155 While alterations in serotonin function are clearly relevant to the successful treatment of PMS symptoms, it remains unclear whether alterations in serotonin function underlie the predisposition

to experience PMS. Future studies will await the development of receptor subtype specific agonists/antagonists and access to subtype-specific imaging ligands. Inhibitors,research,lifescience,medical Polymorphisms in gonadal steroid signaling pathway proteins or in systems regulated by gonadal steroids PMS offers an ideal opportunity to identify genetic contributions to the vulnerability for affective disturbance, since the offending stimuli (steroid triggers) are known. Several polymorphisms in gonadal steroid receptors have been shown to alter receptor transcriptional efficacy (eg, CAG repeat in exon 1 of the Inhibitors,research,lifescience,medical androgen receptor; progins insertion in intron 7

of the progesterone receptor) and to be associated with differential illness risk (ie, prostate cancer or breast cancer).156 -159 Additionally, the susceptibility to Inhibitors,research,lifescience,medical the disruptive effects of estradiol on reproductive development Abiraterone order differs enormously (up to 100-fold) between mouse strains, with the genotype contributing more to the variance than the dose of estradiol Inhibitors,research,lifescience,medical employed.160 There is precedent, then, for inferring that polymorphisms in the gonadal steroid-signaling pathway or in gonadal

steroid-regulated genes may alter the nature or strength of the steroid Inhibitors,research,lifescience,medical signal as well as phenotype. In genetic studies that we have performed to date in 125 women with PMS and 280 controls (C. Roca and B. Harlow, unpublished data), no differences were observed in the frequencies of the following polymorphisms: PvuII, Xbal, and TA repeat (estrogen receptor α); CAG repeat (androgen receptor); progins, CA repeat (progesterone 17-DMAG (Alvespimycin) HCl receptor); T102C, His-Tyr (serotonin 2 A receptor); Cys-Ser (serotonin 2C receptor). A significant difference has been identified, however, for the SLC6A4 promoter polymorphism of the serotonin transporter, with a higher frequency of the L (long) allele (associated with increased transport and increased response to SSRIs)161,162 in the women with P.M.S (C.