A new FSHβ mutation in a 29-year-old woman with primary amenorrhea and isolated FSH deficiency: Functional characterization and ovarian response to human recombinant FSH

Context: Mutations of the FSHβ gene, causing in women isolated FSH deficiency and hypogonadism,are very rare and only a few have been described. Objective: To describe the phenotype and response to recombinant human (rh) FSH of a female patient with a novel homozygous loss-of-function mutation of FSHβ, and to characterize in vitro the molecular mechanisms responsible for the FSH inactivation. Patient: A 29-year-old woman with primary amenorrhea and impaired pubertal development associated with isolated FSH deficiency. Methods and results: Sequencing of the FSHβ gene revealed a homozygous 1 bp (G) deletion at codon 79 (c.289delG) of exon 3 which produced a frameshift at codon 79 (A79fs108X) and a premature stop codon at codon 109. The wild-type and mutant FSHβ cDNAs inserted into expression vector were cotransfected into Chinese hamster ovary cells with the α-subunit. Wild-type FSH was readily detectable in culture medium, whereas no mutant FSH was detectable by either immunoassay or in vitro bioassay. Mutant FSHβ protein could not be detected in western blot.In response to a 15-day treatment with rhFSH, sonography revealed multifollicular development in the ovaries. Circulating levels of estradiol and inhibin B were dramatically increased, whereas anti-Mullerian hormone decreased. Serum LH first decreased and then increased, inducing multiovulation associated with supraphysiologic progesterone and inhibin A levels. Conclusion: A novel FSHβ mutation was detected in a hypogonadal woman. rhFSH was effective in ovulation induction in the patient but with signs of ovarian hyperstimulation. The high pretreatment LH levels could contribute to this excessive ovarian response to rhFSH.