A new FSHbeta mutation in a 29-year-old woman with primary amenorrhea and isolated FSH deficiency: functional characterization and ovarian response to human recombinant FSH.
BACKGROUND
Mutations of the FSHbeta 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 FSHbeta, and to characterize in vitro the molecular mechanisms responsible for the FSH inactivation.


METHODS
A 29-year-old woman with primary amenorrhea and impaired pubertal development associated with isolated FSH deficiency.


RESULTS
Sequencing of the FSHbeta 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 FSHbeta cDNAs inserted into expression vector were cotransfected into Chinese hamster ovary cells with the alpha-subunit. Wild-type FSH was readily detectable in culture medium, whereas no mutant FSH was detectable by either immunoassay or in vitro bioassay. Mutant FSHbeta 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.


CONCLUSIONS
A novel FSHbeta 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.
Kottler
Marie-Laure
ML
Unité de Formation et de Recherche de Médecine Centre Hospitalier Universitaire, Département Génétique et Reproduction, Université de Caen Basse-Normandie, F-14032 Caen, France.
Chou
Yen-Yin
YY
Chabre
Olivier
O
Richard
Nicolas
N
Polge
Camille
C
Brailly-Tabard
Sylvie
S
Chanson
Philippe
P
Guiochon-Mantel
Anne
A
Huhtaniemi
Ilpo
I
Young
Jacques
J
D000328:Adult; D000568:Amenorrhea / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D000818:Animals; D001681:Biological Assay; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D005260:Female; D005640:Follicle Stimulating Hormone / Q000172:deficiency* / Q000627:therapeutic use*; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics*; D006801:Humans; D007118:Immunoassay; D007265:Inhibins / Q000172:deficiency; D009154:Mutation / Q000235:genetics; D010053:Ovary / Q000000981:diagnostic imaging / Q000187:drug effects*; D010375:Pedigree; D011994:Recombinant Proteins / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D014463:Ultrasonography
D037201:Follicle Stimulating Hormone, beta Subunit; D011994:Recombinant Proteins; D007265:Inhibins; D005640:Follicle Stimulating Hormone