**3. Pathophysiology of Endometriosis Related Pain**

Pain has been defined as a "complex constellation of unpleasant sensory, emotional and cognitive experiences provoked by real or perceived tissue damage and manifested by certain autonomic, psychological, and behavioural reactions" [23]. For the perception of pain, a biochemical signal (1) is converted into a neural signal (2) (sensitization of sensory nerve fibres via activation of the nociceptors). At the spinal level, this signal is modulated (3) and referred (attenuated/amplified) to the brain, where the pain perception occurs (4). Steps one and two are called peripheral sensitization and three and four are central sensitizations [14,16].

If severe EM-associated pelvic pain remains untreated, it will recur monthly. Initially, the pain is perceived cyclically (hormonal-dependent pain) reflecting the classical nociceptive inflammatory pain. If this pain occurs repeatedly, such as monthly, the body's warning signals take effect, and it is classified as threatening. At this point, the modulation at the spinal level does not regulate it down but rather increases it (hormonal-independent pain). The release of neurotransmitters is altered and several modulating mechanisms are set in motion: the nociceptive field is expanded and EM symptoms such as dysuria and dyschezia may occur [24].

Increasing pain frightens the person experiencing it and makes pain processing more difficult. Severe cramps, accompanied by vegetative reactions, lead the patient to adopt a pain-relieving posture. However, this leads to a reflex contraction of the pelvic floor muscles and eventually to pelvic floor dysfunction. This increases the experienced pain and is known to lead to dyspareunia [25]. Fear of pain during intercourse can strongly influence the ability to relax and the disorder manifests itself. Changes at the central level develop and the patients have an increased risk of developing complex chronic pain syndromes with bladder dysfunction, irritable bowel syndrome, and vulvodynia [24]. This explains the often severe pain that accompanies patients, even in the absence of pathological findings.
