The effect of growth hormone on the metabolome of follicular fluid in patients with diminished ovarian reserve

Abstract

Background Increasing evidence supports that the co-treatment with growth hormone (GH) enhances ovarian response and oocyte quality during controlled ovarian stimulation (COS) in patients with diminished ovarian reserve (DOR). The composition of follicular fluid (FF) plays an essential role in oocyte development and mirrors the communication occurring between the oocyte and follicular microenvironment. However, the effect of GH on the FF metabolome remains unclear. Methods This prospective observational study recruited DOR patients undergoing in vitro fertilization (IVF) cycles with minimal stimulation protocol for COS. Each patient receiving GH co-treatment was matched to a patient without GH co-treatment by propensity score matching. The FF was collected after isolating oocytes and assayed by gas chromatograph-mass spectrometry (GC-MS) metabolomics. The Pearson correlation was performed to evaluate the relationship between the number of oocytes retrieved and the levels of differential metabolites. The KEGG database was used to map differential metabolites onto various metabolic pathways. Results One hundred thirty-four FF metabolites were identified by GC-MS metabolomics. Twenty-four metabolites, including glutathione, itaconic acid and S-adenosylmethionin (SAM) showed significant differences between the GH and control groups (p-value < 0.05 and q-value < 0.1). In addition, the number of oocytes retrieved was significantly higher in the GH group compared to the control group (3 vs 2, p = 0.04) and correlated with the levels of five differential metabolites. Among them, the levels of antioxidant metabolite itaconic acid were upregulated by GH administration, while SAM levels were downregulated. Conclusions The co-treatment with GH during COS may improve oocyte development by altering FF metabolite profiles in DOR patients. However, given the downregulation of SAM, a regulator of genomic imprinting, the potential risk of imprinting disturbances should not be neglected.

Dehydroepiandrosterone supplementation and the impact of follicular fluid metabolome and cytokinome profiles in poor ovarian responders

“…Secondly, this study is the largest-to-date, providing a global view, specifically of the effect of DHEA on the FF metabolome and cytokine profile in POR patients. Thirdly, the recruitment of women of relatively advanced age, low mean number of recovered oocytes (4.9) and low clinical pregnancy rate (5/52 or 9.6%), which contrast with other studies [ 22 , 33 ] suggest the appropriate inclusion of POR patients.…”

“…We did not detect E1 and E2; because for phenolic hydroxyl group of estrogens to act as proton donors, the signal would be more sensitive in the negative ion mode electrospray ionization [ 78 ] than in the positive ion mode which was used in this study. Aside from previously reported constituents of FF such as linoleic acid [ 17 , 22 ], amino acids [ 18 ], and steroids including progesterone, testosterone [ 79 ], this study also captured metabolic products of ovarian steroidogenesis, cholesterols and glucocorticoids in the FF. Secondly, this study is the largest-to-date, providing a global view, specifically of the effect of DHEA on the FF metabolome and cytokine profile in POR patients.…”

“…As such, constituents of the FF surrounding the oocyte provides a unique biochemical window to the growth and differentiation of the oocyte [ 16 ]. To unravel the biochemical composition of human FF and its impact on oocyte development, metabolomic analyses using gas chromatography–mass spectrometric and proton nuclear magnetic resonance metabolomic analyses have been conducted [ 17 – 22 ], as were proteomic analyses [ 23 – 28 ]. These studies mainly report the FF profiles of IVF patients, whereas the FF metabolome of POR remains poorly characterized.…”

Determination of tryptophan and its indole metabolites in follicular fluid of women with diminished ovarian reserve

“…With the rapid development of biological analysis technology, metabolomics has become an important omics layer in multi-omics studies and has allowed us to explore the pathogenesis of DOR in greater depth. In recent years, studies have reported differences in FF metabolomics between DOR and NOR populations 20 – 22 . In the present study, we similarly found that diminished ovarian reserve function affects FF metabolic characteristics.…”

Metabolomic Analysis Reveals Association between Decreased Ovarian Reserve and In Vitro Fertilization Outcomes

“…Clinically, DOR is characterized by a decreased level of anti-Mullerian hormone (AMH), elevated levels of follicle-stimulating hormone (FSH), and/or a diminished antral follicle count (AFC) [ 17 , 18 , 19 ]. Patients with DOR are at risk of poor ovarian stimulation response, high rates of cycle cancellation, diminished oocyte yield, reduced pregnancy rates, and increased miscarriage rates following IVF treatment [ 20 , 21 , 22 , 23 ]. The estimated prevalence of DOR among cycles recorded in the Society for Assisted Reproductive Technology (SART) registry is projected to be 26% [ 14 , 24 , 25 , 26 ].…”