Over 100 million women are on hormonal contraceptives. All of them contain some form of progesterone, either alone or in combination with estrogen. A study published on Sept. 15th in PLOS Pathogens reports that treatment with progesterone protects female mice against the consequences of influenza infection by reducing inflammation and improving pulmonary function, primarily through upregulation of amphiregulin in lung cells.

Progesterone signals through progesterone receptors present on many immune cells (e.g., NK cells, macrophages, dendritic cells, and T cells) and other cells throughout the body. In general, progesterone appears to dampen immune responses and reduce inflammation. Although the immunomodulatory effects of progesterone-based contraception have been studied in the context of sexually transmitted diseases such as HIV and herpes simplex virus, the potential impact of progesterone on viral infections outside of the reproductive tract has not received much attention.

generic influenza virion
3D influenza/CDC

In the present study, Sabra Klein, from Johns Hopkins University in Baltimore, USA, and colleagues examined whether levels of progesterone that mimic physiological concentrations present after ovulation (and equivalent to levels used in contraceptives) influence the host response to influenza infection. The researchers studied female mice whose ovaries had been removed and whose progesterone was supplied by implanted pellets that kept hormone levels constant.

When female mice were challenged with influenza virus, the researchers found that the exogenous progesterone was able to protect females from the consequences of influenza infection to some extent. Progesterone did not reduce the level of virus present in the mice, but decreased the amount of inflammation and tissue damage in the lungs and promoted faster recovery from the infection.

Consistent with this, the researchers found that progesterone treatment was associated with elevated levels of immune cells called T helper 17 (Th17) cells, which are known to be involved in maintaining mucosal barriers and pathogen clearance at mucosal cell surfaces. Progesterone also increased the levels of a protein called amphiregulin (AREG).

When the researchers supplied AREG to progesterone-depleted influenza-infected females, their disease and recovery characteristics resembled those of females on progesterone treatment. This suggests that progesterone exerts its effects through boosting of AREG levels in the lungs. The researchers were able to support this further with data from mice lacking AREG–in these females, progesterone failed to protect against the serious consequences of influenza infection.

To assess the contribution of progesterone treatment to the repair of damaged lung tissue, the researchers studied mouse respiratory cell cultures that had been mechanically injured. Progesterone increased the levels of AREG following injury in these cultures, as well as the speed of the subsequent wound repair.

“Progesterone”, the researchers conclude, “causes protection against severe outcome from influenza by inducing production of the epidermal growth factor, amphiregulin, by respiratory epithelial cells”. Their study illustrates, they say, “that sex hormone exposure, including through the use of hormonal contraceptives, has significant health effects beyond the reproductive tract”.