The effect of pregnancy on endometriosis—facts or fiction?

It has become increasingly apparent that women suffer a disproportionate amount of pain during their lifetime compared to men. Over the past 15 years, a growing number of studies have suggested a variety of causes for this sex difference, from cellular to psychosocial levels of analysis. From a biological perspective, sexual differentiation of pain appears to occur similarly to sexual differentiation of other phenomena: it results in large part from organizational and activational effects of gonadal steroid hormones. The focus of this review is the activational effects of a single group of ovarian hormones, the estrogens, on pain in humans and animals. The effects of estrogens (estradiol being the most commonly examined) on experimentally induced acute pain vs. clinical pain are summarized. For clinical pain, the review is limited to a few syndromes for which there is considerable evidence for estrogenic involvement: migraine, temporomandibular disorder (TMD) and arthritis. Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain. Forging a more complete understanding of the myriad ways that estrogens can ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men.

Although the histologic diagnosis of endometriosis is usually straightforward, many diagnostic problems can arise as a result of alterations or absence of its glandular or stromal components. The diagnostic difficulty in such cases can be compounded by tissue that is limited to a small biopsy specimen. The appearance of the glandular component can be altered by hormonal and metaplastic changes, as well as cytologic atypia and hyperplasia. Although the last 2 findings are often referred to collectively as "atypical endometriosis," they should be separately recognized as their premalignant potential likely differs. In some cases, the endometriotic glands are sparse or even absent (stromal endometriosis). The stromal component can be obscured or effaced by infiltrates of foamy and pigmented histiocytes, fibrosis, elastosis, smooth muscle metaplasia, myxoid change, and decidual change. Occasional findings in endometriosis that may raise concern for a neoplasm include necrotic pseudoxanthomatous nodules, polypoid growth (polypoid endometriosis), bulky disease, and venous, lymphatic, or perineural invasion. Inflammatory and reactive changes within, adjacent to, or at a distance from foci of endometriosis can complicate the histologic findings and include infection within endometriotic cysts, pseudoxanthomatous salpingitis, florid mesothelial hyperplasia, peritoneal inclusion cysts, and Liesegang rings. The histologic diagnosis of endometriosis can also be challenging when it involves an unusual or unexpected site. Five such site-specific problematic areas considered are endometriosis on or near the ovarian surface, superficial cervical endometriosis, vaginal endometriosis, tubal endometriosis, and intestinal endometriosis, including the important distinction of an endometrioid carcinoma arising from colonic endometriosis from a primary colonic adenocarcinoma. Finally, endometriotic foci can occasionally be intimately admixed with another process, such as peritoneal leiomyomatosis or gliomatosis, resulting in a potentially confusing histologic appearance.

Pain remains the cardinal symptom of endometriosis. However, to date, the underlying mechanisms are still only poorly understood. Increasing evidence points towards a close interaction between peripheral nerves, the peritoneal environment and the central nervous system in pain generation and processing. Recently, studies demonstrating nerve fibres and neurotrophic and angiogenic factors in endometriotic lesions and their vicinity have led to increased interest in peripheral changes in endometriosis-associated pain. This review focuses on the origin and function of these nerves and factors as well as possible peripheral mechanisms that may contribute to the generation and modulation of pain in women with endometriosis.