Follicular lymphoma is the most common low-grade non-Hodgkin lymphoma diagnosed in the United States. Although men have a higher risk of developing non-Hodgkin lymphoma overall, women develop the follicular lymphoma subtype at higher rates.

Researchers have pointed to certain factors that affect the immune response — such as sex hormones, smoking history, Sjögren’s syndrome, and chemical exposure — that may help to explain biological sex differences in follicular lymphoma rates.

Sex Hormones and Follicular Lymphoma

While there are many causes of follicular lymphoma, numerous studies have observed sex-specific differences in disease incidence (rate).

Sex hormones (including estrogen and progesterone) are known to affect the development of lymphocytes (white blood cells, specifically B cells), cytokine production, and cytokine receptor expression. Cytokines are proteins that play a role in inflammation and the immune response. B cells help the body fight infections by producing antibodies.

In follicular lymphoma, B cells grow abnormally in the part of the lymph node called the follicle. Follicular lymphoma develops in the lymph nodes before spreading throughout the lymphatic system, such as to the bone marrow and spleen.

Because of the relationship between sex hormones and immune function, many researchers have studied the effects of sex hormones in oral contraceptives (birth control pills) on follicular lymphoma’s immune response and development.

Birth control pills are commonly used to prevent pregnancy and maintain consistent hormone levels in the body. Birth control pills typically are composed of progesterone and estrogen, hormones that occur naturally in the body. Estrogen helps to increase the production of cytokines, aiding in normal immune system functioning.

Animal studies have found that synthetic estrogen in oral contraceptives can increase mice sensitivity to prolactin, which can cause some types of B cells to become follicular B cells. Researchers believe this change may increase B-cell growth and increase the risk of follicular lymphoma.

A large-scale study found that women using oral contraceptives had a higher chance for follicular lymphoma. Researchers found higher risk when oral contraceptive use started after the age of 21, when it was used for less than five years, and when use stopped more than 20 years before diagnosis with follicular lymphoma.

However, research is mixed. Another large-scale study found that women who started using oral contraceptives before age 25 had a lower average risk of non-Hodgkin lymphoma, including follicular lymphoma.

Overall, studies on the effect of oral contraceptives are limited, and researchers are not entirely confident that oral contraceptive use leads to follicular lymphoma. More studies are needed to understand the association between female sex hormones and follicular lymphoma.

Sex-Specific Risk Factors

Other sex-specific risk factors may explain why some people develop follicular lymphoma at higher rates. Several studies have found that, compared to men, women with a smoking history or Sjögren’s syndrome are at a greater risk of developing follicular lymphoma.

Smoking History

Studies have found a strong link between smoking history and the risk of developing follicular lymphoma. Although men tend to smoke tobacco at higher rates than women, one study found that women with a smoking history are at an increased risk for follicular lymphoma compared to men.

Smoking tobacco can cause certain genetic mutations. Genetic changes directly affect the immune system and its pathways, predisposing people to developing follicular lymphoma.

Sjögren’s Syndrome

Some autoimmune diseases, such as rheumatoid arthritis, lupus, celiac disease, and Sjögren’s syndrome, increase the risk of non-Hodgkin lymphoma. Studies have found that Sjögren’s syndrome is more common in women than men and may increase the risk of developing follicular lymphoma.

Learn more about the stages of follicular lymphoma.

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