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Male Infertility Could Have an Autoimmune Origin

October 19, 2021
Riley Kleemeier

A small number of men are diagnosed with the rare autoimmune disorder called autoimmune polyendocrine syndrome type I (APS-1). Researchers decided to study how this autoimmune disorder can play a role in male fertility. They studied fertility problems in mice in order to find a correlation. 

The results of their study, which were published in The American Journal of Pathology, could impact the treatment and management of male infertility, and will be helpful for future fertility studies to build off of. 

What Is APS-1?

APS-1 is caused by mutations in the autoimmune regulator gene, or AIRE. It is a rare autoimmune disorder that involves a group of symptoms, such as endocrine gland and gastrointestinal dysfunctions. It can also lead to autoimmunity against different organs.

Autoimmune disorders are caused when antibodies and immune cells are “launched by the body against one or several antigens of its own tissues.”  

The most common symptom of APS-1 is chronic mucocutaneous candidiasis (CMC), which is recurrent infections that can occur in the skin, nails, mouth, and other areas. 

More than 75% of patients with APS-1 develop hypoparathyroidism, or dysfunction of the parathyroid glands. This can lead to muscle cramping and spasms, rigidity, and seizures. 

The thyroid gland controls a person’s metabolism Image courtesy of Hormone Health Network.

APS-1 is thought to affect as little as 1 in every 2-3 million newborns in the US. It is a rare and complex disease, but that doesn’t lessen the importance of studying its impacts. It is important to distinguish APS-1 from the more common APS-2. APS-2 is reportedly characterized by type 1 diabetes and autoimmune thyroid diseases. 

The AIRE Gene

AIRE, a gene that is expressed in the thymus, has an important role in the immune system. It teaches the immune system to be able to distinguish between the body’s own cells and “invaders.” 

The thymus is located behind your sternum, between your lungs, and it is only active until puberty. After puberty, the thymus slowly shrinks and is replaced by fat. The thymus produces a hormone called thymosin, which stimulates the development of T cells. By the time you reach puberty, the thymus has created all of your T cells. Image courtesy of Uncover Reality.

Researchers wanted to explore how fertility can be impacted through autoimmune disease. The lead investigator of the study, Margaret G. Petroff, PhD, said that this study is important “because it represents a previously underexplored mechanism by which fertility can be impacted through autoimmune disease.”

The study was conducted on mice who are deficient in AIRE, because they produce many of the same features that humans with APS-1 present. In order to determine the mices’ fertility, the AIRE-deficient mice and wild-type mice were paired with wild-type female mice. 

The mice that were AIRE-deficient had “dramatically reduced mating frequency and fertility,” and the mice who did mate took as long as two weeks to do so. The sperm quality in these mice was also deemed poor — their sperm was rarely able to produce a litter. Viable embryos could not be produced even through in vitro fertilization. 

Upon further studying the mice, researchers found that the AIRE-deficient males produced low levels of testosterone and developed autoimmune diseases. Many of them specifically developed autoimmune diseases against the epididymis, which is where sperm cells are stored. They decided to study this further, as they could not yet rule out the possibility that AIRE was not just expressed in the thymus. They said that “it is possible that the injuries could be caused by a lack of expression in the tissues themselves.” 

A fluorescence reporter model, a model in which cells change color based on past or current expression of AIRE, was used to confirm that the AIRE gene can be expressed in the mouse reproductive system. Dr. Petroff said they were “surprised to find evidence of AIRE in the testis and prostate gland, suggesting that it may have an immune-independent role in these tissues.”


This study emphasized a correlation between impaired central immune tolerance and fertility. But more patients than just those with APS-1 could be helped — researchers believe that the findings of this study could also provide insight into other male autoimmune and “unexplained cases of infertility.” In summarizing their study, researchers said, “AIRE-dependent central tolerance plays a critical role in maintaining male fertility by preventing autoimmune attacks against multiple reproductive targets.” 

Infertility is a struggle that many couples go through, but it can sometimes be hard to determine the exact cause. This study may help doctors pinpoint causes of male infertility and develop specific treatments for them. 

Many men are impacted by infertility, and the information obtained in this study, as well as future studies that can build off of it, may be helpful in developing treatments and prophylactics to delay or halt degenerative processes that affect fertility. Dr. Petroff specifically suggested the use of general immunosuppressive treatments, but she also said that it may be possible to design specific therapies that can target particular immune cells. These therapies could prevent specific cells from causing damage to reproductive organs.

Overall, this study is a potential gateway for more male infertility research. Dr. Petroff explained, “Male factors account for a large portion of infertility in couples, and the mechanisms underlying male infertility are poorly understood.” This study may be able to change that. 


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