AIDS disease progression is a crucial public health question. There is good reason to focus in particular on the effects of the injectable contraceptive medroxyprogesterone acetate (MPA). MPA administered as a 150-mg 3-monthly intramuscular injection is referred to as Depo-Provera or depot MPA (DMPA). DMPA is used by over 50 million women worldwide (1), particularly in areas with high HIV-1 prevalence. Multiple observational studies involving thousands of women suggest that hormonal contraception increases the risk of HIV-1 acquisition and transmission (1–6). In most studies the adjusted hazard ratio (HR) for DMPA is higher than that associated with no contraception or oral contraception (1–6). However, it has been argued that some of these reported elevated risks may be artificially elevated due to methodological limitations and confounding behavioral factors (6). Nevertheless, it is important to appreciate the impact of increased risks if they are indeed real. Adjusted hazard ratios (HRs), reflecting the fold increased risk relative to no contraception, of between 1.5-and 4.5-fold have been recently reported for DMPA (1, 2, 4)(author’s response in Ref. 6). In one study, an HR as high as 10.4 was reported for DMPA (7). A rough estimate shows that 1 to 5 million new HIV-1 infections per 50 million women per annum could possibly be prevented by use of intrauterine devices, implants, or the injectable contraceptive norethisterone enanthate (NET-EN), instead of DMPA. These values are calculated using adjusted HRs of 1.5 to 4.0, respectively, and an HIV-1 incidence rate of 3.5 per 100 woman-years. Thus, this is a critical public health issue and is the topic of extensive and urgent worldwide research and discussions (3, 5, 6, 8, 9)(http://www. who. int/reproductivehealth/publications). Because the current data from observational studies in women are not considered persuasive enough to recommend using methods of contraception other than DMPA (9), more research is urgently required to shed light on this important issue. The key question is what information is needed and how feasible it is to obtain. Some have argued that more large-scale randomized trials are needed (3), but these may not be ethical and are unlikely to be feasible (6, 8). Another approach is to investigate ex vivo the direct biological effects of specific hormonal contraceptives at specific doses and to determine mechanisms on various cellular functions relevant to HIV-1 pathogenesis. This is the approach followed by the group of Zdenek Hel (10) in their seminal paper in this month’s issue of Endocrinology. The central hypothesis examined in the paper by the Hel group is that MPA, more so than physiological concentrations of progesterone (P4), is likely to repress immune function at doses within the range found in the serum of DMPA users, due to its potent glucocorticoid-like immunosuppressive properties, which could influence the pathogenicity of infectious diseases (11–13). Before discussing this hypothesis, it is important to place the study in the context of results from previous studies. Progestins mediate their intracellular effects via alterations in transcription of specific genes by binding to and regulating the activity of steroid receptors, which are ligand-activated transcription factors (11, 14, 15). Although progestins are