A pilot study of premature ovarian senescence: II. Different genotype and phenotype for genetic and autoimmune etiologies.
OBJECTIVE
To assess whether abnormal autoimmune function and number of triple CGG repeats on the FMR1 (fragile X) gene, both historically associated with risk toward premature ovarian senescence, represent independent risk factors.


METHODS
Retrospective cohort study.


METHODS
Academically affiliated, private fertility center.


METHODS
Forty consecutive, new infertility patients, of which 11 presented with a primary diagnosis of repeat pregnancy loss, 23 with prematurely elevated, age-specific baseline follicle stimulating hormone (FSH) levels (i.e., premature ovarian aging) and 6 with premature ovarian failure.


METHODS
Determination of triple CGG repeats on both alleles of the FMR1 gene, assessment of ovarian reserve via FSH and anti-Müllerian hormone levels, and evaluation of autoimmune status by antiphospholipid antibody panel, antinuclear antibody panel, total immunoglobulin levels (IgG, IgM, IgA), thyroid antibodies (antiglobulin and antimicrosomal), antiovarian, and antiadrenal antibodies.


RESULTS
Twenty-two of 40 patients (55%) demonstrated autoimmune abnormalities. Women with and without autoimmune abnormalities did not differ in age. Patients with autoimmune abnormalities, however, demonstrated significantly lower FSH levels and higher anti-Mullerian hormone levels. Although triple repeats on the lower count allele (allele-1) of the FMR1 gene did not differ statistically, autoimmune patients demonstrated in the higher count allele (allele-2) significantly fewer triple repeats, significantly fewer triple repeats >or=30, and, in contrast to nonautoimmune patients, a normal mean level of triple repeats.


CONCLUSIONS
Abnormal autoimmune function and expansions in triple CGG repeats on the FMR1 gene represent distinctively different etiologies for premature ovarian senescence in infertile patients and may, indeed, constitute its two principal causes.
Gleicher
Norbert
N
Department of Obstetrics, Gynecology and Reproductive Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. ngleicher@thechr.com
Weghofer
Andrea
A
Barad
David H
DH
D000328:Adult; D054304:Anti-Mullerian Hormone / Q000097:blood; D015551:Autoimmunity; D015331:Cohort Studies; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D010641:Phenotype; D016649:Primary Ovarian Insufficiency / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D012189:Retrospective Studies; D019680:Trinucleotide Repeat Expansion
D054304:Anti-Mullerian Hormone; D005640:Follicle Stimulating Hormone; D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human