PMDD, Histamine, and Mast Cells: Exploring New Avenues for Treatment

Premenstrual Dysphoric Disorder (PMDD) is a severe form of premenstrual syndrome (PMS) that affects 3-8% of menstruating individuals. It is characterized by extreme mood swings, irritability, fatigue, and physical symptoms like bloating, headaches, and breast tenderness that occur during the luteal phase of the menstrual cycle. PMDD is much more debilitating than PMS, often disrupting daily life, relationships, and work. While the precise cause of PMDD remains unclear, growing evidence suggests a potential connection between histamine, mast cell activation, and the severity of PMDD symptoms.

What Is PMDD?

PMDD is a chronic and serious condition that requires medical attention. Unlike PMS, the symptoms of PMDD are so severe that they interfere with day-to-day functioning. These symptoms typically appear in the week leading up to menstruation and disappear a few days after the period starts. While the exact cause is unknown, PMDD is believed to be linked to an abnormal reaction to the hormonal fluctuations that occur during the menstrual cycle. This abnormal response may result in serotonin deficiencies, which can significantly affect mood and physical well-being.

Symptoms of PMDD include:

• Depressed mood or hopelessness
• Increased anxiety and tension
• Mood swings and irritability
• Fatigue or lethargy
• Changes in appetite and sleep patterns
• Breast tenderness, bloating, and headaches

People with a personal or family history of depression, PMS, or other mood disorders may be at higher risk of developing PMDD. It can also be exacerbated by lifestyle factors like smoking and stress.

The Role of Histamine and Mast Cells in PMDD

Mast cells are immune cells that play a key role in allergic reactions, releasing chemicals such as histamine, prostaglandins, and inflammatory cytokines. Histamine, commonly known for its role in allergic responses, also acts as a neurotransmitter that regulates several physiological processes, including mood, digestion, and pain perception. It has been found to rise and fall with estrogen levels during the menstrual cycle, particularly just before ovulation and during the luteal phase. This makes histamine a likely contributor to premenstrual mood swings and physical discomforts like bloating and breast tenderness.

In individuals with PMDD, histamine appears to be elevated, exacerbating mood-related symptoms like anxiety and irritability. Estrogen, which fluctuates significantly throughout the menstrual cycle, is known to stimulate mast cells to release more histamine. This relationship between estrogen, mast cells, and histamine may be a significant factor in the severity of PMDD symptoms.

Hormonal Dysregulation and Mast Cells

Hormonal changes, particularly those involving estrogen and progesterone, can influence the activity of mast cells, leading to increased histamine release during certain phases of the menstrual cycle. When mast cells release histamine, they can contribute to inflammation, pain, anxiety, and mood swings. Studies have shown that hormone-mediated immune responses, especially those involving mast cells, are significant in explaining why PMDD symptoms worsen during the luteal phase.

Sex hormones like estradiol and progesterone influence mast cell behavior. Estradiol promotes mast cell degranulation, leading to the release of histamine, while progesterone may inhibit this process under certain conditions. This intricate balance explains why women experience increased allergic reactions, migraines, or anxiety during the luteal phase, further complicating the hormonal landscape in PMDD.

Antihistamines: A Potential Treatment for PMDD

Given the role of histamine in PMDD, it raises the question: can antihistamines help alleviate PMDD symptoms? Antihistamines block the action of histamine, potentially reducing mood-related and physical symptoms like irritability, anxiety, bloating, and breast tenderness. Although research is still limited, anecdotal evidence and small studies suggest that antihistamines could offer relief for some individuals with PMDD, especially those with coexisting Mast Cell Activation Syndrome (MCAS) or Histamine Intolerance.

There are two types of antihistamines commonly used:

• H1 Blockers: These antihistamines, such as cetirizine (Zyrtec), loratadine (Claritin), and diphenhydramine (Benadryl), are typically used to treat allergies. In PMDD, they may help alleviate symptoms related to anxiety, mood swings, and physical discomfort.
• H2 Blockers: Famotidine (Pepcid) is commonly used to reduce stomach acid, but some individuals with PMDD have reported improvements in mood and physical symptoms when using H2 blockers, particularly when combined with H1 antihistamines. Doctors often recommend pepcid for histamine intolerance and MCAS because it helps to reduce symptoms of allergies, sensitivities, and inflammation both in the GI tract and throughout the body.

While the use of antihistamines for PMDD is not yet widely researched, these medications are generally well-tolerated and may be worth exploring for individuals whose PMDD symptoms are tied to histamine sensitivity.

Natural Strategies to Reduce Histamine

In addition to antihistamines, several natural approaches may help lower histamine levels and reduce mast cell activation in individuals with PMDD:

• Dietary Changes: Avoiding foods that are rich in histamine or that stimulate histamine release—such as alcohol, aged cheese, tomatoes, and fermented foods—may reduce PMDD symptoms.
• Supplements: Nutritional supplements like quercetin, vitamin B6, and magnesium are known to stabilize mast cells and reduce histamine release, offering relief from PMS and PMDD symptoms.
• Progesterone Therapy: Natural progesterone can enhance the activity of the enzyme diamine oxidase (DAO), which breaks down histamine. By boosting progesterone levels, individuals may experience fewer PMDD symptoms tied to histamine excess.

The Controversy Surrounding PMDD

Despite its recognition as a serious mood disorder, PMDD remains controversial in the medical community. The lack of a clear biomarker and its overlap with other mood disorders complicate diagnosis. Critics argue that PMDD may be pathologizing normal hormonal fluctuations, while others insist that the severity of symptoms justifies its classification as a distinct disorder. Further complicating matters, the condition is often misunderstood or misdiagnosed, leaving many women without effective treatment.

FAQ

Why does Pepcid AC help with PMDD?
Pepcid AC, also known as famotidine, is an H2 blocker that is typically used to reduce the release of stomach acid. In the context of PMDD, H2 blockers like Pepcid AC help by blocking histamine receptors in the gut and immune system, which can decrease overall histamine levels in the body. Elevated histamine is associated with symptoms like anxiety, irritability, and physical discomfort that often worsen during the luteal phase. Reducing histamine levels with Pepcid AC may relieve PMDD symptoms for some individuals.

How does Pepcid help PMDD?
Pepcid AC (famotidine) helps PMDD symptoms by reducing histamine’s impact on the body. It blocks H2 receptors, particularly those associated with the gastrointestinal system, which can help decrease bloating, abdominal discomfort, and some mood-related symptoms tied to histamine activity. By lowering histamine levels, Pepcid AC can contribute to a reduction in PMDD symptoms like anxiety, bloating, and irritability.

What other antihistamines might help with PMDD symptoms?
Various antihistamines and natural supplements may help alleviate PMDD symptoms:

• H1 Blockers: These include over-the-counter antihistamines such as loratadine (Claritin), cetirizine (Zyrtec), and diphenhydramine (Benadryl). H1 blockers target histamine receptors in the brain and other parts of the body, helping to reduce symptoms like anxiety, mood swings, and physical discomforts commonly associated with PMDD.
• H2 Blockers: Famotidine (Pepcid AC) is a well-known H2 blocker that reduces histamine’s effects in the gastrointestinal system, potentially decreasing symptoms like bloating and digestive discomfort, which can worsen in the luteal phase.
• Natural Supplements: Quercetin is a natural flavonoid with antihistamine and anti-inflammatory properties that can help stabilize mast cells and lower histamine levels. Mast cell stabilizers, such as quercetin, cromolyn, and ketotifen, help prevent histamine release, potentially reducing PMDD symptoms for individuals with histamine sensitivity.

When to take Pepcid ac for PMDD?
Doctors typically recommend taking Pepcid AC once in the morning and at night between 10- 60 minutes before eating food. The dose may need to increase or decrease along with your PMDD symptoms and your cycle. You should always consult with your doctor before starting medications.

What is the best antihistamine for PMDD?
The best antihistamine for PMDD varies depending on individual symptoms and responses. Many people find relief with a combination of H1 and H2 blockers, such as cetirizine (Zyrtec) or loratadine (Claritin) alongside famotidine (Pepcid AC). For those who prefer a natural approach, quercetin can act as a natural antihistamine and mast cell stabilizer. Consulting with a healthcare provider can help determine the most effective antihistamine strategy for managing PMDD symptoms.

Can high histamine cause PMDD?
High histamine levels may worsen PMDD symptoms, particularly due to its impact on mood, sleep, and physical discomfort.

Can hormones cause mast cell activation?
Yes, hormonal changes, especially involving estrogen, can trigger mast cells to release histamine, contributing to PMDD symptoms.

What are MCAS symptoms during the period?
MCAS symptoms during menstruation can include severe bloating, headaches, joint pain, fatigue, anxiety, and mood swings due to increased histamine release.

What conditions are related to PMDD?
Conditions related to PMDD include depression, anxiety disorders, irritable bowel syndrome (IBS), and Mast Cell Activation Syndrome (MCAS).

What hormone imbalance causes PMDD?
A relative deficiency in progesterone and fluctuating estrogen levels are thought to play a role in PMDD, alongside a serotonin deficiency.

What aggravates PMDD?
Stress, poor diet, smoking, lack of exercise, and alcohol can all worsen PMDD symptoms. Hormonal imbalances and histamine-triggering foods may also exacerbate symptoms.

Which antihistamine is best for PMDD?
Both H1 blockers (like cetirizine and loratadine) and H2 blockers (like famotidine) have shown potential in reducing PMDD symptoms. A combination of both may offer the best results for some individuals.

How do you snap out of PMDD?
Managing PMDD involves a combination of medication, lifestyle changes, and mental health support. Regular exercise, stress management, and a balanced diet can help alleviate symptoms over time.

Why did I suddenly develop PMDD?
PMDD can develop due to hormonal changes, stress, or underlying health conditions. Some women experience it after childbirth or other major hormonal shifts.

What is the gold standard treatment for PMDD?
Selective serotonin reuptake inhibitors (SSRIs) are considered the gold standard for PMDD treatment, alongside hormonal therapies and lifestyle interventions.

What deficiencies cause PMDD?
Deficiencies in magnesium, vitamin B6, and calcium are linked to more severe PMDD symptoms.

Why is PMDD a controversy?
PMDD’s controversy lies in its diagnostic challenges, overlap with other mood disorders, and its recent recognition as a distinct condition, leading to debates over its classification.

What can mimic PMDD?
Conditions like depression, anxiety, thyroid disorders, and even endometriosis can mimic the symptoms of PMDD.

Does PMDD get worse with age?
PMDD can worsen with age, particularly as women approach perimenopause when hormonal fluctuations become more erratic.

What medication is good for PMDD?
SSRIs, hormonal treatments (such as birth control), and antihistamines are commonly used to manage PMDD symptoms. NSAIDs and nutritional supplements can also help.

Conclusion

PMDD is a debilitating condition that affects many aspects of life, from work and relationships to mental and physical health. While traditional treatments like SSRIs and hormonal therapies remain effective, emerging research on the role of histamine and mast cells offers new hope. Antihistamines, natural mast cell stabilizers, and lifestyle changes could provide additional relief for those who find that histamine plays a role in their PMDD symptoms. As more research is conducted, these approaches may become valuable additions to the PMDD treatment landscape.

References

• Roomruangwong, Chutima, et al. "Menstruation Distress is Strongly Associated with Hormone-Immune-Metabolic Biomarkers." Journal of Psychosomatic Research, vol. 138, 2020, p. 110355, https://doi.org/10.1016/j.jpsychores.2020.110355.
• Zierau, Oliver, et al. "Role of Female Sex Hormones, Estradiol and Progesterone, in Mast Cell Behavior." Frontiers in Immunology, vol. 3, 2012, p. 169, https://doi.org/10.3389/fimmu.2012.00169.
• International Association for Premenstrual Disorders (IAPMD). "What Is the Role of Histamine and Mast Cells in PMS and PMDD? Can Antihistamines Help Alleviate PMDD Symptoms?" IAPMD, https://faq.iapmd.org/en/articles/8057891. Accessed 16 Sept. 2024.

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