Introduction

Cardiovascular disease has an earlier onset of 7-10 years in women compared to men (Maas 2010) and remains the leading cause of death in women (CDC 2013). One of the many links between the female sex hormone, estrogen, and cardiovascular risk may be through platelets, which express the estrogen receptor β and increase its expression upon activation (Wang 2012). Conflicting studies report increased coagulation during the luteal menstrual phase, as evident by increased binding of platelets to fibrinogen resulting in platelet aggregation (Kurrelmeyer 2003) while other studies report no significant menstrual related changes (Jones 1983). The continuous presence of estrogen has been correlated to a reduction of pro-coagulant substances such as fibrinogen, antithrombin and plasminogen activator inhibitor and thus supports the possibility of fluctuation in coagulation with the menstruation. Studies exploring platelet reactivity and platelet count observe sex-related difference and thus set the stage for this review, which hopes to explore the differences in platelet physiology between males and females and their impact on cardiovascular health.

Platelets: Quick to React

Platelet reactivity implies greater rate of activation and platelet aggregation. When compared, platelets from female participants were more reactive than those from males when activated by agonists such as adenosine diphosphate (ADP) and thrombin receptor agonist protein (Wang 2012). While the overall level of fibrinogen is higher in women, platelets from women additionally bind more fibrinogen and demonstrate more spontaneous aggregations than in men. (Diazepam) The increased platelet reactivity is associated with an increased risk of myocardial infarctions (MI)(Wang 2012).

MPV: Why Size Matters

Large platelets, as measured by the mean platelet volume (MPV), are more enzymatically and metabolically active, contain more α-granules with prothrombic substances and have been associated with increased platelet aggregation, increased thromboxane synthesis and β-thromboglobulin release (Chu 2010). Epidemiologically, elevated MPV have been cited as an independent risk factor for recurrent ischemia and death post MI and associated with other cardiovascular morbidities such as obesity, hypertension, diabetes and smoking. The size of the platelets correlates with thrombopoetin, which stimulates platelet production, and interleukin 6; a pro-inflammatory cytokine. While an analysis of the Framingham Heart Study revealed no statistically significant difference in MPV between males and females (Sloan 2015) a small observation study comparing the impact of smoking cessation demonstrated a significant reduction in MPV with smoking cessation in female participants but not in males (Cho 2014).

Aspirin: Different Impact?

Aspirin may benefit women to a different extent than it does men as studies report statistically significant differences in platelet aggregation post treatment. According to the Gene STAR study, platelet aggregation in response to collagen, after aspirin therapy, was 31.8 per cent for women and 27.2 per cent for men (p<0.001) (Wang 2012). However this difference may be due to the higher baseline reactivity of platelets in females (Bailey 2009).

Another Player: Microvesicle

Microvesicles (MV) are submicron-sized vesicles that are released from the plasma of various activated cells including erythrocytes, platelets, leukocytes, endothelial cells and others. MV differ in their functions depending on their cell of origin and state of function and can thus be pro- or anticoagulant and/or pro-inflammatory (Gustafson 2015). MV carrying phosphatidylserine are used to catalyze thrombin production and as such have a pro-coagulant impact. Phosphatidylserine positive MV have been found to be significantly higher (p<0.05) in healthy women as compared to age-matched, healthy men, along with MV containing P-selectin, another pro-coagulant. There were no significant differences in the anticoagulant MV. This may be an additional mechanism contributing to elevated risk of cardiovascular events through induction of a more pro-coagulative state.

Genetic Polymorphism

The impact of sex hormones on cardiovascular risk may differ depending on genetic predisposition. A genetic study by Bray et al (2007) demonstrated two opposing effects from hormone therapy on risk of coronary disease. Postmenopausal women with -5HT>C and 13254T>C polymorphisms in the platelet glycoprotein genes experienced a 6 per cent increase in absolute risk, while women with complementary genotypes experienced a 5 per cent absolute risk reduction. Future studies are needed to explore the mechanism by which these changes are produced.

Conclusion

This review introduces several different risk factors associated with the female sex that remain to be further explored in research in the hopes of refining tools of screening for cardiovascular risk and open new avenues for therapeutic interventions. One wonders if the plants termed as “alteratives” and “blood purifiers” by traditional herbalism have any impact on platelet reactivity and volume and thus, subsequently, cardiovascular health.

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Adrenal fatigue is just one of the examples of the afflictions of the stress of modern life. The stressors we face on a daily basis, such as family and financial problems, increased work load, lack of physical exercise, insufficient rest, poor diet, environmental toxins, electromagnetic radiation all contribute to more stress on the stress-adaptive organs, the adrenal glands and other stress regulating systems in the body.

Men and women respond differently to stress, both physically and mentally.1 They attempt to manage stress in very different ways and also perceive their ability to do so differently. Findings suggest that while women are more likely to report physical symptoms associated with stress, they are doing a better job connecting with others in their lives and, at times, these connections are important to their stress management strategies.1

Stress on the Rise for Women

Women are socialized to be the caretakers of others. More women than men have both a career outside the home and continue to try to juggle traditional responsibilities after hours.1 In fact, over 70 per cent of married women with children under the age of 18 are employed outside the home.2 Women are often known as “multi-taskers’ — struggling to balance a career with the role as ‘perfect’ wife and mother at home. As women progress through life’s stages, hormonal imbalances associated with premenstrual, post-partum and menopause can also affect chemical vulnerability to stress, depression and anxiety.2

The Role of Adaptogens

Adaptogenic herbs are one of the most important groups of herbs to take into the 21st century. Adaptogens not only increase the resistance to the adverse effects of long-term stress but the majority are also tonifying, immune-stimulating and increase the general sense of well-being.4

The term “adaptogen” was first defined by Russian pharmacologist Nikolai Lazarev in 1947. These herbs were classified as a group of substances that could improve the body’s nonspecific resistance after being exposed to various stressing factors, promoting a state of adaptation to that exceptional situation. Israel Brekhman, his successor, established that a plant should meet four requirements in order to be considered an adaptogen: (1) it is harmless to the host; (2) it has a general, nonspecific effect; (3) it increases the resistance of the recipient to a variety of physical, chemical, or biological stressors; and (4) it acts as a general stabilizer/normalizer. 3

By 1984 Russian scientists had published in excess of 1,500 pharmacological and clinical studies on adaptogenic herbs and research continues today with little doubt that adaptogens increase an organism’s adaptation to stress and have a normalizing influence on our physiology.4

The various phases of hormonal change, such as monthly premenstrual time, the perimenopause transition and pregnancy, can challenge a woman’s stress adaptation mechanisms. The ‘hallmark’ hormone of stress, cortisol, is synthesized in the adrenal cortex and regulated via the HPA axis. The effects of cortisol are felt virtually throughout the entire body and impact several mechanisms—especially the regulation of hormonal balance in women. For example, chronic stress suppresses gonadotropin hormones from the pituitary that act on the ovaries and testes, which can lead to the disruption of a normal menstrual cycle and eventually lead to the complete impairment of reproductive function.6

There are several adaptogenic herbs that have been studied extensively and proven very effective in the support of the body during times of increased demands and stress.3   Most notable are Rhodiola (Rhodiola rosea), Ashwagandha (Withania somnifera), Siberian ginseng (Eleutherococcus senticosus) and Maca (Lepidium meyenii). Given the strong connection between cortisol and its impact on hormonal balance, there is an absolute role for adaptogens in women’s health.

Rhodiola rosea

Rhodiola rosea (also known as golden root and Arctic root) has been categorized as an adaptogen by Russian researchers due to its ability to increase resistance to a variety of chemical, biological and physical stressors. It has been used in the traditional medicine systems of Eastern Europe and Asia for more than 3,000 years with a reputation for stimulating the nervous system, improving depression, enhancing work performance, improving sleep, eliminating fatigue and preventing high-altitude sickness.3   Rhodiola seems to help the body adapt to stress by affecting the levels and activity of serotonin, dopamine and norepinephrine.3 It is believed that the changes in the above monoamine levels are due to inhibition of the activity of the enzymes responsible for monoamine degradation and facilitation of neurotransmitter transport within the brain.15

Rhodiola appears to offer an advantage over other adaptogens due to its ability to exert relaxation and antianxiety in periods of acute stress. In one randomized, placebo-controlled trial of 60 patients with stress-related fatigue, rhodiola was found to have an antifatigue effect that increased mental performance, particularly the ability to concentrate; it also decreased the cortisol response to stress of awakening from sleep.7

Rhodiola may also enhance fertility. It has been shown to enhance thyroid function in animal studies as well as improve egg maturation. This led to a study of 40 women with amenorrhea and infertility to be treated with 100 mg of rhodiola twice daily for two weeks. Normal menses were restored in 25 women, 11 of whom became pregnant.8

Rhodiola has a very low level of toxicity. Some anxious individuals may be over activated and become agitated with Rhodiola. Rhodiola is not recommended for individuals with bipolar disorder.3

Ashwagandha (Withania somnifera)

Also known as Indian ginseng, Ashwagandha is considered an adaptogen and rejuvenating tonic in Ayurveda. It provides both adrenal and immune support, increasing resistance to environmental stressors, is beneficial for pain relief, has antioxidant effects, reducing inflammation and stimulating thyroid function, has anti-stress effects by modulating cortisol levels as well as stimulates respiratory and immune function.3 In fact, in one double blind study, chronically stressed individuals taking Ashwagandha had significant reductions in anxiety, serum cortisol, C-reactive protein, pulse rate, and blood pressure compared with the placebo group.9

Reductions in cortisol as well as optimal thyroid function may encourage balanced hormones for optimal fertility in those women struggling to conceive.11 Toxicity studies in humans are limited with ashwagandha.

Siberian Ginseng (Eleutherococcus senticosus)

Siberian ginseng, also known as eleuthero, has been used for centuries in Eastern countries, including China and Russia as an “adaptogen”. Research indicates that Eleutherococcus increases the ability to accommodate to adverse physical conditions, improve mental performance, and enhance the quality of work under stressful conditions.3 Research has also shown decreases in the testosterone: cortisol ratio as well as improvements in heart rate and systolic and diastolic blood pressure in response to a particular stressor. In fact, Eleutherococcus accounted for a 60 per cent reduction in systolic blood pressure, which suggests that this herb may be helpful for stress adaptation.3

Premenstrual syndrome and perimenopause are their own kind of stress on the system and many women find their threshold of tolerating stress decreases and fatigue can result. Fluctuations in estrogen, progesterone, cortisol and thyroid interact with brain neurotransmitters such as serotonin, dopamine, GABA and therefore, eleuthero may be a beneficial herb to restore vitality in women who are chronically fatigued or who have decreased mental and physical performance and/or stamina.12

Eleuthero may elevate serum digoxin levels.14

Maca (Lepidium meyenii)

Maca, the herbal root from Peru, is best known as an adaptogenic plant. Its uses have shown to be beneficial for the endocrine and reproductive systems— in treating chronic fatigue and infertility, and to support hormonal balance and enhanced stamina. Research suggests that maca’s therapeutic actions are due to plant sterols stimulating the hypothalamus, pituitary, adrenal and ovarian glands, and therefore, also affecting the thyroid and pineal gland. Maca has been found to be useful in perimenopausal and menopausal women for hot flashes as well as helping with sleep, mood, fertility and energy.   Research on menopausal women indicates that maca can stimulate the body’s production of estrogen and reduce levels of cortisol. In one double-blind, randomized four month study of women in early postmenopause, patients were given either a placebo or two 500-mg capsules of maca twice per day for a total of 2g per day. After two months, estrogen production had increased and FSH and cortisol had decreased. The maca also had a small effect on increasing bone density and alleviated numerous menopausal symptoms including hot flashes, insomnia, depression, nervousness, and diminished concentration.10

Adaptogens continue to be an important group of herbs effective in various health conditions—especially in women’s health and indicated not only to counteract stress and its resulting damage on hormonal balance but may also be used to elicit a healthy state. Although the above adaptogens are considered very safe, not much research has been conducted during pregnancy and lactation and therefore, they are not recommended during those times. Adaptogens have an important role for prevention and should be considered as key supplements in many women’s health conditions.