Research into female reproductive tract disorders_v.1

• Research type

  Research Study

• Full title

  Investigation into the role of local hormones and prostaglandins in female reproductive tract disorders_v.1

• IRAS ID

  117359

• Contact name

  Kay Marshall

• Contact email

  kay.marshall@manchester.ac.uk

• Sponsor organisation

  The University of Manchester

• Research summary

  mmary of Research
  Investigation into the role of local hormones and prostaglandins in female reproductive tract disorders

  Summary of ResultsOur research focused on conditions like endometriosis, where womb (uterus) lining-like cells are found elsewhere in the body, typically on the bowel, ovaries or bladder. With each menstrual cycle (period), break down and regrowth of these cells can cause inflammation, pain and the formation of scar tissue. Living with common symptoms of chronic pain and subfertility can be debilitating and have a significant impact on mental health and wellbeing. Research was therefore needed to improve innovation into diagnostic and treatment options, which are currently limited especially for women who desire pregnancy.

  Did the study achieve its objective?
  The purpose of this study was to obtain new insights into women’s reproductive disorders to improve the diagnosis and treatment of conditions such as endometriosis and endometrial cancer. We wished to investigate sex steroid pathways, prostaglandins (PGs) and aldo-keto reductase (AKR) enzymes that could lead to progression of disease. In particular, we focused on whether the small molecules that help to regulate inflammation (bioactive lipid mediators & cytokines) within the tissues and local environment changed according to condition type, disease severity and pre- or postmenopausal status. The effect of possible treatments were also studied using primary cells to model disease.
  Recruited participants included women undergoing routine surgery for endometriosis, fibroids, heavy menstrual bleeding, benign ovarian cysts, BRCA gene mutations and low/ high grade endometrial cancer. Many of these women experienced chronic pelvic pain and used medications to inhibit their endogenous (natural) hormones and menstrual cycle. Some participant groups were therefore limited in number and there were no healthy controls; these were factored into our data analysis.
  Overall, we successfully recruited 88 participants to our research study and were able to discover differences in the lipid profiles, prostaglandin receptors and AKR expression between women with and without endometriosis and endometrial cancer.

  What were the main findings of the study?
  This study revealed some interesting pathways that may be involved in the establishment and progression of reproductive disease. We found that the uterine lining (endometrium) from women with endometriosis contained more AKR enzymes compared to women without the disease. Most remarkable was the amount of this enzyme in ovarian lesions (endometriosis) but not in the surrounding fat. This finding may be a useful avenue for further exploration.
  As a result of the above, the effect of a specific enzyme inhibitor was examined. In cultured primary endometrial cells, it significantly reduced growth and showed anti-oestrogenic properties through hormones, PGs and their receptors. At high concentrations, it conversely did not interrupt isolated uterine contractions; this reflects its good safety profile. The AKRs are therefore emerging as a potentially important drug target worthy of further investigation.
  We also looked for a ‘finger print’ in our samples that may help in more speedy, less interventional, diagnosis of disease. We found that total lipid concentrations were lower in women with endometriosis compared to the endometriosis-free group. Of these, expression of one family of lipids, notably those derived by the action of the 15-lipoxygenase (LOX) enzyme showed the greatest reduction. This lipid balance was resolved in women taking hormonal treatments, which may explain why they find symptom improvement.
  Interestingly, 15-LOX products were even more scarce in women with low and high grade endometrial cancer. A lack of these anti-inflammatory mediators could exacerbate cancer growth and malignancy. We also found dysregulated endometrial lipids and cytokines that are hallmarks of oxidative stress and may lead to acute or chronic inflammation. We plan to continue this work to understand their role in reproductive disease and determine a signature for accurate diagnosis.

• REC name

  South West - Cornwall & Plymouth Research Ethics Committee

• REC reference

  13/SW/0123

• Date of REC Opinion

  8 May 2013

• REC opinion

  Favourable Opinion