Genetics: Association of dopamine D₂ receptor gene haplotypes with anovulation and fecundity in female hispanics

Dopamine is an important neurotransmitter in the hypo-thalamic control of gonadotrophin secretion. Neuron response is mediated through one of five different dopamine receptors. We explored the association of D₂ receptor gene polymorphisms with disorders of ovulation. We utilized a multiplex allele specific polymerase chain reaction (PCR) to detect two bi-allelic polymorphisms (four potential haplotypes) in intron 5 and exon 6 of the D₂ receptor gene. A second PCR/restriction endonuclease digest was utilized to verify this. Using these assays, 185 female Hispanics (51% with known ovulatory dysfunction and 49% with normal function) were haplotyped. One allele (3) was not present in the population and there were no significant differences in remaining allele distribution between ovulatory and anovulatory patients. However, significant associations were noted between alleles and gonadotrophins and fecundity. The 4 allele had a different reproductive profile compared to the 2 allele. The 4 allele was associated with significantly higher concentrations of lutein-izing hormone (LH) (means ± SE) (19.2 ± 2.2 versus 12.3 ± 1.3 mIU/ml, P < 0.02) and follicle stimulating hormone (FSH) (13.2 ± 2.0 versus 10.0 ± 0.6 mIU/ml, P < 0.05), significantly lower concentrations of prolactin (7.9 ± 0.8 versus 14.9 ± 3.5 ng/ml, P < 0.02) and higher parity (1.4 ± 0.12 versus 0.92 ± 0.13) and lower miscarriage rates (0.89 ± 0.1 versus 1.33 ± 0.24, P < 0.04). We conclude that D₂ receptor alleles may be associated with reproductive success through altered gonadotrophin secretion and that this effect may be independent of ovulatory function.