Effects of follicle-stimulating hormone (FSH) and human chorionic gonadotropin in individuals with an inactivating mutation of the FSH receptor.
OBJECTIVE
To study the gonadal steroid responses to FSH and hCG in individuals with the inherited Finnish-type inactivating Ala189Val mutation of the FSH receptor gene.


METHODS
Prospective clinical and descriptive study.


METHODS
University hospital.


METHODS
Two women and one man homozygous for the Ala189Val mutation of the FSH receptor gene, and ovarian biopsies from four affected and four healthy women, and four normal fetuses.


METHODS
Individuals were treated with increasing doses of recombinant FSH (300 IU/day start, 900 IU/day final) and/or a single dose of hCG (5000 IU). Ovarian biopsies were used in immunohistochemical analyses for detection of aromatase cytochrome P450 and transcription factor GATA-4. In situ 3'-end labeling analyses were used for detection of apoptosis.


METHODS
Measurements of serum concentrations of follicle-stimulating hormone, leuteinizing hormone, inhibin A and B, estradiol, testosterone (T), androstenedione, and prolactin, immunostaining for ovarian aromatase, GATA-4, and apoptosis.


RESULTS
Administration of FSH had no effect on production of the steroids. Similarly, human chorionic gonadotropin (hCG) treatment, alone or after FSH administration, failed to raise serum steroid concentrations. Ovarian apoptosis was absent, and the expression of transcription factor GATA-4 and aromatase was negligible in the ovarian biopsies from Ala189Val homozygous individuals.


CONCLUSIONS
The Ala189Val mutation of the FSH receptor gene results in a complete block of FSH action in vivo. Furthermore, the failure of hCG to increase both ovarian estradiol and testosterone secretion emphasizes the possible contribution of FSH in regulating ovarian androgen synthesis, and supports the concept that both gonadotropins are necessary for appropriate ovarian steroidogenesis in humans.
Vaskivuo
Tommi E
TE
Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland.
Aittomäki
Kristiina
K
Anttonen
Mikko
M
Ruokonen
Aimo
A
Herva
Riitta
R
Osawa
Yoshio
Y
Heikinheimo
Markku
M
Huhtaniemi
Ilpo
I
Tapanainen
Juha S
JS
D000328:Adult; D017209:Apoptosis / Q000502:physiology; D001141:Aromatase / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000502:physiology; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000494:pharmacology*; D050991:GATA4 Transcription Factor; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000502:physiology*; D010053:Ovary / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D011962:Receptors, FSH / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
D006063:Chorionic Gonadotropin; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D011962:Receptors, FSH; D011994:Recombinant Proteins; D014157:Transcription Factors; D005640:Follicle Stimulating Hormone; D001141:Aromatase