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A Common Single Nucleotide Polymorphism in Exon 10 of the Human Follicle Stimulating Hormone Receptor Is a Major Determinant of Length and Hormonal Dynamics of the Menstrual Cycle

Department of Obstetrics and Gynecology (R.R.G., K.G., B.S., L.K.) and Institute for Reproductive Medicine (J.G., E.N., M.S.), Münster University Hospital, D-48149 Münster, Germany

Address all correspondence and requests for reprints to: Prof. Dr. Manuela Simoni, Institute for Reproductive Medicine, Münster University Hospital, Domagkstrasse 11, D-48149 Muenster, Germany. E-mail: manuela.simoni{at}ukmuenster.de.

Context: FSH is essential for follicular maturation. Data from ovarian hyperstimulation cycles suggest that FSH action is attenuated by a frequent single nucleotide polymorphism of the FSH receptor gene exchanging Asn for Ser at codon 680.

Objective: We hypothesized that the FSH receptor genotype influences menstrual cycle dynamics.

Design: Menstrual cycle was monitored from the midluteal phase through ovulation until the consecutive menstruation.

Setting: The study was conducted at the University research center.

Subjects: Women homozygous for the Asn⁶⁸⁰ (n = 12) and Ser⁶⁸⁰ (n = 9) variants with normal menstrual cycles volunteered for the study.

Interventions: There were no interventions.

Main Outcome Measurements: Follicular growth, serum LH, FSH, estradiol, progesterone, inhibin A, inhibin B and antimullerian hormone were measured.

Results: During the luteo-follicular transition, serum levels of estradiol, progesterone, and inhibin A were significantly lower, and FSH started to rise earlier in the Ser⁶⁸⁰/Ser⁶⁸⁰ group. FSH levels were steadily and significantly higher, and the mean area under the FSH curve was 31% greater in this group (P < 0.002). No differences were observed in estradiol, inhibin B, and growth velocities of dominant follicles. The time from luteolysis to ovulation was significantly longer in women with the Ser⁶⁸⁰/Ser⁶⁸⁰ (13.6 ± 1.01 d) compared with Asn⁶⁸⁰/Asn⁶⁸⁰ (11.3 ± 0.61 d, P < 0.05) genotype with a significant difference in total menstrual cycle length (29.3 vs. 27.0 d, respectively; P < 0.05).

Conclusions: The FSH receptor Ser⁶⁸⁰/Ser⁶⁸⁰ genotype is associated with higher ovarian threshold to FSH, decreased negative feedback of luteal secretion to the pituitary during the intercycle transition, and longer menstrual cycles.

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