Association between estrogen receptor-beta gene polymorphisms and ovulatory dysfunctions in patients with menstrual disorders

Estrogen plays a significant role in human ovulation. It acts as an importa nt positive regulator of the preovulatory gonadotropin surge necessary to i nitiate the cascade of events leading to ovulation. The steroid hormone exe rts its physiological responses through the estrogen receptor (ER), of whic h two subtypes, ER alpha and ER beta, are known. ER beta messenger ribonucl eic acid occurs maximally in the ovaries and granulosa cells; thus, ER beta may be essential for normal ovulation. In a recent gene knockout study, it has been shown that ER beta gene null female mice develop normal reproduct ive tract and ovaries during pre- and neonatal periods, but have an abnorma l frequency of spontaneous ovulation in adulthood. In the present case-cont rol study, we explored the association of two recently described ER beta ge ne polymorphisms, RsaI and AluI, with ovulatory dysfunctions. The respectiv e frequencies of these polymorphisms were significantly higher in patients than in controls (P = 0.009 and P = 0.059). The polymorphisms were signific antly associated with ovulatory dysfunctions, especially in patients homozy gous for the polymorphisms (P = 0.016 and P = 0.038, respectively). The com pound homozygosity of the polymorphisms was seen only in patients (n = 5) a nd not controls (P = 0.009). The serum levels of LH, FSH, and progesterone were lower in the homozygous and compound homozygous than in the respective nonpolymorphic patients. All five compound homozygous patients had ovulato ry dysfunctions with no etiological pathology. Our results suggest that ER beta gene RsaI and AluI polymorphisms may be associated with ovulatory defe cts in some patients, especially those with unknown causes.