Although pain is a central feature of endometriosis, the patterns of pain are also highly variable in their presentation, severity, duration, cyclicity, associated features, response to treatment and likelihood of recurrence. Many endometriosis sufferers also exhibit hyperalgesia and allodynia, pointing to a lowered threshold for the central perception of pain.
Endometriosis is a condition of remarkable variability (see Table 1), which may present in many different ways. Hence, diagnosis is often greatly delayed.
There is increasing evidence that endometriosis is essentially an ‘endometrial disease’, with a strong familial component and less well-understood environmental and reproductive influences. Basic functions of the ‘eutopic’ endometrium (this is uterine endometrium in women with endometriosis in contrast to the ‘ectopic’ endometriotic tissue) that are disturbed in women with endometriosis, when compared with women without endometriosis, include increased aromatase enzyme activity (ability to make its own local oestrogen), increased angiogenesis (ability to grow new blood vessels), increased neurogenesis (ability to attract nerve fibres to grow in), increased cell adhesion molecules, increased proliferative activity and decreased apoptosis (accentuated viability of tissue fragments shed at menstruation) and greatly modified leukocyte presence and function (also apparently geared to support viability of shed tissue fragments). These disturbances all seem to point to exaggerated survival of cellular fragments shed at menstruation, with enhanced potential for adherence to peritoneum and subsequent growth.
Table 1. Endometriosis is a highly variable condition.
|1||In its manner of presentation.|
|2||In age of symptom onset – frequently in adolescence.|
|3||In delay to diagnosis – especially in adolescence.|
|4||In the types of symptoms experienced – usually much more complex than just pain: infertility, menstrual bleeding patterns, exaggerated and painful abdominal bloating, other gastrointestinal symptoms, urinary symptoms, extreme lethargy.|
|5||In anatomical sites of ectopic lesions – are there different ‘phenotypes’ of endometriosis (peritoneal, ovarian endometriomas, deep invasive lesions) or are they variants of the same disease process?|
|6||In response to medical or surgical treatment.|
|7||In likelihood of early recurrence of disease.|
|8||In ‘natural’ history of the disease progress over years.|
Our research group was surprised to be able to demonstrate the presence of numerous nerve fibres in eutopic endometrium (and increased in myometrium), when the endometrium is a tissue that is not normally innervated. These nerve fibres are accompanied by a greatly enhanced presence of nerve growth factor (NGF) and its receptor, and by other neurotrophins. NGF is a stimulator of pain sensation. The nerve fibres included sensory, sympathetic and parasympathetic axons and we found similar presence and density of these nerve fibres in the ectopic lesions. They were particularly frequent around deep invasive lesions close to or involving the rectum, which broadly correlates with the fact that these deep invasive lesions are among the most painful and tender of all endometriotic lesions. We have managed to identify, with considerable difficulty, a small number of women who have no pain symptoms whatsoever. Most women who are said to have no pain have just not complained and have learned to live with it. These women also have an extensive network of nerve fibres in the endometrium, myometrium and in lesions. The eutopic endometrium and ectopic lesions exhibit very disturbed leukocyte numbers and function – macrophages, uterine natural killer cells, dendritic cells and regulatory T cells appear to be particularly disturbed. There is a substantial ‘inflammatory’ component to the pathophysiology of endometriosis. Key factors involved in pain generation and perception are listed in Table 2.
Table 2. Postulated factors and mechanisms influencing pain generation and perception.
|1||The uterus (especially endometrium) is much more densely innervated than the normal pelvis, including sensory, sympathetic and parasympathetic nerve fibres.|
|2||Endometriotic lesions also have a dense nerve supply.|
|3||Endometriosis is an inflammatory condition with disturbances of numbers and function of most leukocytes.|
|4||Nerve growth factor (NGF) is intensely expressed in eutopic endometrium (endometrium of endometriosis sufferers) and in lesions. NGF is a potent sensitiser of pain fibres.|
|5||Many leukocytes present in eutopic endometrium and lesions synthesise and secrete nerve growth factor.|
|6||Prostaglandin metabolism is disturbed in eutopic endometrium and in lesions and some prostaglandins are potent stimulators of pain. Other inflammatory mediators may play a role.|
|7||Recent evidence suggests that many women with endometriosis have reduced thresholds for the perception of pain stimuli.|
|8||Some women with persistent pain following previous surgery have features suggestive of neuropathic pain.|
Management of the pelvic pains of endometriosis
Effective management of pain requires definition of the symptoms experienced, characterisation of the anatomical extent of lesions and exploration of the patient’s lifestyle – and fertility wishes. Hence, individualisation of the therapeutic approach is becoming increasingly important. Nowadays, many patients are well informed of the options, especially from the internet.
Approaches to management are simple in principle, but broad and complex in practice. For a comprehensive discussion the reader is referred to the documents listed under ‘further reading’. In principle, the focus remains directed to four overlapping approaches: good analgesic advice, medical management, surgical excision and sound information in regards to lifestyle management.
Analgesia begins with the traditional non-steroidal agents and paracetamol in effective doses, moving on to stronger agents such as tramadol, oxycodone and even occasional pethidine or morphine. Chronic pain with a neuropathic component may respond to gabapentin.
Medical therapy is based primarily on hormonal suppression. It does not make logical sense to treat women who have an oestrogen-sensitive disease with the combined pill, but it does work well for a minority of endometriosis sufferers. Most research points to the fact that progestogen-alone therapy is much more effective and may be continued over many years. There is a strong move towards the use of the delivery systems such as the levonorgestrel intrauterine system and the subdermal etonogestrel implant. We have been using a combination of these two systems with great effect in particularly resistant pain cases for the past five years. The place of therapies like gonadotrophin releasing-hormone analogues and danazol is decreasing.
The approaches to surgical excision of endometriosis have improved greatly in recent years and it is clear these procedures should generally be carried out by advanced laparoscopic surgeons with special experience in endometriosis. The best opportunity for complete excision is at the very first laparoscopy, but even then the recurrence rates are substantially higher than is generally recognised. Many patients will benefit from continuous progestogen therapy following surgery, in order to minimise recurrence.
There is a widespread awareness that many cases of endometriosis merit management in specialised clinics with availability of pain specialists, psychologists, reproductive endocrinologists, in addition to the gynaecologist and the gynaecological laparoscopic surgeon. Early diagnosis, awareness of the variability and individualisation of the therapies are keystones of effective management.
Many women in the community are now aware of ‘endo’ and are asking searching questions about management. This disease and its multiplicity of pain symptoms is going to remain as one of our biggest challenges for years to come.
- Al-Jefout M, Tokushige N, Hey-Cunningham AJ, Manconi F, Ng C, Schulke L, Berbic M, Markham R, Fraser IS. Microanatomy and function of the eutopic endometrium in women with endometriosis. Expert Reviews in Obstetrics and Gynecology 2009; 4: 61-79.
- Fraser IS. Recognising, understanding and managing endometriosis. Medicine Today 2008; 9: 31-41.
- Brosens I (editor). Endometriosis. Best Practice and Research in Clinical Obstetrics and Gynaecology 2004; 18:175-371.
- Guidelines on the Treatment of Endometriosis. European Society for Human Reproduction and Embryology (http://www.guidelines.endometriosis.org).