IL-1ß Stimulates Brain-Derived Neurotrophic Factor Production in Eutopic Endometriosis Stromal Cell Cultures: A Model for Cytokine Regulation of Neuroangiogenesis.

Endometriosis implants are comprised of glandular and stromal elements, macrophages, nerves, and blood vessels and are commonly accompanied by pelvic pain. We propose that activated macrophages are recruited to and infiltrate nascent lesions, where they secrete proinflammatory cytokines, promoting the production of chemokines, neurotrophins, and angiogenic growth factors that sustain an inflammatory microenvironment. Immunohistochemical evaluation of endometriosis lesions reveals in situ colocalization of concentrated macrophages, brain-derived neurotrophic factor (BDNF), and nerve fibers. These observations were coupled with biochemical analyses of primary eutopic endometriosis stromal cell (EESC) cultures, which allowed defining potential pathways leading to the neuroangiogenic phenotype of these lesions. Our findings indicate that IL-1ß potently (EC50 = 7 ± 2 ng/mL) stimulates production of EESC BDNF at the mRNA and protein levels in an IL-1 receptor-dependent fashion. Selective kinase inhibitors demonstrate that this IL-1ß effect is mediated by c-Jun N-terminal kinase (JNK), NF-κB, and mechanistic target of rapamycin signal transduction pathways. IL-1ß regulation of regulated on activation normal T cell expressed and secreted (RANTES), a prominent EESC chemokine, also relies on JNK and NF-κB. An important clinical implication of the study is that interference with BDNF and RANTES production, by selectively targeting the JNK and NF-κB cascades, may offer a tractable therapeutic strategy to mitigate the pain and inflammation associated with endometriosis.

Progesterone resistance in endometriosis: origins, consequences and interventions.

Endometriosis is a common cause of pelvic pain and affects up to 10% of women of reproductive age. Aberrant progesterone signaling in the endometrium plays a significant role in impaired decidualization and establishment of ectopic endometrial implants. Eutopic endometrial cells from women with endometriosis fail to downregulate genes needed for decidualization, such as those involved in cell cycle regulation, leading to unbridled proliferation. Several causes of progesterone resistance in the endometrium have been postulated, including congenital "preconditioning", whereby the in utero environment renders infants susceptible to neonatal uterine bleeding and endometriosis. Progesterone action is crucial to decreasing inflammation in the endometrium, and deviant progesterone signaling results in a proinflammatory phenotype. Conversely, chronic inflammation can induce a progesterone-resistant state. Repetitive retrograde endometrial shedding begets chronic peritoneal inflammation, which further exacerbates progesterone resistance. Genetic causes of progesterone resistance include progesterone receptor gene polymorphisms, altered microRNA expression, and epigenetic modifications to progesterone receptors and their targets. Environmental toxins such as dioxin play a possible role in the genesis of endometriosis by permitting an inflammatory milieu. A consequence of impaired progesterone action is that hormonal therapy is rendered ineffective for a subset of women with endometriosis. Synthetic progestins, such as dienogest, may overcome this phenomenon by increasing progesterone receptor expression and decreasing proinflammatory cytokines. Other modalities include high dose depot formulations of progestins, medicated intrauterine devices and the likely advent of oral GnRH antagonists. Unearthing root causes of progesterone inaction in endometriosis will aid in the development of novel therapeutics geared toward prevention and treatment.

Pathogenesis of endometriosis: Interaction between Endocrine and inflammatory pathways.

Despite an estimated prevalence of 11% in women and plausible historical descriptions dating back to the 17th century, the etiology of endometriosis remains poorly understood. Classical theories of the histological origins of endometriosis are reviewed below. Clinical presentations are variable, and signs and symptoms do not correlate well with the extent of disease. In this summary, we have attempted to synthesize the growing evidence that hormonal and immune factors conspire to activate a local inflammatory microenvironment that encourages endometriosis to persist and elaborate mediators of its two cardinal symptoms: pain and infertility. Surprisingly, in the search for novel therapeutics for medical treatment of endometriosis, some compounds appear to have dual pharmacological functions, simultaneously modifying the endocrine and immune system facets of this complex gynecologic syndrome. We predict that these lead drugs will provide more therapeutic choices for patients in the future.

Clinical assessment and management of the endometrium in recurrent early pregnancy loss.

Unexplained and recurrent loss of pregnancies is a heartbreaking and frustrating condition. The routine diagnostic workup for pregnancy loss includes hormonal evaluation, screening for genetic or chromosomal defects, immunologic and thrombophilic testing, and evaluation of congenital or acquired Müllerian defects. In cases of idiopathic pregnancy loss, defects in endometrial receptivity are increasingly being investigated. The role of the endometrium in pregnancy loss has historical roots but remains controversial. Exciting new directions based on microRNAs, proteomics, and epigenetics promises to keep this area of investigation both interesting and complex. With each new diagnostic and therapeutic biomarker identified comes a greater potential for diagnosis and treatment of women. The clinical assessment of the endometrium remains an important part of the investigation of couples with unexplained pregnancy loss.