Potential Threat refers to an activation due to potential harm that is distant and uncertain or of low certainty [27]. The Generalized Unsafety Theory of Stress [28] postulates that the human stress response serves as a default mode, which can be deactivated through the perception of safety signals. The theory can explain prolonged stress responses in the absence of acute stressors.

Living with endometriosis always entails the possibility of disease progression, of the development of new symptoms, and of the worsening of persisting symptom manifestation [29]. Endometriosis patients live with potential low imminence threats, such as pain or flare-ups, and without remediate treatment, which could otherwise serve as a signal of safety. Therefore, endometriosis is often experienced as a highly uncontrollable disease [30]. Uncontrollable stress led to higher rates of endometriosis progression in rats [31]. The absence of safety signals might play a role as it could possibly lead to higher vigilance in regard to onset or worsening of symptoms. This, in turn, supports constant symptom monitoring as an additional factor for a dysregulated stress response.

Childhood stress, e.g., negligence and abuse, are considered to be risk factors for the development of endometriosis [30] [32], since these adverse events may cause persistent alterations in the neural and hormonal stress responses [34] relevant to pain severity and disease progression, such as a chronic inflammatory response and dysregulated hypothalamic–pituitary–adrenal axis (HPA axis). Individuals with diagnosed endometriosis are also more likely to be diagnosed with post-traumatic disorder compared to people without endometriosis [14]. Childhood abuse and PTSD can leave victims with the concept of the world as an unsafe place in general [33], causing further suspicion of potential threat in many situations of everyday life. 

The RDoC subconstruct of Sustained Threat describes prolonged exposure to negative experiences, either external or internal. Some patients are exposed to unpleasant states, such as chronic pain and light or heavy bleeding [35], on most days, not only during certain phases of their menstrual cycle. Chronic pain, among other symptoms, often equals chronic stress and contributes to the lasting dysregulation of the HPA axis in individuals with endometriosis [36]. This dysregulation often leads to higher levels of pro-inflammatory agents which lower the pain threshold [37] and, in turn, can cause higher subjective chronic stress [36]. Even the treatment and day-to-day management of the disease and of subfertility is possibly perceived as a sustained threat. Lazzeri et al. [38] found a link between treatment intensity and levels of perceived stress in endometriosis patients with a strong association between repeated surgery and higher self-reported measures of psychological stress. Research on other long-term effects of medical treatment on HRQoL is relatively scarce. Most studies on long-term mental health effects report an overall positive outcome of both pharmacological [39,40] and surgical treatment [41,42]. In their review, D’Alterio et al. [43] report that surgical and pharmacological treatments have comparable long-term effects on pain levels and QoL. However, the follow-up intervals in these studies were rather short (up to 18 months). This is critical, since pain recurrence after surgery can occur many months later [44,45], which might, in turn, lead to a lower QoL.

The Loss subconstruct of the negative valence systems refers to both the episodic and sustained unwanted disappearance of any object or situation that is not easy to replace. It includes loss of relationships, status, or behavioral control, and is associated with negative emotions as well as rumination and possible shifts in attention. The subjective experience of loss is the result of individual evaluation based on values and beliefs, leading to interindividual differences regarding the extent and intensity of perceived loss. Oftentimes, patients with endometriosis must deal with many kinds of loss from all areas of life: they are likely to lose predictability in everyday life [46], resulting in possible loss of income [10] as well as loss of social relationships, satisfying sex life, and hobbies due to the interference of symptoms with social and other activities [47].

Furthermore, some patients report experiencing loss of their identity as a woman because of possible struggles with fertility and not being able to meet society’s expectation of womanhood [48]. The burden through infertility becomes even higher with experienced pregnancy loss [49]. In their qualitative study, Hållstam et al. [50] summarized living with endometriosis as a constant struggle for coherence with difficulties in establishing meaning and feeling understood. Patients described feelings of loneliness and guilt, sorrow over childlessness and existential grief [50].

Rush and Misajon [51] identified loss of control as a central topic relevant to patients with endometriosis. Young patients in particular reported feelings of frustration regarding educational/job opportunities and intimate relationships [51]. The loss domain is often associated with symptoms of depression [20] that are also quite common among patients with endometriosis; patients with endometriosis show symptoms of depression more often than healthy controls [52] and are more likely to be diagnosed with major depression or other forms of depression over their lifetime [13].

The experience and intensity of chronic pain is discussed as a moderating variable for depressive symptoms [53,54], although some of the behaviors listed as typical for the Loss domain, such as worrying and being biased toward negatively valenced information, might also influence the psychological burden of living with endometriosis. In their study, Van Aken et al. [25] found that pain catastrophizing independently influences health-related quality of life (HRQoL), even when pain intensity was included in their regression model. When looking at sexual stress, negative metacognitive beliefs seem to play an even larger role. In the cross-sectional study of Zarbo et al. [55], negative metacognitive beliefs predicted sexual distress in hierarchical logistic regression, while dyspareunia and chronic pain did not. Their findings provide support for the presumption that cognitive processes, such as rumination and metacognitive beliefs, have an additional, independent effect on psychological symptom severity. Donatti et al. [56] identified a solution-oriented focus on clear-cut problems instead of catastrophizing as a successful coping strategy associated with decreased symptoms of depression. The cognitive restructuring of unhelpful thoughts was identified as another helpful coping strategy by González-Echevarría et al. [57], as it was associated with higher HRQoL. Facchin et al. [58] highlight the need for actively restoring continuity in living with endometriosis to overcome a sense of disruption and loss. Hållstam et al. [50] stress the importance of professional support and acknowledgement throughout the process of grief, so that a sense of coherence and the experience of a purpose in life can be re-established.