Finally, in patients with polycystic ovary syndrome (PCOS), the administration of metformin combined with drospirenone/ethinylestradiol has been shown to reduce the frequency of CD4+CD28null T cells (51), a subset of CD4+ Th1 cells lacking the co-stimulatory receptor CD28 thought to be involved in autoimmune diseases such as RA (52). This evidence concerns the gene CD4 and rheumatoid arthritis.