Introduction

Endometriosis is a chronic gynecological disorder, defined by the presence of endometrial-like tissue outside the uterine cavity [1]. The prevalence of the disease can reach about 10% of reproductive-age women [2, 3], leading to negative physical and psychological impact in patient’s lives [4, 5]. The pathogenesis involves several hormonal, inflammatory, genetic, and epigenetic mechanisms, which may play a role in the establishment and progression of endometriotic lesions and their clinical manifestations [6, 7]. A number of possible endometriosis risk factors have been described by epidemiologic studies, though a real cause-effect association is barely established [8].

Stress is defined as a threat or an anticipation of a threat to an organism’s homeostasis and can be understood as any stimulus, either psychological or physical, capable to promote an unbalance in the body’s environment [9]. The physiological stress response is a quite complex process and involves several metabolic and neurobiological changes, with peripheral and central repercussion. Whenever an acute stressful stimulus occurs, an adaptive response is triggered through the activation of two coordinated brain systems: the sympathetic nervous system (SNS) and the hypothalamus-pituitary-adrenal (HPA) axis. At first, the SNS, by releasing catecholamines, promotes an increase in the systemic inflammatory activity. The HPA axis, in its turn, stimulates glucocorticoid production, which is responsible for counterbalancing the excessive inflammatory response. Both pathways contribute to enhance blood glucose levels, which provides the necessary energy to cope with the stressor [9,10,11,12,13,14].

The characteristics of the stressful stimulus, such as its duration and intensity, and how it is individually perceived, can drastically alter the stress response. For instance, an acute stressor often stimulates the occurrence of a beneficial adaptive response. Conversely, if the same stressor becomes chronic, it can generate an extended catabolic process, predisposing to cumulative damage of cells and organs targeted by the stress hormones, with health consequences such as metabolic and gastrointestinal diseases, hypertension, and immune-inflammatory disorders [14,15,16,17].

In the last years, a number of studies have demonstrated a possible link between high levels of chronic stress and endometriosis. So far, clinical evidence shows that patients with endometriosis report higher levels of perceived stress, anxiety, and depression than healthy women [18, 19]. Stress intensity is positively correlated to the severity of the disease, pain intensity, and emotion regulation, [20,21,22] and the adoption of coping strategies seems to improve the adaptation to stress [23, 24]. Moreover, experimental studies have shown that previous exposure to repeated and excessive stress accelerates the development and increases the severity of endometriosis in rats [25, 26]. However, it is still debatable whether any cause-effect link really exists and which mechanisms explain this relationship.

Both endometriosis and stress are challenging disorders that must be better investigated, individually and together. The present review aims to address the latest evidence regarding the correlation between these two conditions and discuss a putative bidirectional aspect of such association.

Is Endometriosis a Cause of Stress?

Endometriosis has two cardinal symptoms: pelvic pain and infertility [27]. Both symptoms per se are capable of evoking a chronic stress response, but their consequences can also be remarkably stressful, giving rise to a vicious cycle. For instance, infertility provokes family demands and fear of frustrating social expectations [28, 29], whereas pelvic pain causes sexual dysfunction and work absenteeism [30], which all may contribute to generate more anxiety and chronic stress. Endometriosis is also surrounded by uncertainty about the disease progression, the success of treatments, the long-term health risks, and the reproductive future, which can be additional sources of stress [31,32,33]. Furthermore, women with endometriosis experience a delay of 4 to 7 years from first presentation of symptoms to the diagnosis [34, 35], which may further enhance the levels of stress perceived by the patient (Fig. 1).

Fig. 1
figure 1

The possible bidirectional cause-effect relation between endometriosis and chronic stress. The figure shows some physical symptoms and social consequences of endometriosis that might induce prolonged stress, and some mechanisms triggered by chronic stress that could boost endometriosis. The arrows highlight the vicious cycle resulting from the association between endometriosis and chronic stress

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Objectively assessing the levels of stress that a person is submitted to is not simple, and the two main strategies that have been used in order to reach this purpose are questionnaires and biomarkers. The first ones can evaluate the frequency and intensity of stress symptoms and the amount of psychological stress perceived. The perceived stress scale (PSS), for example, is a validated psychometric instrument that quantifies the frequency of stressful situations in the last month, in particular those characterized by loss of control, unpredictability, and overload. The stress levels measured by PSS can be high or very high in more than 70% of women with endometriosis [21]. The stress intensity is the highest among women with the most severe disease forms [21] and who have been submitted to multiple surgeries [20]. Stress intensity is higher in women with severe pelvic pain and lower in those who adopt good coping strategies [23, 24]. The application of a therapeutic protocol involving physical and psychological therapy on women with endometriosis and chronic pelvic pain was effective in reducing perceived stress, increasing vitality, and improving physical functioning [36].

An indirect measure of stress level is the health-related quality of life (QoL) [5] evaluated by using different tools, including the Short Form Health Survey (SF-36 or SF-12, a 36- or 12-item questionnaire which investigates both physical and mental components of health-related QoL) or those specific for endometriosis, such as the Endometriosis Health Profile [37]. Endometriosis has a significantly negative impact on health-related QoL scores, and the factors involved are mainly linked to pain symptoms [38]. A recent study by Marki et al. reported that both physical pain symptoms and emotional regulation difficulties, the latter being mediated by psychological stress, had a negative impact on health-related QoL of women with endometriosis [22]. In addition, other factors contribute to the psychological health and stress perception of women with endometriosis, such as self-esteem, body esteem, and emotional self-efficacy [39].

The second way to assess the levels of stress is by measuring the products of the stress response cascade. Among the stress biomarkers usually assessed in clinical studies, the most characteristic one is cortisol. In fact, a prolonged and intense stress stimulus may disrupt the HPA axis and alter the normal pattern of cortisol release. Interestingly, the deregulation of the HPA axis can culminate in either an over response (i.e., hypercortisolism) or a paradoxical phenomenon of adrenal fatigue leading to hypocortisolism [15, 17]. In fact, incongruent patterns of cortisol alterations have been observed in women with endometriosis.

Higher hair cortisol levels were found in patients with endometriosis than in healthy women of similar age, parity, education level, and body mass index (BMI) [40]. Similarly, increased serum cortisol levels were detected in infertile women with endometriosis compared to fertile healthy women, and the highest levels were found in those with advanced stage endometriosis [41]. Interestingly, physical and psychological interventions have been shown to normalize salivary cortisol levels of women with endometriosis and chronic pain [36]. On the other hand, some studies have observed the opposite trend [42, 43]. Petrelluzi et al. showed that patients with endometriosis and chronic pelvic pain had low concentrations of salivary cortisol, measured in three samples collected 8 h apart, and a high level of perceived stress, associated with a poor quality of life [42]. Quinones et al. observed among patients with endometriosis an association between salivary hypocortisolism and infertility and dyspareunia, but not dysmenorrhea [43].

The use of cortisol as a stress biomarker has some limitations. The normal release of this glucocorticoid obeys circadian and ultradian pulsatile rhythms, with a wide variation in pulse frequency and amplitude, and can be influenced by external factors. Such variability renders difficult the long-term analysis of cortisol concentrations and the differentiation between acute and chronic stress by using plasma, urine or saliva samples. Cortisol concentration in the scalp hair, in its turn, provides an average measure of free cortisol levels over a period of time, [44] and hence it seems to be more appropriate for measuring chronic stress [10, 40].

Another marker of chronic stress is salivary alpha-amylase, which reflects the adrenergic axis of the stress response [45, 46], but we are not aware of any study on salivary alpha-amylase levels in women with endometriosis. Serum levels of acute stress hormones, such as prolactin and urocortin-1, are elevated in women with endometriosis [47, 48], but no relationship with pain intensity or level of stress response has been evaluated so far in such patients.

Altogether, the available evidence from clinical studies clearly indicates that endometriosis is a condition associated with high levels of stress. Although it is possible to induce from data available that the disease may cause chronic physical and psychological stress, most studies were cross-sectional and thus had no possibility to demonstrate a temporal relationship between the stress response and the evolution of endometriosis. However, the evidence that the stress intensity assessed by PSS decreased 1 month after the surgical treatment of moderate-to-severe endometriosis suggests that treating the disease contributed to reduce the stress levels of the patients [21].

Does Stress Affect the Course of Endometriosis?

The second vector of the equation endometriosis-stress is the possibility that the stress response affects the evolution of endometriosis. Investigating this cause-effect relation is not an easy task because it would require leaving symptomatic patients without treatment. Current diagnostic methods do not provide any screening test for initial endometriosis and therefore render virtually impossible to investigate in humans whether stress is a risk factor for the establishment of endometriotic implants. Despite the lack of any clinical trial that evaluated a direct effect of chronic stress on the onset, progression, and invasiveness of endometriotic lesions, recent studies allow us to hypothesize that such relation might exist.

A retrospective case-control study [49] showed that mothers of women with endometriosis were significantly more likely to have smoked during the patient’s gestation, increasing the risk of antenatal hypoxemia. In addition, those affected reported more frequently perinatal complications during their gestation, such as prematurity, lower birth weight, and preeclampsia [49,50,51]. We therefore hypothesize that the intrauterine and neonatal exposure to prolonged physical stress stimuli could be linked to the future development of endometriosis. In our opinion, the intrinsic mechanisms involved in this process might be diverse from those implicated in adulthood. While in adults the chronic stress response might directly enhance the progression of endometriotic lesions, early in life the remodeling of neurobiological systems responsible for the stress response [11] might induce epigenetic factors predisposing the future onset of the disease.

If chronic stressful events in the perinatal period may increase the risk of endometriosis in the future, we should next consider the same hypothesis regarding stressful events in childhood. In effect, negligence and abuse during childhood may evoke persistent changes in neural and neuroendocrine systems and consequently hyperactivity of the HPA axis. The combination of precocious exposure to adversity and the presence of a genetic predisposition to anxious personality could produce a personal tendency to have exacerbated stress responses to external stimuli [17, 52]. Recently, a prospective cohort study showed that the risk of endometriosis was greater among women with history of severe physical abuse or severe sexual abuse when compared with those not reporting any previous maltreatment. In particular, the risk of laparoscopically confirmed endometriosis increases up to 79% for women reporting severe-chronic abuse of multiple types [53]. Similarly, results from a case-control study showed that childhood sexual abuse, emotional abuse/neglect, and inconsistency experiences were associated with the diagnosis of endometriosis, suggesting the importance of early stress exposure [54].

Furthermore, small body size/low BMI in childhood and adolescence has been linked on one side with chronic stress [55] and on the other side with the risk of endometriosis [56, 57]. In fact, endometriosis was reported to be more common among women who were leaner at 8 years, at menarche, and at 20–25 years [58]. The body size during childhood seems to be so important that those who were the smallest size between 5 and 10 years have an 18% increased risk to develop endometriosis later in life [57]. In addition, an inverse correlation has been shown between BMI during early adulthood and endometriosis development: young women who were underweight had a relative risk of 1.31 to be affected by the disease [56]. Moreover, patients with the lowest BMI (< 18.5) had the highest risk to develop more severe phenotypes, such as deep infiltrating endometriosis [59].

Nevertheless, the association between low BMI and endometriosis remains unexplained (Fig. 2). An enhanced activity of HPA axis has been demonstrated in patients with anorexia nervosa and in high-performance athletes, inducing a condition of chronic stress [55]. Strenuous physical activity has been reported to increase by 16% the risk of endometriosis [60], while leisure activity seems to decrease this risk to some extent [61]. Thus, stress stimuli, linked to dietary restriction or high intensity physical activity, seem to facilitate endometriosis development. Experimentally, Goetz et al. have demonstrated in mice that endometriosis induces weight loss by disrupting hepatic metabolism [62]. They showed a higher expression of four genes related to an anorexigenic effect and a reduced expression of two genes associated with obesity and metabolic disease in mice with induced endometriosis [62]. Surprisingly, caloric restriction promotes autophagy and blocks the lesion growth in this animal model [63].

Fig. 2
figure 2

Weight loss is associated with stress (in certain clinical conditions) and with endometriosis onset (in animal model). However, the association between low body fat and endometriosis remains unexplained. The known reproductive consequences of weight loss (framed in red) are theoretically protective against endometriosis, but, paradoxically, epidemiological data link low body fat to increased endometriosis risk

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A number of inflammatory and immune-related conditions have been linked to high levels of perceived stress, while the occurrence of early stressful events and many of them seem to be related to endometriosis as well [52, 64, 65]. A Danish nationwide cohort study showed that women with endometriosis have an increased risk of inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, even 20 years after diagnosis [66]. Women with endometriosis have also high risk to develop allergic manifestations, such as hay fever, sinus allergic rhinitis, and food allergy [67]. Furthermore, autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, multiple sclerosis, fibromyalgia, and chronic fatigue syndrome, are more likely to be diagnosed in women with endometriosis [68,69,70,71].

Distress and pain symptoms have a negative impact on each other, leading to the so-called sickness response, associated with a vicious cycle caused by the underlying neuroendocrine–immune imbalance [16, 72]. Chronic fatigue syndrome, fibromyalgia, asthma, and rheumatoid arthritis have been associated with hypocortisolism, probably due to receptor resistance mechanisms [73]. Other chronic pelvic pain syndromes such as inflammatory bowel disease and interstitial cystitis seem to cause a hyperactivity of the HPA axis, despite the limited data available [52, 74, 75]. Enhanced cortisol levels have been described, as well, in syndromic mood and anxiety disorders [76].

The chronic pain experienced by patients with endometriosis and other chronic pain disorders might have a psychosomatic component, beyond physical and biomolecular causes. In fact, although endometriosis severity does not correlate with pelvic pain intensity, stress probably does [77, 78]. According to a recent cross-sectional study, more than half of interviewed women with endometriosis resulted positive to mental health disorders as assessed by the Patient Health Questionnaire, whose results strongly correlated with pain severity: women with severe pain had multiple psychiatric diseases, and the somatoform disorder was the most common [19]. Furthermore, anxiety and depression traits and a higher tendency of pain catastrophizing are commonly present in endometriosis patients and can amplify the perception of pain [77, 79, 80]. It is possible that such relationship could lead to the above cited “sickness response,” contributing to the evolution of the disease.

Studies using animal models of endometriosis have also been used to shed light onto the possible effect of stress in the course of endometriosis. Female rats exposed to the stress model of forced swimming during 10 days, and a control group without stress were subsequently grafted with autologous uterine fragments to induce peritoneal endometriosis [25]. Compared to the non-stressed group, the rats that had been previously exposed to swimming stress developed larger and more numerous endometriotic lesions [25]. When applied 2 weeks after the induction of endometriosis, swimming stress also accelerated the growth of endometriotic implants and mast cell infiltration in the implant area, besides increasing the expression of nerve growth factor in the remaining uterine horn [26]. Moreover, when the animal was given the possibility of “controlling” the swimming stress by floating on a platform, the endometriosis lesions evolved similarly to those of non-stressed controls [81]. This suggests that the level of stress controllability appears to modulate the behavior and pathophysiology of endometriosis, offering evidence for potential therapeutic interventions.

Another series of experiments by Guo and coworkers tested the effects of psychological stressors on the development of endometriosis in mouse model. Exposure to a predator outside the mouse’s cage for 24 h every other day for 2 weeks after inducing endometriosis caused a worsening in the evolution of the disease, characterized by faster lesion growth, macrophage infiltration, and increased angiogenesis [82]. Immobilization stress, either before or after endometriosis induction, was able to boost lesion growth and local angiogenesis, an effect that was prevented by treatment with propranolol, indicating that beta-adrenergic input to the endometriotic lesions was involved in the deleterious effects of the stress [83]. Another study on psychological stress and pain perception in mouse model of endometriosis showed that animals subjected to water avoidance stress for 7 days developed more severe symptoms, but interestingly stress reversed the allodynic effect caused by endometriosis, maybe due to the stress-induced analgesia phenomenon [84].

Conclusions

Women with endometriosis have increased stress, as indicated by psychological and endocrine stress measures, and the stress intensity correlates with pain severity and disease extension. On the other hand, chronic stress may represent a primary cause of endometriosis, and, therefore, avoiding or treating chronic stress might potentially reduce the risk of developing endometriosis. Furthermore, perinatal and childhood stress should be considered as risk factors for endometriosis. However, many questions remain to be addressed, in order to clarify the causal link between endometriosis and stress and to assess whether stress-reducing therapies are effective to mitigate symptoms and/or slow down the development of endometriotic lesions.