The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 54

68. How does mast cell disease affect pregnancy?

One of the things mast cells normally do in the body is regulate the female reproductive cycle. Mast cells in the endometrium, the uterine lining that is shed during menstruation, become activated and release mediators in the days before and during menstruation. Many of the symptoms of premenstrual syndrome (PMS) occur because of mast cell degranulation. These symptoms include things like cramps and bloating.

Because mast cells are involved in controlling the reproductive cycle, they are responsive to the effects of hormones like estrogen and progesterone. In particular, estrogen can directly cause mast cell degranulation.

In some allergic conditions like asthma, patients often have flares right before or during their menstrual period. This is often the case with mast cell patients as well. The change in hormones, the built in mast cell activation, and the bleeding, can all cause mast cell symptoms.

A study on the effects of the pregnancy on mastocytosis found that there was a lot of variability in what patients experienced. 33% of women had symptom improvement during pregnancy. In these women, their symptoms mostly improved beginning in the first trimester and continued throughout their pregnancy. 45% of patients had no change in symptoms during pregnancy. The remainder had worsened symptoms.

Mastocytosis did not seem to affect the outcome of pregnancy compared to the normal population. Premedication was recommended at the start of labor. Many women safely received anesthesia. In women who reacted, 2/3 had not premedicated. Induction of labor with medication was well tolerated. Both vaginal delivery and Caesarean section was performed safely on women with mastocytosis. The frequency of Caesarean section, miscarriage, prematurity and low birth weight were similar to the general population.

In some instances, severe allergic reactions and anaphylaxis can induce early labor, so patients should be aware of this risk.  Histamine can trigger uterine contractions.

An important thing to consider is that mast cell patients may have to change or stop some of their medications while pregnancy to avoid effects upon the fetus. In particular, the use of epinephrine is discouraged in pregnancy because it causes uterine contractions. Mast cell patients should have an alternative plan for anaphylaxis that excludes epinephrine where possible. Any mast cell patient who is pregnant or considering becoming pregnant should have detailed discussions with their providers about it.

For more detailed reading, please visit the following posts:
Pregnancy in mastocytosis
Effects of estrogen and progesterone and the role of mast cells in pregnancy

Interplay between mast cells and hormones: Part 3 of 8

Hormone Location released Major functions Interaction with mast cells Reference
Dopamine Hypothalamus

Adrenal gland (medulla)

Inhibit prolactin released from pituitary

Increase heart rate and blood pressure

Inhibit norepinephrine release

 

 

Enhances mast cell degranulation

Perpetuates immediate and late phase hypersensitivity reactions

H3 receptor activation inhibits dopamine production

Dopamine is released by mast cells

H1 inverse agonists increase dopamine release

Histamine increases dopamine release

Mori T, et al. D1-like dopamine receptors antagonist inhibits cutaneous immune reactions mediated by Th2 and mast cells. Journal of Dermatological Science 2013: 71, 37-44.

Xue L, et al. The effects of D3R on TLR4 signaling involved in the regulation of METH-mediated mast cell activation. International Immunopharmacology 2016: 36. 187-198.

Endothelin Stomach Promotes smooth muscle contraction of stomach

Very potent vasoconstrictor

Activates mucosal mast cells

Mast cells regulate endothelin levels to prevent loss of blood flow to tissues

Boros M, et al. Endothelin-1 induces mucosal mast cell degranulation and tissue injury via ETA receptors. Clin Sci (Lond) 2007: 103(48), 31S-34S.

Hultner L, Ehrenreich H. Mast cells and endothelin-1: a life-saving biological liaison. Trends Immunol 2005: 26(5), 235-238.

 

Epinephrine/ adrenaline Adrenal gland (medulla), sympathetic nervous system Fight or flight response

Increases heart rate, force of heart contraction, blood pressure, energy breakdown, production of ACTH, bloodflow and energy to the brain and muscles

Suppresses nonessential functions and significantly decreases GI motility and excretion of urine and stool

Epinephrine inhibits IgE mediated released of histamine, prostaglandins and TNF

Epinephrine inhibits mast cell proliferation, adhesion and movement within the body SCF reduces action of epinephrine on mast cells by decreasing B2 adrenergic receptors

 

 

Cruse G, et al. Counterregulation of beta(2)-adrenoceptor function in human mast cells by stem cell factor. J Allergy Clin Immunol 2010: 125(1), 257-263.

Scanzano A, Cosentino M. Adrenergic regulation of innate immunity: a review. Front Pharmacol 2015.

Erythropoietin Kidney Stimulate red blood cell production

Protects nerve cells and tissues

During low oxygen events, mast cells express receptors for erythropoietin

Erythropoietin can bind at the CKIT receptor

Decreases inflammatory response to infection (decreases IL-6 and TNF)

Wiedenmann T, et al. Erythropoietin acts as an anti-inflammatory signal on murine mast cells. Mol Immunol 2015: 65(1), 68-76.
Estradiol and other estrogens Ovaries, placenta, adipose tissue, testes Drive female secondary sex characteristics

Increase metabolism, uterine and endometrial growth, bone production, and the release of cholesterol in bile

Increase production of proteins in liver, cortisol, sex hormone binding globulin, somatostatin, clotting factors II, VII, IX, X, antithrombin III and plasminogen, HDL, triglycerides

Decrease LDL, production of adipose tissue, GI motility

 

 

Modulate salt and water retention

Inhibits programmed cell death of germ cells

E2 is a very potent mast cell degranulator

E2 drives mast cell degranulation in ovaries to trigger ovulation

Enhances IgE mediated degranulation

Increased production of leukotrienes

Increases mast cell density in ovaries

Zaitsu M, et al. Estradiol activates mast cells via a non-genomic estrogen receptor-a and calcium influx. Mol Immunol 2007: 44(8), 1977-1985.

Zierau O, et al. Role of female sex hormones, estradiol and progesterone, in mast cell behavior. Front Immunol 2012: 3, 169.

Follicle stimulating hormone (FSH) Pituitary Stimulates maturation of ovarian follicles

Stimulates maturation of seminiferous tubules, production of sperm and production of androgen binding protein

Triggers mast cell degranulation

Increases mast cell density in ovaries

Theoharides TC, Stewart JM. Genitourinary mast cells and survival. Transl Androl Urol 2015: 4(5), 579-586.

Jaiswal K, Krishna A. Effects of hormones on the number, distribution and degranulation of mast cells in the ovarian complex of mice. Acta Physiol Hung 1996: 84(2), 183-190.

Gastric inhibitory polypeptide/ glucose-dependent insulinotropic polypeptide (GIP) Duodenum, jejunum Triggers release of insulin

Involved in fatty acid metabolism

Involved in bone formation

May suppress release of stomach acid triggered by histamine McIntosh CHS, et al. Chapter 15 Glucose-Dependent Insulinotropic Polypeptide (Gastric Inhibitory Polypeptide; GIP). Vitamins & Hormones 2009: 80, 409-471.
Gastrin Stomach, duodenum, pancreas Release of gastric acid

Release of pepsinogen, the precursor to pepsin

Triggers secretion of pancreatic enzyme

Triggers emptying of gallbladder

Increases stomach motility

Triggers release of histamine in enterochromaffin-like cells to trigger gastric acid secretion

Triggers mast cell degranulation

Gastrin releasing peptide, which induces gastrin release, triggers histaminergic itching response

Akiyama T, et al. Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch. Pain 2014: 155, 80-92.

 

Symptoms, mediators and mechanisms: A general review (Part 2 of 2)

 

Gynecologic symptoms    
Symptom Mediators Mechanism
Irregular and painful menstruation Histamine (H1), bradykinin Smooth muscle constriction
Uterine contractions Histamine (H1), serotonin, bradykinin Smooth muscle constriction

Increased estrogen

 

 

Neurologic symptoms    
Symptom Mediators Mechanism
Appetite dysregulation Histamine (H1), histamine (H3), leptin Dysfunctional release of neurotransmitters, suppression of ghrelin
Disorder of movements Histamine (H2), histamine (H3) Dysfunctional release of neurotransmitters, increases excitability of cholinergic neurons
Memory loss Histamine (H1), histamine (H3) Dysfunctional release of neurotransmitters
Headache Histamine (H1), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

Low serotonin

 

Decreased blood flow to brain

Depression Serotonin (low), TNF, histamine (H1) Low serotonin

Disordered release of dopamine

Irregular sleep/wake cycle Histamine (H1), histamine (H3), PGD2 Dysfunctional release of neurotransmitters
Brain fog Histamine (H3), inflammatory cytokines Dysfunctional release of neurotransmitters, neuroinflammation
Temperature dysregulation Histamine (H3) Dysfunctional release of neurotransmitters, dysfunctional release of catecholamines

 

 

Miscellaneous symptoms    
Symptom Mediators Mechanism
Bleeding diathesis (tendency to bleed easily) Tryptase, heparin Participation in anticoagulation pathways

Role of sex hormones in hereditary angioedema

Sex hormones are well known for influencing symptoms of immune mediated conditions. Estrogen can affect cell proliferation and activation. Menses, pregnancy, menopause, and use of oral contraception are known to affect hereditary angioedema (HAE) but it is not yet clear how.

One hypothesis is that estrogen may activate the kallikrein-kinin system, thereby increasing production of bradykinin. Another hypothesis is that estrogen can affect the expression of the FXII gene, which produces the initiating molecule in the bradykinin pathway. Estrogen may also regulate the B2 receptors that bradykinin binds to. While all of these ideas are possible, there have not yet been any definitive findings.

In female patients, onset of HAE often correlates with the start of puberty. Menses, pregnancy and delivery also correlate with flare ups of HAE. Puberty makes HAE attacks more frequent and severe in 56.7% of cases; menses does the same in 35.3%; ovulation, 14%. Use of estroprogestin contraceptives irritate and worsen HAR in 63-80% of HAE women. The first trimester of pregnancy is known to be a difficult time for HAE women, as circulating estrogen is particularly high and many women discontinue maintenance therapy out of safety concerns for the fetus.

In patients with type III HAE in whom a Factor XII mutation has been identified, episodes occur almost exclusively during periods of high estrogen. This initial observation led to type III to be called “estrogen dependent HAE”, but this only refers to a subset of patients and has fallen out of use. Estrogen levels do not affect symptoms in other type III HAE patients (without the Factor XII mutation) and in many acquired angioedema patients.

Female HAE patients of reproductive age, who are not using oral contraceptives, often have polycystic or multifollicular ovaries. Ovulation is a complex multistep process in which two steps are controlled by C1INH.

 

 

References:

Zuraw, B. L., et al. A focused parameter update : Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013; 131(6); 1491-1493e25.

Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

Kaplan AP, et al. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 2010 Aug; 47(13):2161-9.

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Ohsawa, Isao, et al. Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol 114 (2015) 492-498.

 

 

 

 

Effects of estrogen and progesterone and the role of mast cells in pregnancy

The term estrogen generally refers to estrogen estradiol (E2.)  This steroid hormone is induced when gonadotropin releasing hormone (GnRH) is released in the hypothalamus and acts on the pituitary gland.  This in term releases follicle stimulating hormone (FSH) which acts on the follicle, resulting in the release of estrogen.  Secretion of GnRH is stimulated by a protein called kisspeptin. High levels of estrogen or progesterone inhibit the secretion of kisspeptin.  Hormone levels are regulated in this way. 

Estrogen is mostly produced by the ovaries and placenta, but is made in smaller amounts by the liver, adrenal glands, breasts and fat cells.  E2 promotes secondary female sex characteristics, increases metabolism, increases fat stores, stimulates endometrial and uterine growth, promotes vaginal lubrication, thickens the vaginal wall, maintains integrity of blood vessels and skin, reduces bone resorption and increases bone formation.  It also promotes effective coagulation by increasing platelet adhesion.  E2 increases HDL cholesterol and triglycerides while decreasing LDL and fat deposition.  It balances salt and water retention, increases cortisol levels, reduces bowel motility, and increases the amount of cholesterol found in bile.  It also promotes wound healing and has anti-inflammatory properties.

With progesterone, E2 promotes and maintains the uterine lining, as well as increasing the amount of oxytocin released during pregnancy.  Estrogen surge induces the secretion of luteinizing hormone, triggering ovulation. 
Progesterone (P4) also regulates salt and water balance, prepares the uterus for implantation, affects vaginal tissue and cervical mucus to prevent sperm from entering the uterus during pregnancy, suppresses menstruation, decreases maternal immune response to pregnancy, decreases contractility of uterine smooth muscle and inhibits lactation during pregnancy.  With prolactin, progesterone prepares breast tissue for milk production after childbirth.  Drop in progesterone levels during pregnancy is thought to be a key step in induction of labor.  Progesterone also has a variety of other regulatory effects, though the exact nature of these functions is not entirely clear.
Progesterone receptors on cells can be increased by the action of estrogen.  Furthermore, the activity of progesterone is amplified by the presence of estrogen.
The importance of mast cells in reproductive biology has been known for over sixty years.  Mast cells express receptors for both estrogen and progesterone.  These hormones together attract mast cells from the peripheral tissues to the uterus.  Furthermore, they induce the maturation of mast cells and directly cause degranulation in a dose dependent manner.  Together, they induce more degranulation than individually.
During pregnancy, embryo-derived histamine releasing factor induces secretion of histamine by uterine mast cells.  Histamine is also secreted by endothelial and decidual cells.  Mast cells have a protective role in ensuring successful embryo implantation.  Mast cells also positively influence the growth of blood vessels and participate in tissue remodeling so that the pregnancy can be sustained through placental growth and adequate blood supply. Degranulation increases uterine contractility through histamine and serotonin action.  Allergic activation causes significant contractions. 
In placentas from intrauterine growth retardation, mast cell concentrations are significantly decreased.  When mast cell numbers are diminished, the cells formed following implantation are at different stages, and are smaller and delayed.  Pregnancies with this feature generally do not survive.
In some cases, severe allergic reactions are thought to be responsible for preterm labor.  Additionally, degranulation in pre-eclampsic patients caused increased vascular resistance, likely from vasoconstriction by histamine.  Asthmatic pregnant women are known to be at a higher risk of pre-eclampsia.  People with other mast cell diseases should likewise by monitored for this condition.
Estrogen and progesterone levels can be correlated to symptoms in asthma.  Postmenopausal women taking hormone replacement therapy have a higher risk of new onset asthma.  30-40% women have asthma with more symptoms during the premenstrual period when estrogen and progesterone concentrations are dynamic.  Many women with mast cell disease likewise report more degranulation when menstruating.  Mast cell density in non-uterine tissues is much higher in pregnant woman, likely due to the higher hormone concentrations. 
A paper released in 2013 referenced a 2001 study by Metcalfe and Akin that found that women with SM were more likely to have preterm labor and delivery.  However, a 2011 study in Spain found that only 3/45 (6.7%) women delivered prematurely.  The rate of preterm birth in the general Spanish population is 7.4%.  It is unclear whether this change was due to increasing understanding of SM and more effective treatment, or due to the changes in diagnostic criteria between these studies.
The presence of mast cells is crucial for healthy pregnancy.  However, excessive activation can cause contractions and increased symptoms for pre-eclampsia patients.  The most recent study demonstrates that overwhelmingly, women with SM deliver healthy babies at the appropriate time.

 

References:
Woidacki, K., Jensen, F., Metz, Zenclussen, A. (2013). Mast cells as novel mediators of reproductive processes. Front. Immunol. 10.
Woidacki, K., Popovic, M., Metz, M., Schumacher, A., Linzke, N., Teles, A., et al. (2013). Mast cells rescue implantation defects caused by c-kit deficiency. Cell Death Dis.4, e462.
Metcalfe, D. D., and Akin, C. (2001). Mastocytosis: molecular mechanisms and clinical disease heterogeneity. Leuk. Res. 25, 577–582.
Jensen F, Woudwyk M, Teles A, Woidacki K, Taran F, Costa S et al. (2010). Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation. PLoS One 2010; 5: e14409.
Matito, A., et al.  (2011.) Clinical impact of pregnancy in mastocytosis: A study of the Spanish network on mastocytosis (REMA) in 45 cases.  Int Arch Allergy Immunol; 156: 104-111.