Progesterone in contraceptives promotes flu healing
Over 100 million women are on hormonal contraceptives. All contain some form of progesterone, either alone or in combination with estrogen. Researchers found treatment with progesterone protects female mice against influenza by reducing inflammation and improving pulmonary function.
Healing is primarily through an increase in amphiregulin, a protein found in the lungs and coded for by the gene AREG. The study was conducted by Sabra Klein PhD, and her colleagues at Johns Hopkins University in Baltimore, Maryland and published on Sept. 15th in the journal PLOS Pathogens.
Progesterone signals are picked up by progesterone receptors located on varying immune cells throughout the body — e.g., NK cells which are critical in the function of the immune system, macrophages which are white blood cells that engulf and digest cell debris, dendritic cells that act as messengers between the innate and the adaptive immune systems, and T cells that mature in the thymus and are part of our adaptive immune system initiating a response to a specific pathogen, then recreating that response to that same pathogen throughout our lives.
Progesterone appears to dampen immune responses and reduce inflammation. Although immune modifying effects of progesterone-based contraception have been studied in sexually transmitted diseases — HIV and herpes simplex virus — the impact of progesterone generally on viral infection hasn't received much attention.
Klein examined whether levels of progesterone similar in concentrations present after ovulation — and equal to levels used in contraceptives — influences a host's response to influenza (flu) infection. They studied female mice without ovaries whose progesterone was supplied by implanted pellets to keep their hormone levels constant.
When the female mice were given flu virus, researchers found their progesterone response was able to protect them from the consequences of flu infection. Although progesterone did not reduce their level of virus, it decreased their amount of inflammation and tissue damage in their lungs and promoted a faster recovery from the infection.
Researchers also found the progesterone elevated levels of immune cells called T helper 17 (Th17) cells — known to help maintain a mucosal barrier to pathogens like the flu, and clear it at the mucosal cell surface.
And progesterone increased the level
of amphiregulin (AREG) protein.
When researchers supplied AREG to female mice depleted of progesterone, their disease and recovery resembled that of females taking progesterone. This suggests progesterone exerts its effect by boosting AREG levels in the lungs. Researchers supported this result with data from mice lacking AREG. In females without AREG, progesterone failed to protect against the serious consequences of a flu infection.
To assess the contribution progesterone treatment made to the repair of damaged lung tissue, researchers examined mouse respiratory cell cultures that had been mechanically injured. Progesterone increased the cell cultures levels of AREG following injury, as well as the speed of the subsequent wound repair.
"Progesterone protects against severe outcome from influenza by inducing production of the epidermal growth factor, amphiregulin, in respiratory epithelial cells." Illustrating, "sex hormone exposure, through the use of hormonal contraceptives, has significant health effects beyond the reproductive tract."
Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract have not been evaluated. Administration of exogenous progesterone (at concentrations that mimic the luteal phase) to progesterone-depleted adult female mice conferred protection from both lethal and sublethal influenza A virus (IAV) infection. Progesterone treatment altered the inflammatory environment of the lungs, but had no effects on viral load. Progesterone treatment promoted faster recovery by increasing TGF-β, IL-6, IL-22, numbers of regulatory Th17 cells expressing CD39, and cellular proliferation, reducing protein leakage into the airway, improving pulmonary function, and upregulating the epidermal growth factor amphiregulin (AREG) in the lungs. Administration of rAREG to progesterone-depleted females promoted pulmonary repair and improved the outcome of IAV infection. Progesterone-treatment of AREG-deficient females could not restore protection, indicating that progesterone-mediated induction of AREG caused repair in the lungs and accelerated recovery from IAV infection. Repair and production of AREG by damaged respiratory epithelial cell cultures in vitro was increased by progesterone. Our results illustrate that progesterone is a critical host factor mediating production of AREG by epithelial cells and pulmonary tissue repair following infection, which has important implications for women’s health.
Worldwide, the use of hormonal contraceptives is on the rise as a primary intervention for improving women’s health outcomes through reduced maternal mortality and increased childhood survival. There are many hormone contraceptive formulations, all of which contain some form of progesterone. Although the effects of hormone contraceptives and progesterone, specifically, have been evaluated in the context of infections of the reproductive tract, the effects of progesterone at other mucosal sites, including the respiratory tract have not been systematically evaluated. We have made the novel observation that administration of progesterone to female mice depleted of progesterone confers protection against both lethal and sublethal influenza A virus infection. In particular, progesterone reduces pulmonary inflammation, improves lung function, repairs the damaged lung epithelium, and promotes faster recovery following influenza A virus infection. Progesterone causes protection against severe outcome from influenza by inducing production of the epidermal growth factor, amphiregulin, by respiratory epithelial cells. This study provides insight into a novel mechanistic role of progesterone in the lungs and illustrates that sex hormone exposure, including through the use of hormonal contraceptives, has significant health effects beyond the reproductive tract.
Funding: This study was supported by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (grant numbers AI112838 and HHSN272201400007C to SLK and AI097417 to AP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Citation: Hall OJ, Limjunyawong N, Vermillion MS, Robinson DP, Wohlgemuth N, Pekosz A, et al. (2016) PLoS Pathog 12(9): e1005840. doi:10.1371/journal.ppat.1005840
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