first-line treatment for most of women with endometriosis to improve their symptoms, but also to plan the most adequate timing of surgery or assisted reproductive technologies (ART) treatment, or to prevent post-surgical disease recurrence [
1,
24,
25]. The choice of the most appropriate therapy is based on the intensity of pain, age, desire to conceive, but also on the impact of the disease on QoL on each patient [
26].
Currently, hormonal treatments are the most effective drugs for the treatment of endometriosis and are based on the pathogenic mechanisms involved in the disease. The goal is to stop cyclic menstruation: by blocking ovarian estrogen secretion or by causing a pseudopregnancy state [
21]. The endocrine background provides the rationale for the current and future hormonal drugs for treating women with endometriosis.
4 Clinical implications: pain, infertility and systemic comorbidities in endometriosis
Endometriosis is a heterogeneous disease also in terms of clinical presentation. Common symptoms include dysmenorrhea and non-menstrual pelvic pain, which may develop into chronic pelvic pain [
17]. with a relevant impact on daily life [
120]. Other endometriosis-related pain are dyspareunia, dyschezia, and dysuria, usually associated with DIE lesions [
121,
122]. According to the anatomical involvement of bowel, patients may alternate constipation and diarrhea, dischezia or blood in the stool (in particular perimenstrually) [
122,
123] or when urinary tract is affected, recurrent dysuria, cyclic macrohaematuria or interstitial cystitis are observed [
124]. Chest and shoulder pain should be considered suspecting diaphragmatic endometriosis [
125], whereas endometriosis in the ileo-caecal or peri-appendiceal region has been significantly associated to abdominal pain, nausea, vomiting and diarrhea [
126,
127].
Regarding the physiopathology of endometriosis-related pain, nociceptive (including inflammatory), neuropathic and a combination of these mechanisms are involved [
128], under the influence of hormonal aberrations, stress, inflammation, and the interplay between the peripheral and central nervous systems [
129‐
131]. Neurogenic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are reported to be overexpressed in the peritoneal fluid and in endometriotic lesions of affected women [
132]. Neurotrophic factors are also responsive to estrogens, prostaglandin and cytokine and stimulate the growth and sensitization of sensory nerve fiber terminals [
133,
134], particularly in DIE, presenting high nerve fibers density [
135]. The development of a vicious cycle characterized by nociceptor sensitization and local neo-neurogenesis, triggered by inflammatory and immune mediators, is observed in endometriosis [
136]. Endometriotic lesions themselves send noxious signals to dorsal root spinal cord neurons and activate spinal microglia to maintain pain stimuli, resulting in a central sensitization [
137]. In fact, a number of central changes are observed: alterations in the behavioral and central response to noxious stimulation, changes in brain structure, altered activity of both the HPA and the autonomic nervous system and psychological distress [
131], with larger volume in regions involved in pain modulation and endocrine function regulation [
137‐
139]. Indeed, chronic pain and stress experienced by patients with endometriosis might cause multiple psychiatric diseases (Fig.
3) and the somatoform disorder is the most common [
140]. Anxiety and depression traits, and a higher tendency of pain catastrophizing are commonly present in endometriosis patients and can amplify the perception of pain [
141,
142]. Another frequently present, but often neglected, symptom in women with endometriosis is chronic fatigue, although the exact mechanism remains not fully understood [
143].
Women with endometriosis show a higher prevalence of systemic comorbidities has been shown, even though it is still unclear whether a common endocrine, immune and inflammatory background predispose to the development of those conditions or a high levels of perceived stress [
144,
145]. An increased risk of inflammatory bowel diseases (Chron’s disease, ulcerative colitis) [
146] allergic manifestations [sinus allergic rhinitis, and food allergy) [
147], autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, multiple sclerosis, fibromyalgia) are more likely to be diagnosed in women with endometriosis, also underlying a neuroendocrine–immune imbalance [
148‐
153].
Infertility is the other major symptom of endometriosis, even though a diagnosis of endometriosis does not always imply infertility. Endometriosis is identified in approximately 30% of women in infertile couples [
154]. The disease adversely affects fertility by different mechanisms acting at the level of pelvic cavity, ovary and uterus [
155]. Pelvic cavity is an hostile environment because the chronic inflammatory changes in the peritoneal fluid and the distortion of normal anatomy of the fallopian tubes hindering tubo-ovarian contact and affecting sperm-oocyte interaction; ovary produces low quality oocytes, impaired folliculogenesis, and luteal function, with ovarian reserve reduced by OMA and/or by surgery. Besides, in endometriosis uterus itself has an altered endometrial receptivity mainly due to local growth factors changes (integrin, LIF, activin, CRH), to hormonal aberrations (ER and PR) [
9] and to dysperistalsis of myometrium, due to the association to adenomyosis [
156,
157]. However, the evidences supporting the impairment of endometrial receptivity in endometriosis are still controversial. The endometrial chronic inflammation, together with progesterone resistance, estrogen dominance, aberrant cell signaling pathways and reduced expression of key homeostatic proteins in women with endometriosis, are disruptive to endometrial receptivity [
158]. On the contrary, data from
in vitro fertilization (IVF) and egg donations, other than basic data regarding the transcriptomic signature of the endometrium, seem to indicate that endometrial receptivity gene signature during the window of implantation is similar between infertile women with and without endometriosis, suggesting a major effected played by embryo and oocyte quality more than to the endometrial factor itself [
159].
6 Conclusions
Endometriosis is a chronic disease requiring a lifelong management. Based on patient’s symptoms and the desire of pregnancy, an individualized approach aiming to reduce pain, stress, stress-related comorbidities and to improve QoL should be used for an adequate management [
1,
21,
25]. Until a few years ago, the suspect of endometriosis represented an indication for surgery, also used to make the diagnosis through the visualization and histology confirmation of endometriotic lesions. Research development has shown a clear endocrine pathogenesis for endometriosis and thus hormonal therapies represent now a cornerstone of its management, as first choice, before surgery and after surgery in order to reduce the risk of recurrence. The goal is to limit non-indicated surgical procedures because of disease recurrence risk, surgical complications [
22,
23,
278], and negative effects on ovarian reserve [
279]. The modern approach for endometriosis requires a life-long management plan with the aim of maximizing the use of medical treatment, that can be safely prescribed without histological confirmation of the disease [
182,
280‐
282], and avoiding repeated surgical procedures [
20]. Medical hormonal treatment should be the first-line therapeutic option also for patients who have not an immediate desire to become pregnant. Currently, hormonal treatments are the most effective drugs for the treatment of endometriosis and are based on the pathogenic mechanisms involved in the disease. The block of menstruation through an inhibition of HPO axis and consequent amenorrhea or pseudodecidualisation impairs the development or the activity of endometriotic implants. A modern endometriosis management includes a patient-focused approach taking care of overall wellbeing, considering stress, QoL and systemic comorbidities.
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