Common 677C→T mutation of the 5,10-methylenetetrahydrofolate reductase gene affects follicular estradiol synthesis

Hecht, Stephanie; Pavlik, Roman; Lohse, Peter; Noss, Ulrich; Friese, Klaus; Thaler, Christian J.

doi:10.1016/j.fertnstert.2007.11.011

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Volume 91, Issue 1 , Pages 56-61, January 2009

Common 677C→T mutation of the 5,10-methylenetetrahydrofolate reductase gene affects follicular estradiol synthesis

Stephanie Hecht
- Department of Obstetrics and Gynecology, Division of Endocrinology and Reproductive Medicine, Grosshadern, Ludwig Maximilians-University, Munich, Germany
Roman Pavlik
- Department of Obstetrics and Gynecology, Division of Endocrinology and Reproductive Medicine, Grosshadern, Ludwig Maximilians-University, Munich, Germany
Peter Lohse, M.D.
- Department of Clinical Chemistry, Grosshadern, Ludwig Maximilians-University, Munich, Germany
Ulrich Noss, M.D.
- Centre for Reproductive Medicine, Munich, Germany
Klaus Friese, M.D.
- Department of Obstetrics and Gynecology, Division of Endocrinology and Reproductive Medicine, Grosshadern, Ludwig Maximilians-University, Munich, Germany
Christian J. Thaler, M.D.
- Department of Obstetrics and Gynecology, Division of Endocrinology and Reproductive Medicine, Grosshadern, Ludwig Maximilians-University, Munich, Germany
- Reprint requests: Christian J. Thaler, M.D., Department of Obstetrics and Gynecology, Division of Endocrinology and Reproductive Medicine, Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, D-81377 Munich, Germany (FAX: 49-89-7095-7588).

Received 14 March 2007; received in revised form 5 November 2007; accepted 5 November 2007. published online 13 February 2008.

Objective

To investigate the influence of the 5,10-methylenetetrahydrofolate reductase 677C→T mutation on the E₂ synthesis in human granulosa cells (GCs).

Design

In vitro cell culture study.

Setting

Research laboratory of a university hospital.

Patient(s)

Follicular fluids (n = 139) and GCs (n = 66) were obtained from patients undergoing controlled ovarian hyperstimulation for IVF with or without ICSI.

Intervention(s)

Granulosa cells were cultured for a total of 5 days. On day 3, the cells either were stimulated with recombinant (r-) FSH or r-LH (80 IU/L for 48 h) or were sham stimulated.

Main Outcome Measure(s)

Estradiol and protein content were measured in the pooled follicular fluids of each individual. At the end of each GC-culturing period, the concentrations of E₂ were measured in the supernatants of triplicate cultures by immunoassays. The 5,10-methylenetetrahydrofolate reductase 677C→T genotype was determined by RFLP analysis.

Result(s)

The E₂-protein ratio of homozygous T/T carriers was significantly lower compared with that of homozygous C/C individuals. Furthermore, basal and r-FSH– as well as r-LH–stimulated E₂ synthesis of GC obtained from homozygous T/T patients was significantly reduced, compared with GC from heterozygous C/T and homozygous C/C subjects.

Conclusion(s)

Decreased E₂ in follicular fluid and decreased E₂ synthesis of GC from homozygous T/T individuals suggest that reduced follicular E₂ is a result of impaired E₂ production of human GC.

Key Words: MTHFR 677C→T mutation, estradiol synthesis, granulosa cells, follicular fluid