Keywords
cardiac syndrome X - catamenial angina - menstruation - estrogen - progesterone
The authors of the present study wish to use the term “menstruation-related angina” to refer to the occurrence of angina symptoms in women in relation to their menstrual cycle. Literature reveals two kinds of menstruation-related anginas—one, cardiac syndrome X (CSX) and the other, catamenial angina viz. menstruation angina. For the latter, the term “catamenial angina” will be used in this review, to avoid confusion with the term menstruation-related angina, which is the main title of this review article. [Table 1] summarizes the salient features of the two conditions.
Table 1
Overview of menstruation-related anginas
|
Cardiac syndrome X
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Catamenial angina
|
|
Affects
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Premenopausal and postmenopausal women aged 45–55 y; rarely seen in men
|
Females of all ages from puberty to menopause with existing/preexisting or predisposed to coronary artery disease
|
|
Synonym/s
|
Microvascular angina
Chest pain with normal coronary arteries
|
Menstruation angina
|
|
Clinical presentation
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- Recurrent anginal-type retrosternal chest pain that starts during exercise or rest and may continue even after exercise
- No evidence of lesions > 50% on imaging
- No evidence of significant coronary vascular abnormalities on angiogram
- Chest pain may radiate toward the left arm
|
- Recurrent left-sided chest pain that starts 1–2 d before, during, or 1–2 d after menstruation and may last for 3–5 d
- Initially, pain is nonexertional and relieved by rest or analgesics
- Eventually (usually after 2–3 mo), pain is sudden and sharp and may radiate up to the jaw or travel down the arm
|
|
Additional findings
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Microvascular dysfunction, heightened cardiac pain sensitivity
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Diaphoresis, hot flushes, persistent lethargy
|
|
Potential contributing factors
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Insulin resistance, hyperglycemia, chronic inflammation with increased C-reactive protein, vascular or nonvascular smooth muscle dysfunction
|
High BMI, anemia, hyperglycemia, peripheral and central cyanosis
|
|
Pathogenesis
|
Decreased estrogen decreases cardioprotective effects (e.g., decreased inhibition of the proinflammatory protein Rho-kinase)
|
|
Treatment and management
|
Nitrates with β blockers and analgesics; lifestyle modifications
|
CSX is characterized by typical or atypical anginal chest pain without evidence of significant coronary vascular abnormalities visualized on the angiogram. Although reported in very few men also, it is a type of ischemic heart disease most prevalent in perimenopausal and postmenopausal females.[1] “Microvascular angina” and “chest pain with normal coronary arteries” are the synonyms used to describe CSX.[2] Although previously thought to be a benign condition, current literature associates CSX with adverse cardiovascular events namely myocardial infarction, stroke, cardiac death, all-cause mortality, and hospitalization for heart failure.[3] While prompt diagnosis and treatment is imperative to avoid the high morbidity and complications associated with this condition, the diagnosis is challenging since it is a diagnosis of exclusion. Management is equally difficult as the pathogenesis of its onset is not fully understood. It probably involves microvascular dysfunction of the coronary arteries, resulting in MI and irregular cardiac sensitivity to pain.[1]
Catamenial angina, on the other hand, is chest pain 2 days prior to or after menstruation seen in women with existing coronary artery disease (CAD), preexisting CAD,[4] or predisposed to CAD. The other synonym used to describe this is “catamenial angina.” However, this has not received as much attention as other menstrual cycle-related discomforts and diseases.[5]
[6]
[7] Choo[8] has mentioned in his case report that catamenial angina can affect females of all ages from puberty to menopause and must be kept in mind while attending to any female patients presenting with recurrent chest pains associated with their menstrual cycles. This is because an earlier introduction of therapy could help arrest further myocardial damage.
The purpose of this review is to provide a compiled update on the current understanding of both the above-mentioned classes of menstruation-related angina, their pathophysiology, diagnosis, and therapeutic strategies.
Epidemiology
CSX is reported to be more common in women (70%) than men[9] and generally occurs in perimenopausal or postmenopausal females aged 45 to 55 years (mean age 48.5 years).[2]
[10] Among subjects receiving coronary angiography due to chest pain suspecting a myocardial infarction (MI), as high as 41% of females and as low as 8% of males are reported to have CSX.[11]
As already mentioned in the introduction section in the present study, according to Choo,[8] catamenial angina can affect females of all ages from puberty to menopause. The very few studies available to date report this condition in women aged 35 to 47 years[7]
[8]
[11]
[12] and also in postmenopausal women.[13] One study reports that in a 43-year-old woman diagnosed with spontaneous coronary artery dissection (SCAD), episodes of chest pain always occurred much before the diagnosis of SCAD, during or a couple of days before or after menstruation.[14] This finding is noteworthy, given that as high as 90% of patients with SCAD are females.[15]
Clinical Features
CSX patients typically present with recurring anginal-type retrosternal chest pains with no evidence of lesions > 50% on imaging. The onset of chest pains may be during exercise or rest, and continued chest discomfort may occur even after exercise. Chest pain may radiate toward the left arm. Additional findings include microvascular dysfunction and heightened cardiac pain sensitivity in some patients. Etiology and pathogenesis of CSXs are not completely understood. Microvascular dysfunction of coronary vessels contributing to ischemia is believed +to be one of the major etiologies of CSX. Other contributing factors could include insulin resistance, hyperglycemia, chronic inflammation with increased C-reactive protein, and vascular or nonvascular smooth muscle dysfunction could be the potential contributing factors to CSX.[1] A careful assessment of patients for the potential pathophysiology of their manifestations is important here. A thorough assessment of risk factors for CAD and differentiation of chest pain from all noncardiac causes, including psychological possibilities, is also important.[1]
[16]
[17]
The classical presentation of catamenial angina is recurrent left-sided chest pain that starts 1 to 2 days before, during, or 1 to 2 days after the beginning of menstruation when the ovarian hormones are lowest in the menstrual cycle and sometimes lasts for 3 to 5 days. In the beginning, the pain is nonexertional and is frequently relieved by rest or analgesics. Eventually (usually after 2–3 months), the patient develops sudden sharp chest pain which may radiate up to the jaw and travel down the arm. The patient also suffers from diaphoresis, hot flushes, and persistent lethargy.[8] From available reports till date, women presented with no cardiac risk factors, although increased body mass index, anemia, and hyperglycemia, as well as peripheral and central cyanosis have been reported.[8]
[11] Electrocardiogram findings were seen to change from one cycle to the next.[8] Where the pain was right sided, an association of the angina is made to thoracic endometriosis that can produce pleuritic chest pain, pleural effusion, hemothorax, and pneumothorax, all of which resolve after 6 days of menstruation.[18] Left-sided catamenial angina associated with catamenial pneumothorax has been reported as an unusual case.[19] Occurrence of the chest pain in association with menstruation was similar to what was observed by Kawano et al.[20] This study reports that women with coronary vasospasm were found to have most ischemia in the days immediately before the beginning of menstruation when estrogen levels were low, and there was less flow-mediated brachial artery vasodilation.[11] The similarity in pattern of catamenial angina to that seen in women in Kawano et al's study gives a hormonal implication in catamenial angina. A hormonal role in catamenial angina has also been implied in another research study by Lloyd et al (2000)[12] on blood hormone levels and heart activity in nine women patients in their late 30s with a history of heart disease during all phases of their cycles. The worst treadmill exercise performance and the quickest time to angina pain (290 seconds) were seen in the early follicular phase when levels of estrogen and progesterone are known to be lowest. The best performance and slowest time to angina pain (418 seconds) occurred in mid-cycle, when estrogen reaches its peak concentration. In the setting of decreased cardioprotective effects due to decreased estrogen, patients with catamenial angina have a risk of developing hypertension, and atherosclerotic and vasospastic disorders in the long term.[21]
Pathogenesis
It has been postulated that ovarian hormones have a protective effect on the cardiovascular system.[20] To understand the impact of hormones on menstruation-related angina, the authors of the present study wish to revisit the menstrual cycle and the function of ovarian hormones.
Menstrual Cycle and Hormones
The normal cycling of menstruation is governed by the coordination between the hypothalamus, pituitary gland, and ovaries. The cycle mainly consists of the menstrual, follicular or proliferative phase, ovulatory, and the luteal or secretory phase. During the follicular phase, hypothalamus secretes gonadotrophin-releasing hormone on the anterior pituitary gland, which in turn secretes follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These hormones act on ovarian follicles. Initially, each follicle is made up of immature oocytes surrounded by layers of theca cells and granulosa cells. The theca cell develops receptors that bind with LH and start secreting a large amount of androstenedione. Meanwhile, granulosa cells develop receptors for FSH and produce enzyme aromatase which in turn converts androstenedione into 17 β-estradiol which is estrogen. By the second week, granulosa cells also begin to develop receptors for LH. As follicles continue to grow, estrogen is released into the bloodstream sending a signal to the pituitary gland to secrete less amount of FSH. As FSH decreases some of the follicles stop growing and die off. However, the dominant follicle that has more receptors for FSH continues to grow and keep secreting estrogen. Due to this higher amount of estrogen, the pituitary gland secretes a whole lot of FSH and LH. This surge of FSH and LH stimulates ovulation, resulting in the rupture of the dominant follicle and the release of oocytes. Following ovulation, the remanent of the ovarian follicle becomes corpus luteum made up of theca calls and granulosa cells. Both these cells keep producing estrogen. However, granulosa cells also respond to LH that activates cholesterol side chain cleavage enzyme. This enzyme converts more cholesterol to pregnenolone which is a progesterone precursor, and this is the start of the luteal phase. Granulosa cells in this phase produce more progesterone than estrogen. Progesterone sends a signal to the pituitary gland to decrease FSH and LH. These granulosa cells also produce inhibin, which is a signal for the pituitary to inhibit FSH secretion. Due to this process, estrogen starts declining and progesterone becomes dominant.
Decrease in estrogen and increase in progesterone are major factors for the endometrium to be receptive to fertilization. Thus, under the influence of progesterone, the uterus enters the secretory phase. After a 15-day window for fertilization, if fertilization does not take place, corpus luteum is replaced by corpus albicans which do not make estrogen and progesterone, and their level starts declining. When progesterone reaches its lowest level, the spiral arteries collapse, and the functional layer of endometrium prepares to shed through menstruation.[22] A schematic representation of changes associated with the menstrual cycle is shown in [Fig. 1].
Fig. 1 Schematic representation of changes in menstrual cycle. FSH, follicle-stimulating hormone; LH, luteinizing hormone.
Estrogen, Progesterone, and the Cardiovascular System
Estrogen plays an important role in the cardiovascular system. It acts on cardiomyocytes and exerts an antihypertrophic effect which is mediated by myocyte-enriched calcineurin-interacting protein, natriuretic peptide precursor A, and histone deacetylases.[23]
[24]
[25]
[26] By enhancing adenosine triphosphate (ATP) synthesis and decreasing reactive oxygen species (ROS) production through increased superoxide activity, estrogen enhances mitochondrial efficiency.[27]
[28] Additionally, estrogen reduces the expression and activity of ion channels which lowers contractility thereby affecting cardiac electrical conductance.[29]
[30] Estrogen also has an antiapoptotic effect on cardiomyocytes.[31]
[32]
[33] In terms of the vascular system, estrogen increases nitric oxide (NO) synthesis and expression of vasodilating factors while lowering the vasoconstrictive factors resulting in encouraged vasorelaxation, proliferation, and migration in endothelial cells.[34]
[35]
[36]
[37]
[38]
[39]
[40] Additionally, 17 β-estradiol stimulates angiogenesis by increasing the production of vascular endothelial growth factors, which then boosts the activity of endothelial NO synthase (eNOS).[41]
[42] This hormone also prevents atherogenesis while promoting regeneration. It also inhibits activation of nuclear factor-kappa β and other proinflammatory cytokines thereby reducing inflammation.[43] Rho-kinase, a protein that plays a role in muscle contraction and actin cytoskeleton, can induce inflammatory lesions leading to coronary vasospastic response. But if Rho-kinase is inhibited for a longer duration, it can resolve coronary vasospastic activity. Estrogen inhibits Rho-kinase mRNA expression in human coronary vascular smooth muscle cells and thereby averting vasospasm.[21]
[44]
Cardioprotective roles, although not as much as of estrogen, has been reported in the case of progesterone too. It has been demonstrated that progesterone promotes cardiomyocyte proliferation and β-oxidation.[8]
[45] Furthermore, it was discovered that enhanced eNOS activity and changed calcium availability via increased endoplasmic reticulum Ca2+ATPase expression stimulated the vasorelaxation of endothelial cells and vascular smooth muscle cells.[46]
[47] Additionally, following progesterone therapy, high-density lipoprotein and low-density lipoprotein appear to rise and fall, respectively, thereby lowering atherogenesis.[48] It has also been reported that progesterone boosts vascular system NADPH oxidase activity, thereby increasing the production of ROS.[49]
[Table 2] depicts a summary of the actions of estrogen and progesterone on the cardiovascular system.
Table 2
Ovarian hormones and effect on cardiovascular system
|
Hormone
|
Cell type affected
|
Effect
|
|
Estrogen
|
Cardiomyocytes
|
Inhibits apoptosis
|
|
Inhibits ROS production
|
|
Decreases contractility
|
|
Attenuates hypertrophy
|
|
Increases ATP synthesis
|
|
Vascular smooth muscle cells
|
Promotes proliferation
|
|
Modulates factors controlling fibroblast migration
|
|
Reduces proinflammatory effects
|
|
Causes vasorelaxation
|
|
Endothelial cells
|
Causes vasorelaxation
|
|
Promotes proliferation
|
|
Modulates factors controlling migration
|
|
Promotes angiogenesis
|
|
Progesterone
|
Cardiomyocytes
|
Increases β-oxidation
|
|
Promotes proliferation
|
|
Vascular smooth muscle cells
|
Causes vasorelaxation
|
|
Increases ROS production
|
|
Antiatherogenic effect
|
|
Endothelial cells
|
Causes vasorelaxation
|
|
Increases ROS production
|
|
Antiatherogenic effect
|
Abbreviations: ATP, adenosine triphosphate; ROS, reactive oxygen species.
The cardioprotective roles of both hormones as discussed earlier and the precipitous drop of particularly estrogen at the end of ovulation as well as at the end of menstrual cycle implicates a major role to estrogen in the pathogenesis of menstruation-related anginas. Studies do discuss about coronary artery spasms or constriction, resulting in reduced blood flow to the heart and subsequent chest pain or angina in the hypoestrogenic milieu.[50] Besides hormones, other underlying CADs or other cardiovascular conditions can also be responsible for catamenial angina.[51]
Evaluation
Evaluating menstruation-related angina (CSX or catamenial angina) should begin with a history and physical examination. Exercise tolerance test (ETT), electrocardiogram, and echocardiogram may be conducted before any invasive tests.[1]
[14]
Patients with CSX are reported to exhibit ST-segment depression on exercise stress tests and transient ST depression on Holter monitoring. Severe angina during dobutamine stress echocardiogram with ST-segment depressions and lack of contractile anomalies of the left ventricle are distinctive of endothelial dysfunction and may indicate CSX.[1] Given that CSX is primarily a diagnosis of exclusion (typical or atypical anginal chest pain, ST-segment depression, and no evidence of coronary vessel obstruction more than 50% on angiography), a coronary angiography is useful to diagnose CSX by exclusion. ETT can also be done again following administration of short-acting sublingual nitrates as they may reveal ST-segment changes in some patients. Although effective in alleviating symptoms in CAD patients, the short-acting sublingual nitrates have also been reported to be ineffective in relieving chest pain in CSX patients.
In women with catamenial angina, based on the case presentation published by Choo,[8] ST-segment elevation and Q waves in the anterior leads and ST-segment depression in the inferior leads may be expected. However, these findings changed in the next menstrual cycle to ischemic changes only in the inferior region. In such cases, monthly serial electrocardiograms will prove useful. Estrogen and progesterone measurements should be considered during different phases of menstruation. Cardiac function tests may be considered depending on the clinical presentation. For example, troponin T and creatine kinase levels may be measured and followed up if a myocardial infarction is suspected. Coronary angiogram may prove useful in evaluating artery occlusions.
Although noninvasive modalities such as brachial artery reactivity and peripheral arterial tonometry are suggested in CSX to evaluate endothelial function,[20] the same may be employed in catamenial angina also.
Complications
Decline in quality of life, restraint in daily activities, and inability to attend work can be prominent in both the menstruation-related anginas. Difficult diagnosis prompting extensive workup and costly, time-consuming assessment is another barrier to be kept in mind. The challenge of achieving therapeutic efficacy from pharmacotherapy could prolong symptoms and prompt hospital admissions. Where the prognosis is not good, patients can face diagnostic challenges and procedures, potentially causing disability.[52]
Management
The goals in the management of menstruation-related angina should include:
-
Reducing or curing the troublesome symptoms as early in the life of the female as possible.
-
Improving the quality of life.
-
Treating the associated comorbid condition if any.
Although there are no specific guidelines to treat the two menstruation-related anginas and hence, management should be case on case. Treatment modalities should include pharmacologic as well as nonpharmacological management.
Pharmacological Therapy
Anti-ischemic agents and analgesics for pain are the main pharmacologic modalities in CSX and catamenial angina. Beta-blockers, statin therapy, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and antianginal agents such as ranolazine are found useful in CSX,[1] and nitroglycerin, nicorandil, calcium channel blockers, β-blockers, and aspirin are found useful in catamenial angina. Hormonal therapy to reduce angina symptoms has been suggested in catamenial angina.[53]
Patients with menstruation-related anginal chest pain should be initiated on therapy with nitrates. Nitrates alongside β-blockers are currently the mainstay of treatment in CSX.[16] Nitrates and nitroglycerin are converted in the body to NO which acts via the guanylyl cyclase pathway. The subsequent activation of many proteins kinase-dependent phosphorylations by cyclic guanosine monophosphate (cGMP) improves calcium absorption into the sarcoplasmic reticulum, raises extracellular calcium, and activates the calcium-gated potassium channel.[54]
[55] The subsequent dephosphorylation of myosin light chains in smooth muscle cells produce the intended vasodilatory effect due to arterial smooth muscle relaxation.[56] A nicotinamide nitrate called nicorandil is used as an antianginal. It acts in two different ways. First, nicorandil increases transmembrane potassium conductance and relaxes peripheral and coronary arterioles via activating ATP-dependent potassium channels. Second, nicorandil causes dilatation of the coronary arteries and peripheral veins by raising intracellular concentrations of cGMP thanks to its nitrate moiety. Thus, nicorandil optimizes coronary flow while concurrently reducing myocardial work through reductions in afterload due to its capacity to widen arteries and veins. These factors account for nicorandil's efficacy in treating angina and hypertension.[57]
[58]
Beta-blockers lower blood pressure by decreasing cardiac output via the renin–angiotensin pathway. They impart chronotropic and inotropic effects resulting in decreased oxygen demand, and thereby angina.[59]
[60] Propranolol, nebivolol, and carvedilol are known to improve exercise tolerance and angina symptoms. Newer better blockers such as nebivolol and carvedilol are reportedly more effective than conventional β-blockers.[16]
Where therapeutic response is not achieved, calcium channel blockers may be an alternative to β blockers. They efficiently lower blood pressure by widening arteries by lowering calcium flux into the heart and artery cells. In the presence of calcium, the cells contract more forcefully resulting in vasoconstriction. Calcium channel blockers prevent calcium from entering cells, allowing blood vessels to open and relax. Some formulations of these compounds are authorized for the treatment of angina or cardiac dysrhythmias when taken in conjunction with other medications.[61] Nifedipine, verapamil, and diltiazem improve exercise tolerance and reduce anginal symptoms; however, they are not as effective as β-blockers in patients with CSX.
Ranolazine (the neuronal voltage-gated sodium channel regulator) is reported to be useful in CSX. Statins and ACE inhibitors are also useful due to their vasodilatory effects.[1]
Although in some women with catamenial angina, atherosclerotic changes have been reported by Choo,[8] fibrinolytic therapy needs to be considered with caution in catamenial angina unless absolutely necessary. In their review, Stewart and Kline[62] discuss that fibrinolytic agents activate native plasminogen to plasmin which hydrolyzes fibrin and leads to accelerated clot lysis. This in turn reduces the thrombus burden and results in earlier hemodynamic improvement. However, the major complication associated with systemic fibrinolysis is life-threatening bleeding. Therefore, the use of these agents needs to be carefully weighed for their risk versus benefit. There are several commonly recognized contraindications to systemic fibrinolysis and absolute contraindications include active bleeding among others tabulated by Stewart and Kline.[62] Hence, it is recommended that in catamenial angina, the bleeding risk, and the weight of the contraindication for each individual patient should be considered on a case-by-case basis dependent on the severity of the specific clinical scenario at hand.
Nonpharmacological
Alongside pharmacological therapy, lifestyle modifications such as exercise training, smoking cessation, weight loss, and dietary changes should be advised. Such modifications are known to have beneficial effects on endothelial function and hence reduce adverse cardiovascular events in CSX and catamenial angina.[53]
[63]
Conclusion
The relationship between estrogen and menstruation-related angina is complex and not fully understood. The exact mechanism by which estrogen influences angina symptoms in women with normal coronary angiograms is still being investigated. Further research is needed to elucidate the underlying factors to successfully address and treat menstruation-related anginas. Patients need to be thoroughly educated and advised about the diagnostic and therapeutic challenges in the background of very little understanding of the pathophysiological mechanisms. An efficient interprofessional health care team and its proper communication with the patient or caregiver can lead to early diagnosis and treatment initiation.
Summary
Two menstruation-related anginas are reviewed in this article: CSX and catamenial angina. CSX involves recurring anginal-type retrosternal chest pains in perimenopausal or postmenopausal women during exercise or rest with no evidence of lesions > 50% on imaging. Catamenial angina is menstruation-associated recurrent nonexertional left-sided chest pain alongside diaphoresis, hot flushes, and persistent lethargy. Pathophysiology of both anginas are centered around decreased levels of estrogen. Currently, treatment is empirical. Nitrates alongside β-blockers and analgesics for pain are the mainstay of treatment in menstruation-related anginas. Exercise training, smoking cessation, weight loss, and dietary changes are nonpharmacological modalities.
Since the role of genomic and nongenomic estrogen pathways in cardioprotection is a full review topic in itself, the authors have not delved into the details of those pathways in the present review article, and this is a limitation of the article. Detailed reviews or original research on genomic and nongenomic pathways of estrogen and their roles in cardioprotective functions of estrogen will throw more light on the pathogenesis of menstruation-related anginas and their treatment/management. Such studies should specifically aim at studying menstruation-related angina patients. Also, given the few numbers of reported cases till date, a questionnaire-based survey in the general population could be useful in obtaining more information on prevalence related to catamenial angina. In addition, current treatment for menstruation-related angina is mainly empirical and hence calls for randomized controlled trials to evaluate treatment options.
