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

Estrogen plays a significant role in human ovulation. It acts as an important positive regulator of the preovulatory gonadotropin surge necessary to initiate the cascade of events leading to ovulation. The steroid hormone exerts its physiological responses through the estrogen receptor (ER), of which two subtypes, ER alpha and ER beta, are known. ER beta messenger ribonucleic 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 reproductive tract and ovaries during pre- and neonatal periods, but have an abnormal frequency of spontaneous ovulation in adulthood. In the present case-control study, we explored the association of two recently described ER beta gene polymorphisms, RsaI and AluI, with ovulatory dysfunctions. The respective frequencies of these polymorphisms were significantly higher in patients than in controls (P = 0.009 and P = 0.059). The polymorphisms were significantly associated with ovulatory dysfunctions, especially in patients homozygous for the polymorphisms (P = 0.016 and P = 0.038, respectively). The compound homozygosity of the polymorphisms was seen only in patients (n = 5) and 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 ovulatory dysfunctions with no etiological pathology. Our results suggest that ER beta gene RsaI and AluI polymorphisms may be associated with ovulatory defects in some patients, especially those with unknown causes.