Abstract
BackgroundAdvanced glycation end-products (AGE), which accumulate with insulin resistance and aging, impair folliculogenesis and may decrease endometrial receptivity. Hishi (Trapa bispinosa Roxb.) extract, a safe herbal medicine, strongly inhibits AGE formation in vitro. We determined whether Hishi lowers AGE and increases live births in older assisted reproductive technology (ART) patients.MethodsThis prospective randomized open-label controlled trial included 64 patients 38 to 42 years old undergoing ART with or without Hishi extract between June 11, 2015 and July 12, 2019. None had over 2 ART failures, diabetes, uterine anomalies, or exhausted ovarian reserve. After allocation, the Hishi group received Hishi extract (100 mg/day) until late pregnancy or failure. The control group received no extract. Both groups underwent 1 cycle of conventional infertility treatment; 1 long-protocol cycle of ovarian stimulation, oocyte retrieval, in vitro fertilization/intracytoplasmic sperm injection, and fresh embryo transfer (ET); and, if needed, cryopreserved ET until live birth or embryo depletion. Serum AGE were measured before and during ART, as were AGE in follicular fluid (FF).ResultsCumulative live birth rate among 32 Hishi patients was 47%, significantly higher than 16% among 31 controls (p<0.01; RR, 4.6; 95% CI, 1.4 – 15.0; 1 control dropped out). Live birth rate per ET, including fresh and cryopreserved, was significantly higher with Hishi (28% in 47 ET vs. 10% in 49 ET; p<0.05; RR, 3.4; 95% CI, 1.1-10.4). Among variables including age, day-3 FSH, anti-Müllerian hormone, and Hishi, logistic regression identified only Hishi as significantly associated with increased cumulative live birth (p<0.05; OR, 5.1; 95% CI, 1.4 - 18.3). Hishi significantly enhanced oocyte developmental potential, improved endometrial receptivity in natural cycles, and decreased AGE in serum and FF. Larger serum AGE decreases with Hishi were associated with more oocytes becoming day-2 embryos.ConclusionsHishi decreased AGE in serum and FF and improved oocyte developmental potential and endometrial receptivity, increasing live births in older patients. Treatment of infertility by AGE reduction represents a new addition to infertility treatment. Therapeutic trials of Hishi for other AGE-associated diseases might be considered.Trial registrationUMIN registration in Japan (UMIN000017758) on June 1, 2015. https://www.umin.ac.jp/ctr/index.htm
Highlights
Advanced glycation end-products (AGE), which accumulate with insulin resistance and aging, impair folliculogenesis and may decrease endometrial receptivity
Study design A prospective open-label randomized clinical trial was conducted to determine whether Hishi extract improved assisted reproductive technology (ART) outcomes in patients at relatively advanced ages, and to clarify whether improvement was associated with AGE reduction
These improvements likely resulted from AGE reduction in ovarian follicles and endometrium
Summary
Advanced glycation end-products (AGE), which accumulate with insulin resistance and aging, impair folliculogenesis and may decrease endometrial receptivity. We determined whether Hishi lowers AGE and increases live births in older assisted reproductive technology (ART) patients. Advanced glycation end-products (AGE) are cross-linked molecules formed by nonenzymatic reactions of carbonyl groups with amino groups of proteins, lipids, or nucleic acids [1]. AGE participate in aging [2] and in conditions involving insulin resistance (IR) such as metabolic syndrome, type 2 diabetes, hypertension, atherosclerosis, dyslipidemia, polycystic ovary syndrome (PCOS), and central obesity [1, 3, 4]. An insulin sensitizer, improves pregnancy rates in PCOS [11] and non-PCOS patients with repeated past failures of assisted reproductive technology (ART) [12].
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