The health status of the female reproductive cycle is a reflection of both local and systemic health. The wide range of signs, symptoms and disorders that can occur as a result of an imbalanced cycle can present as reproductive or non-reproductive issues. The synergistic nature of systemic functionality in the body is demonstrated by the interaction between histamine, oestrogen, progesterone and cortisol. This article reviews the current evidence regarding histamine metabolism and the mechanistic and functional links between histamine, oestrogen and progesterone.
Overview of histamine metabolism
Histamine is a pleiotropic biogenic amine required for the normal function of many processes in the body including inflammation, immunity, neuromodulation and gastric acid secretion.[1,2] Normally, the formation, storage, utilisation and breakdown of histamine is tightly controlled by several measures due to its capacity to stimulate significant biological effects. However, the integrity of such measures can be adversely influenced by a number of endogenous and exogenous factors.
In the cellular organelle, the Golgi apparatus, histamine is synthesised by the decarboxylation (removal of a carbon atom) of L-histidine, a process catalysed by the inducible enzyme histidine decarboxylase (HDC).[1,3] HDC is present in mast cells and basophils (which store histamine) and enterochromaffin-like, histaminergic neurons, lymphocytes, monocytes, platelets, neutrophils, and gastric and dendritic cells, which produce histamine in response to specific stimulus (as opposed to storing it).[1-4]
One of the steps that determines the biological effect of histamine is its binding to its receptors (H1-4), with each receptor-type varying in binding capacity, physiological location and the processes consequentially induced.[2,3,5]
The H1 receptor is expressed on smooth muscle tissue, vascular endothelial cells and the brain. It is involved in immune- (IgE) and inflammatory-mediated processes initially due to the activation of this receptor. The classic histamine-associated effects include vasodilation, erythema and oedema, as well as symptoms such as allergic rhinitis, dermatitis, urticaria, asthma and anaphylaxis.[2-4] H1 also mediates adrenal catecholamine-release and central nervous system (CNS) neurotransmission.
The H2 receptor is located on immune, gastric mucosal, brain, adipocyte, vascular and uterine smooth muscle cells. Its activation is involved in the regulation of gastric acid secretion, gastrointestinal motility, and cell growth and differentiation. It is also suggested to have an immune-suppressive affect via inhibition of white blood cell chemotaxis (i.e. neutrophils, basophils, eosinophils).[2,4,6]
The H3 receptor has a significant presence on CNS histaminergic neurons, eosinophils, dendritic cells and monocytes. It regulates the secretion of neurotransmitters, nerve supply to the heart and blood vessels and smooth muscle contraction.[2,6]
Lastly, the H4 receptor is mainly expressed on haematopoietic cells, as well as on various immune cells (i.e. mast cells, eosinophils, T cells, basophils and monocytes), keratinocytes and dendritic cells. Its activation thought to be involved in inflammation and allergic processes.[2,4,6]
Another internal measure that influences histamine’s biological effects is its stimuli-induced release by either immune- or non-immunological processes.
Immune-mediated (‘classic’) histamine release involves mast cells and basophils, which degranulate stored histamine after antigen-induced IgE antibodies bind to membrane receptors.[5,7]
Non-immunological histamine release involves the degranulation of stored histamine from mast cells and basophils or the passive transport of histamine in non-storing cells, which can be induced by endogenous (neuropeptides, cytokines, complement) or exogenous (alcohol, food, medication) factors.[1,2,5]
Along with appropriate levels of endogenous histamine being produced, another vital measure influencing histamine’s impact on the body is effective metabolism and inactivation. In humans this involves two primary pathways: histamine N-methyltransferase (HNMT) catalysed-methylation of the imidazole ring and deamination of the main amino group involving diamine oxidase (DAO). The end-result of both pathways are compounds that have limited histamine-receptor binding capacities.[1,7]
Histamine metabolism by HNMT
The HNMT pathway metabolises the majority (50-80%) of endogenous histamine and consequently the expression of this cytosolic protein is widespread, including in kidney, liver, spleen, intestinal, spinal cord, placental and ovarian tissues.[1,8]
Histamine inactivated by this pathway is derived from cellular synthesis or transported from the extracellular space, whereupon it is converted to N-tele-methylhistamine with the addition of a methyl group from S-adenosyl-L-methionine and then to M-methylimidazole acetic acid before leaving the body via the urine.
Across the population, the levels of both HNMT and DAO expression and activity have been observed to exhibit significant inter-individual variability, making the establishment of ‘normal’ levels challenging.[1,2,9]
Histamine metabolism by DAO
Because this pathway inactivates exogenous histamine, DAO is largely expressed and released following a stimulus by intestinal epithelial cells, with a smaller presence in kidney and placental tissues.[1,2,9]
The intestinal absorption of histamine is largely inhibited by DAO, while any histamine that is absorbed is deaminated (removal of an amine group) to imidazole acetaldehyde, ammonia and hydrogen peroxide by the intestinal epithelial cells.[1,8]
Vitamins B6 and C and copper are essential cofactors for DAO activity.
Histamine intolerance is the consequence of excess levels of endogenous histamine inducing a broad range of systemic physiological effects in the body.[5,8] It has a complex clinical presentation, with variability observed in the type and severity of signs and symptoms that occur within and between individuals.
This is due in part to the range of organs and tissues that express histamine receptors, with symptoms of histamine intolerance presenting in gastrointestinal (diarrhoea, abdominal pain, cramps, bloating, reflux), respiratory (sneezing, rhinorrhoea, nasal congestion or swelling, phlegm, cough, asthma), cardiovascular (arrhythmias, tachycardia, palpitations), integumentary (urticarial, pruritis, flushing), CNS (headache, dizziness, anxiety, sleep disturbances) and reproductive tissues or organs (dysmenorrhoea, menstrual headache).[5,7,8]
The complexity of the clinical presentation of histamine intolerance is also due to
the many internal and external factors that can contribute to its onset, broadly categorised as exogenous factors that cause high levels of histamine or suboptimal functioning of the endogenous processes that metabolise histamine.[5,7]
These endogenous processes include impaired DAO or HNMT enzyme activity (which can be genetic or acquired), excess histamine synthesis (due to, mastocytosis, allergies) or gastrointestinal issues (damaged intestinal enterocytes, GIT bleeding, dysbiosis).[1,3-5,8]
Exogenous factors that may contribute to histamine intolerance relate to particular foods, medications and stress.
Foods relevant to histamine intolerance include those that: contain high levels of histamine (fermented foods such as sauerkraut, processed meat, dried anchovies, fish sauce, spinach, tomatoes, cocoa, eggplant, fish, chicken, yoghurt, soy, red wine); induce histamine release from mast cells (citrus foods, pineapple, bananas, strawberries, papaya, tomatoes, additives); or other biogenic amines that may interfere with the binding of histamine to mucosal mucine resulting in more histamine in circulation.[1,5,8,9]
Histamine-associated mechanisms associated with medication include inhibition of DAO activity (muscle relaxants, narcotics, analgesics, local anaesthetics, antihypnotics, antihypertensives, antiarrhythmics, diuretics, antibiotics, antiemetics, bronchodilators, antiseptics, mucolytics, H2-receptor antagonists, antidepressants); stimulation of histamine release (painkillers, antibiotics, anti-hypotensives, anti-hypertensives, antitussives, cytostatics, diuretics, local anaesthetics, muscle relaxants, narcotics) or inactivation of vitamin B6 (antihypertensives, antibiotics, hormonal contraceptives).[5,8]
Stress can also play a role due to the activation of mast cells by stress-induced hormones. The impact of chronic stress on the integrity of the intestinal epithelial lining, adversely influencing the histamine-inactivating capacity of intestinal DAO, is another process potentially contributing to increased levels of circulating histamine.
The link between histamine, oestrogen and progesterone
The complexity of histamine intolerance extends to the interaction between histamine, oestrogen and progesterone in the female body.
Mast cells are a key factor underlying these interactions, with the presence of both oestrogen and progesterone receptors on mast cells and mechanistic evidence (in vitro and in vivo) suggesting a regulatory role of these steroid hormones on mast cell functionality and activity.[10,11,12]It has also been suggested that mast cell reactivity and histamine concentrations vary between males and females.
The binding of oestrogen to mast cell receptors stimulates the expression of H2 and H3 receptors, and induces rapid histamine degranulation, synthesis and release.[11,13-15]
Histamine, within female reproductive tissue, is derived from uterine- and ovarian epithelial and mast cells, and endometrial and myometrial endothelial cells.[5,12,15] It can also be derived from monoamine transporters in endometrial tissue, as these have a high affinity for histamine uptake. Oestrogen can also influence endogenous histamine levels by downregulating DAO activity.[17,18]
The degranulation and activity of histamine appears to fluctuate with menstrual hormonal secretions. During a healthy menstrual cycle, there is a characteristic hormonal pattern involving luteinising hormone (LH), follicle stimulating hormone (FSH), oestrogen and progesterone.
Animal data has demonstrated that cellular histamine concentrations in ovarian and uterine mast cells varies across the menstrual cycle, and the activation of mast cells within endometrial tissue is most significant during the premenstrual phase following the decrease in progesterone and oestradiol.[12,14,20]
A correlation between urinary histamine metabolites and plasma oestrogen levels in premenopausal women has been observed, as has significant associations between elevated midcycle serum oestradiol levels and skin prick test reactivity to histamine.[21,22]
Also, in healthy reproductive-age women, the application of histamine solution to the nasal mucosa induced a significant localised response, which correlated with peak midcycle oestradiol concentrations, that did not occur during the menstrual or luteal phases when oestrogen levels were significantly lower.
The interaction between histamine and oestrogen is a two-way process, with histamine able to induce dose-dependent oestradiol synthesis by ovarian granulosa cells through H1 activation, thereby having an additive effect on endogenous oestrogen levels.[5,24]
Overall, this evidence demonstrates that: histamine can stimulate oestrogen production; oestrogen induces mast cell degranulation in female reproductive tissues; and elevated oestrogen levels during the menstrual cycle induces histamine release and may also influence tissue histamine responsiveness.
An association between oestrogen, histamine and progesterone, and also cortisol, further highlights the complexity of the relationship between these hormones in the body.
The interactive and somewhat regulatory relationship between oestrogen and progesterone that occurs during the menstrual cycle can be observed in relation to the effect of progesterone on histamine release. Progesterone has an inhibitory effect on histamine secretion following mast cell binding. However this effect is likely tempered by the regulation of progesterone expression and activity at a genomic level by oestrogen.[10,13,14,25,26] This may be particularly relevant in women who present clinically with low progesterone and elevated oestrogen, in terms of the histamine-stimulating effect of oestrogen and the physiological impact of high histamine on the body.
The hypothalamic-pituitary-adrenal (HPA) hormonal response to stress results in mast cell degranulation and consequently elevated levels of histamine (i.e. stress à histamine). In the hypothalamus, H1 and oestrogen receptors sit together, so oestrogen can influence hypothalamic H1 receptor activity (i.e. oestrogen à histamine), while histamine can also stimulate cortisol synthesis by adrenal cells. (i.e. histamine à cortisol).[26-28] Elevated histamine-induced cortisol may inhibit the synthesis of progesterone and oestrogen via the ‘cortisol or progesterone steal’ mechanism, however studies are required to confirm this effect of histamine in humans.
The relationship between oestrogen, progesterone and histamine may contribute to the experience in women with histamine intolerance of menstrual related headaches and dysmenorrhoea, partly due to the inflammatory and contractile effects of histamine.
This interactive association is also demonstrated by hormonal associated fluctuations in asthma severity that is more prevalent in reproductive-aged women.[11,15,29] Plasma oestradiol and progesterone concentrations have been shown to correlate with clinical asthma symptoms and bronchial responsiveness, with women often experiencing more frequent and severe asthma symptoms during the preovulatory and premenstrual phases.
It has also been observed that allergies, in which histamine is closely involved, are more prevalent in women with hormonal-imbalance-related conditions such as endometriosis.
Overall it is clear that there is an interconnection in the body between histamine, oestrogen, progesterone and cortisol in regards to systemic functionality. It can also be stated that an endogenous imbalance in these substances can cause or contribute to many reproductive or non-reproductive issues. Further research is required to further clarify the mechanistic connection between histamine, oestrogen, progesterone and cortisol and determine the clinical relevance of this association in specific conditions or pathologies.
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