The Hormone Connection
If you’re a woman between 25 and 50 struggling with Mast Cell Activation Syndrome (MCAS), you’re not alone—and your hormones may be playing a bigger role than you think.
Research shows that MCAS predominantly affects women during their reproductive years, and the connection between female sex hormones and mast cell behavior is both profound and scientifically well-documented [1][2].
Understanding how estrogen, progesterone, and the menstrual cycle influence mast cell activation can help you anticipate symptom flares, optimize treatment timing, and make informed decisions about pregnancy and menopause management.
Why MCAS Affects More Women Than Men
The gender disparity in MCAS isn't coincidental. Multiple studies have demonstrated that female sex hormones—particularly estrogen and progesterone—directly influence mast cell behavior [1]. This explains why:
MCAS symptoms often worsen during specific phases of the menstrual cycle
Many women first develop MCAS symptoms during puberty, pregnancy, or perimenopause
Asthma and allergic diseases (both mast cell-mediated) are up to three times more common in women during reproductive years [1]
Postmenopausal women on hormone replacement therapy have an increased risk of new-onset asthma [1]
The key lies in understanding that mast cells express receptors for both estrogen and progesterone, making them exquisitely sensitive to hormonal fluctuations [1].
The Estrogen Effect: Turning Up Mast Cell Activity
Estrogen is the primary driver of increased mast cell activation in women. Research has consistently shown that estrogen enhances mast cell degranulation—the process by which mast cells release histamine and other inflammatory mediators [1][2].
How Estrogen Activates Mast Cells
When estrogen binds to estrogen receptors (particularly ESR1) on mast cells, it triggers a cascade of events:
Direct activation of mast cells, making them more "trigger-happy"
Enhanced degranulation response when mast cells encounter allergens or other triggers
Increased production and release of histamine, tryptase, and inflammatory cytokines [1][2]
A groundbreaking study published in Frontiers in Immunology found that estradiol (the most potent form of estrogen) not only promotes mast cell activation but also induces mast cell maturation and migration to tissues like the uterus [3]. This explains why many women experience pelvic pain, endometriosis-like symptoms, or bladder issues (interstitial cystitis) as part of their MCAS presentation.
Environmental Estrogens: An Emerging Concern
Research has revealed an alarming connection between environmental pollutants and rising rates of allergic diseases. Xenoestrogens—estrogen-like compounds found in plastics, pesticides, and water contamination—can activate mast cells and enhance their degranulation response [1]. This may partially explain the dramatic increase in allergic diseases and MCAS over the past 30 years, particularly in industrialized countries.
Progesterone: The Protective Hormone
While estrogen amplifies mast cell activity, progesterone acts as a natural mast cell stabilizer [2]. Progesterone:
Inhibits mast cell degranulation
Reduces histamine release
Counterbalances estrogen's pro-inflammatory effects
This opposing relationship between estrogen and progesterone is crucial for understanding symptom patterns throughout the menstrual cycle.
The Menstrual Cycle: A Monthly Rollercoaster
For women with MCAS, the menstrual cycle can feel like a predictable pattern of symptom flares and relief. The science explains why.
Follicular Phase (Days 1-14): The Estrogen Rise
During the first half of your cycle, estrogen levels gradually increase while progesterone remains low. As estrogen climbs:
Mast cells become increasingly activated
Histamine levels rise
MCAS symptoms may begin to intensify
Ovulation (Day 14): The Peak
Estrogen reaches its highest level just before ovulation. Many women report:
Increased flushing, hives, or skin reactions
Worsening brain fog and anxiety
Heightened food sensitivities
Increased gastrointestinal symptoms
Luteal Phase (Days 15-28): The Progesterone Protection
After ovulation, progesterone rises significantly while estrogen drops (but remains present). This is often when women with MCAS feel their best, as progesterone's mast cell-stabilizing effects provide relief [2].
However, there's a critical twist: DAO enzyme activity also changes with the menstrual cycle.
The DAO Connection: Your Body’s Histamine Breakdown System
Diamine oxidase (DAO) is the primary enzyme responsible for breaking down histamine in your gut and bloodstream. A landmark study published in Clinical Biochemistry revealed that serum DAO levels are significantly higher during the luteal phase (after ovulation) compared to the follicular phase [4].
This means:
Follicular phase (Days 1-14): Lower DAO activity = reduced ability to break down histamine = more symptoms
Luteal phase (Days 15-28): Higher DAO activity = better histamine clearance = fewer symptoms
The combination of rising progesterone (mast cell stabilizer) and increased DAO (histamine breakdown) during the luteal phase creates a "sweet spot" for many women with MCAS—until the premenstrual drop.
The Premenstrual Crash
In the days before menstruation, both estrogen and progesterone plummet. This sudden withdrawal can trigger:
Perimenstrual symptom flares affecting 30-40% of women with mast cell-related conditions [1]
Increased histamine levels as DAO drops
Loss of progesterone's protective effects
A phenomenon called "perimenstrual asthma" in women with asthma [1]
This is why many women with MCAS report that their worst symptoms occur in the week before their period.
Pregnancy: A Complex Hormonal Shift
Pregnancy represents one of the most dramatic hormonal changes a woman can experience—and for women with MCAS, it's unpredictable.
The Paradox of Pregnancy and MCAS
Research shows that mast cells play essential beneficial roles in pregnancy, contributing to implantation, placentation, and fetal growth [5]. However, pregnancy also involves:
Massive increases in estrogen (up to 1000-fold by the third trimester)
Elevated progesterone (which should stabilize mast cells)
Dramatically increased DAO production by the placenta [6]
The placenta produces such high levels of DAO that it's been described as a "metabolic barrier to prevent excessive histamine entry" into fetal circulation [6]. This explains why some women with MCAS experience symptom improvement during pregnancy—the placental DAO effectively lowers their histamine burden.
When Pregnancy Worsens MCAS
However, not all women experience relief. A comprehensive review published in the Journal of Obstetrics and Gynaecology documented that MCAS can adversely affect all stages of pregnancy [7], including:
Increased risk of mast cell degranulation during labor and delivery
Potential anaphylactoid reactions
Complications requiring careful medical management [7][8]
The key appears to be whether the massive increase in placental DAO can compensate for the estrogen-driven increase in mast cell activation. Individual responses vary significantly.
Menopause: The Final Hormonal Transition
Menopause brings another dramatic shift: declining estrogen and progesterone levels. For women with MCAS, this transition is highly individual.
Why Some Women Improve
The drop in estrogen means:
Reduced mast cell activation from estrogen stimulation
Fewer perimenstrual flares (since there's no longer a cycle)
Potential symptom stabilization
Why Some Women Worsen
However, other factors complicate the picture:
Loss of progesterone's protective effects (no more mast cell stabilization)
Hormone replacement therapy (HRT) can reactivate mast cells—postmenopausal women on HRT have an increased risk of new-onset asthma [1]
Age-related changes in immune function and gut health
Increased inflammation associated with metabolic changes
Research on histamine intolerance notes that serum DAO levels in premenopausal women are associated with the menstrual cycle, with higher activity during the luteal phase [9]. After menopause, this cyclical pattern disappears, potentially affecting histamine clearance in unpredictable ways.
The Estrogen-Histamine Feedback Loop
Perhaps the most insidious aspect of the hormone-MCAS connection is the bidirectional feedback loop between estrogen and histamine:
Estrogen triggers mast cells to release histamine [1][2]
Histamine stimulates the ovaries to produce more estrogen [10]
More estrogen triggers more mast cells to release more histamine
The cycle continues, creating a self-perpetuating inflammatory spiral
This explains why women with MCAS often develop symptoms of estrogen dominance—a condition where estrogen levels are disproportionately high relative to progesterone. Breaking this cycle requires addressing both mast cell activation and hormonal balance simultaneously.
Practical Implications: What This Means for You
Understanding the hormone-MCAS connection empowers you to:
1. Track Your Cycle
Keep a detailed symptom diary that includes:
Days of your menstrual cycle
Severity of MCAS symptoms
Potential triggers
Response to treatments
This data can help you and your healthcare provider identify patterns and optimize treatment timing.
2. Time Your Treatments
Consider:
Increasing mast cell stabilizers during the follicular phase (when estrogen is rising)
Supplementing with DAO enzyme during the premenstrual period (when natural DAO drops)
Tightening dietary restrictions during high-estrogen phases
3. Evaluate Hormonal Interventions Carefully
If you're considering:
Birth control pills: May worsen MCAS symptoms due to synthetic estrogens
Hormone replacement therapy: Discuss MCAS-friendly options with your provider
Progesterone supplementation: May help stabilize mast cells, but requires medical supervision
4. Support Natural Progesterone Production
Since progesterone stabilizes mast cells:
Manage stress (cortisol competes with progesterone production); consider a nutraceutical that lowers cortisol
Ensure adequate sleep
Support ovulation through nutrition and lifestyle
Discuss bioidentical progesterone with your healthcare provider
-
This can only help if you still ovulate; this will not help if you’re post-menopausal
TOP 10 MCAS-FRIENDLY PROGESTERONE-SUPPORTING FOODS:
Pumpkin seeds (excellent source of magnesium and zinc)
Hemp seeds (excellent source of magnesium; very good source of zinc and omega-3; provides protein)
Quinoa (excellent source of magnesium; good source of zinc; provides protein)
Chia seeds (excellent source of omega-3; very good source of magnesium)
Flax seeds (freshly ground for better absorption; excellent source of omega-3)
Broccoli* (fresh only; excellent source of vitamin C; moderate source of magnesium)
Sweet potatoes (good source of B6; moderate source of magnesium)
Oats (certified gluten-free only; good source of zinc and B vitamins)
Kale (fresh only; good source of vitamin C; moderate source of magnesium)
Brussels sprouts* (fresh only; excellent source of vitamin C)
OTHERS:
These foods are rich in key nutrients for progesterone production.
Carrots (fresh only, moderate source of B6)
Almonds (in moderation, good source of magnesium)
Buckwheat (good source of magnesium; gluten-free grain)
Millet (good source of magnesium; gluten-free grain)
Cauliflower* (fresh only; good source of vitamin C)
Sweet peppers (fresh only; very good source of vitamin C)
Mango* (fresh only; good source of vitamin C)
*These foods are either in the “use cautiously” category or not part of a low FODMaP diet
5. Reduce Xenoestrogen Exposure
Minimize exposure to environmental estrogens:
Avoid plastic food containers (use glass or stainless steel)
Choose organic produce when possible
Filter your drinking water
Avoid synthetic fragrances and personal care products with parabens
Avoid milk and dairy (they contain xenoestrogens, including naturally occurring hormones from pregnant cows/mammals and other endocrine-disrupting compounds)
Avoid meat (synthetic chemicals from pollutants like pesticides and industrial processes, as well as growth hormones administered to livestock, can accumulate in meat)
The Bottom Line
The predominance of MCAS in women aged 25-50 is not coincidental—it's a direct result of the profound influence that estrogen and progesterone have on mast cell behavior. Estrogen activates mast cells and promotes histamine release, while progesterone stabilizes them [1][2]. The menstrual cycle creates a monthly pattern of fluctuating mast cell activity, with DAO enzyme levels rising and falling in sync [4].
Pregnancy and menopause represent major hormonal transitions that can either improve or worsen MCAS symptoms, depending on individual factors and the balance between estrogen-driven activation and progesterone/DAO-mediated protection [5][6][7].
For women living with MCAS, understanding these hormonal influences isn't just academic—it's essential for predicting symptom patterns, timing treatments effectively, and making informed decisions about hormonal interventions. By working with healthcare providers who understand both MCAS and women's hormonal health, you can develop a comprehensive management strategy that addresses the unique challenges of being a woman with this complex condition.
References
[1] Zierau O, Zenclussen AC, Jensen F. Role of female sex hormones, estradiol and progesterone, in mast cell behavior. Frontiers in Immunology. 2012 Jun 19;3:169. doi: 10.3389/fimmu.2012.00169.
[2] Jensen F, Woudwyk M, Teles A, Woidacki K, Taran F, Costa S, Malfertheiner SF, Zenclussen AC. Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation. PLoS One. 2010 Dec 7;5(12):e14409. doi: 10.1371/journal.pone.0014409.
[3] Jeziorska M, Salamonsen LA, Woolley DE. Mast cell and eosinophil distribution and activation in human endometrium throughout the menstrual cycle. Biology of Reproduction. 1995 Aug;53(2):312-20. doi: 10.1095/biolreprod53.2.312.
[4] Hamada Y, Shinohara Y, Yano M, Yamamoto M, Yoshio M, Satake K, Toda A, Hirai M, Usami M. Effect of the menstrual cycle on serum diamine oxidase levels in healthy women. Clinical Biochemistry. 2013 Jan;46(1-2):99-102. doi: 10.1016/j.clinbiochem.2012.10.013.
[5] Woidacki K, Zenclussen AC, Siebenhaar F. Mast cell-mediated and associated disorders in pregnancy: a risky game with an uncertain outcome? Frontiers in Immunology. 2014 May 27;5:231. doi: 10.3389/fimmu.2014.00231.
[6] Maintz L, Novak N. Histamine and histamine intolerance. American Journal of Clinical Nutrition. 2007 May;85(5):1185-96. doi: 10.1093/ajcn/85.5.1185.
[7] Dorff SR, Afrin LB. Mast cell activation syndrome in pregnancy, delivery, postpartum and lactation: a narrative review. Journal of Obstetrics and Gynaecology. 2020 Apr;40(3):289-296. doi: 10.1080/01443615.2019.1674259.
[8] Gašparović VE, Rustemović N, Opačić M, Božić M. What makes a pregnant woman with mastocytosis a high risk patient? Acta Clinica Croatica. 2020 Jun;59(2):234-240. doi: 10.20471/acc.2020.59.02.06.
[9] Hrubisko M, Danis R, Huorka M, Wawruch M. Histamine Intolerance—The More We Know the Less We Know. A Review. Nutrients. 2021 Jul 2;13(7):2228. doi: 10.3390/nu13072228.
[10] Krishna A, Beesley K, Terranova PF. Histamine, mast cells and ovarian function. Journal of Endocrinology. 1989 Feb;120(3):363-71. doi: 10.1677/joe.0.1200363.
Disclaimer
This article is for educational purposes only and is not intended as medical advice. Always consult with your healthcare provider before making dietary changes, especially if you have MCAS or other medical conditions.