ABSTRACT
Context
Follicle stimulating hormone (FSH) mediates cyclic follicle growth and development and is widely used for controlled ovarian stimulation in women undergoing infertility treatment. The ovarian response of women to FSH is variable, ranging from poor response to ovarian hyperstimulation.
Objective
We investigated whether genetic alterations of the FSH receptor (FSHR) contribute to this variability.
Design and Patients
Our approach was to study women undergoing treatment with In Vitro Fertilization (IVF) falling into the edges of the normal distribution of ovarian response to FSH, with respect to age.
Setting
Yale Fertility Clinic.
Methods
We extracted RNA from cumulus cells surrounding the oocytes of women undergoing IVF and analyzed the FSHR mRNA by RT-PCR and sequencing.
Results
We identified four abnormal FSHR splicing products (3 exon deletions and 1 intron insertion) in the FSHR mRNA in 37% (13/35) of women tested. All alterations affected the extracellular ligand-binding portion of the receptor without causing a frameshift. When transfected in HEK293T cells, all four splicing variants showed markedly decreased cAMP activation compared to controls. Untransfected cells showed no response to FSH, while all the cell lines showed normal cAMP activation when treated with Forskolin, a non-receptor mediated cAMP stimulant. None of the normal or mutant forms showed any response to luteinizing or thyroid stimulating hormones.
Conclusions
Our findings strongly indicate FSHR variants as being an intrinsic genetic cause of some forms of infertility and identify a need for functional characterization of these variants and the investigation of more individualized ovarian stimulation protocols.
Functional characterization of naturally-occurring constitutively activating/inactivating mutations in equine follicle-stimulating hormone receptor (eFSHR)
