Uterine fibroids (i.e. leiomyomas) affect 30 to 50% of reproductive-age women that are strongly associated with reducing the likelihood of pregnancy (RR=0.3-0.7) when compared to unaffected women. Surgical removal of fibroids can restore fertility, however, the benefits are often short due to a high recurrence rate of fibroids. Post-operative consequences are another concern as adhesions can negatively impact a woman?s fertility and overall health. Pharmacological approaches to reduce uterine fibroids include hormonal therapies, however, they also lead to pharmacologically-induced menopause thereby preventing pregnancy. For this reason, there is a critical and unmet need to identify safe and orally bioavailable non-hormonal and non-surgical treatment options for women with fibroids that distort the uterine cavity. One such approach is being investigated in the parent grant (1R01HD100367) evaluating the hypothesis that EGCG can reduce fibroid size and increase the likelihood of pregnancy. Briefly, the parent grant is supporting a placebo-controlled clinical trial to evaluate live birth outcomes for women with unexplained infertility who have uterine fibroids. The objective of this proposal is to complement the parent project (1R01HD100367) to identify clinically relevant mechanisms of folate depletion and determine if a clinically relevant natural product drug interaction (NPDI) exists between fertility treatment and green tea extract. a consortium as described in RFA-HD-19-022 was formed. Yale will serve as the DCC and a clinical site, John Hopkins will coordinate the single IRB and be a clinical site. Investigators at UIC have experience with EGCG and clinical trials and will serve as lead PI. MTHFR represents the most studied enzyme in the folate pathway for neural tube defects and with strong evidence that polymorphisms decrease enzyme activity it represents a clinically relevant target. Another critical enzyme in the folate pathway is dihydrofolate reductase (DHFR) which has been shown to be inhibited by select small molecules including green tea catechins. We are proposing to stratify subjects by wildtype MTHFR, MTHFR (C677T), and MTHFR (A1298C). The prevalence of MTHFR mutations can range from 30 to 40% in the American population for C677T and ~50% for A1298C. Green tea extract has been reported to decrease folic acid levels through two mechanisms that include the inhibition of dihydrofolate reductase (DHFR) and decreasing the bioavailability of folic acid. Our hypothesis is that green tea catechins have weak inhibitory DHFR properties that may increase the risk of folic acid depletion in women expressing known MTHFR polymorphisms. To test our hypothesis, we have proposed two specific aims.
Specific Aim 1. To determine if MTHFR polymorphisms increase the risk of folate depletion in women receiving green tea extract.
Specific Aim 2. To determine if a clinically relevant natural product-drug interaction (NPDI) exists in women receiving green tea polyphenols who have been randomized to either clomiphene or letrozole.
The proposed research is relevant to public health because MTHFR gene mutations in combination with specific phytochemicals have the potential to decrease active folic acid blood levels in women of child bearing age. The proposed research is relevant to a part of NIH?s mission which is to foster fundamental creative discoveries, innovative research strategies, and their applications as a basis for ultimately protecting and improving health.