A large factor in modern stress that is linked to every other source is the psychosocial burden that relationships, finances, work, and society place upon women. As evidenced by the high divorce rate, increasing declarations of bankruptcy among women, the growing population of female prisoners (at least in the US), work demands in the COVID-19 pandemic, and ever-shifting cultural expectations of beauty, physique, and comportment, women are placed under tremendous strain in the face of a rapidly changing society [2,3]. These stresses are often chronic and difficult to counter because they involve forces outside of direct control and result in anxiety, hypersensitivity to pain, and compensation that can increase smoking, drinking, and calorie consumption [4,5,6,7,8]. Additionally, the compression of life choices and constantly shifting goalposts is evidenced in the pressure on teenagers to choose colleges, career paths, and family planning well before physical or intellectual maturity. Again, the battle metaphor is often used, as political and cultural leadership often prefers to offload the burden of short-sighted or poor choices onto individuals versus engineering society-wide fixes.

Divorce is a chief driver of stress among women, with 2.7 occurring per 1000 people versus a marriage rate of 6.1 per 1000 people (CDC.gov) [9]. A recent study of the effects of divorce on the well-being, economic, domestic, and housing situation of women subjected to divorce found that, unlike men who suffered transiently, women experienced chronic losses in financial security but, similarly to men, they suffered in all areas of health and well-being [10]. Another more recent study in older Australian adults found that smoking, anxiety, and depression were linked to divorce in both genders in variable ways depending on socioeconomic and educational statuses [11].

Financial issues, especially during global economic shifts precipitated by the current COVID-19 pandemic, are also a primary source of stress for women. Studies have shown that financial concerns tend to affect women negatively regardless of social or familial support, different from men whose financial stress tends to inversely correlate with family support [12]. Women were found to provide half or more income globally (Europe: 59%, US: 55%), making working women a large population of active labor that could be adversely impacted by the economic disruptions of a global pandemic [13].

Crime and the results of criminal activity may entangle women either as perpetrators or victims. It is well-known that women are the chief victims of domestic violence (e.g., 31.3% of all Japanese women vs. 19.9% of all Japanese men) and also suffer from harassment or stalking at higher rates than men [14]. A 2011 national study of women in Australia also found that women experiencing serious personal or financial stressors were also more likely to suffer violence (actual or threatened) [15]. This kind of stress is additive to the other causes and can result in constant engagement of the “fight or flight” response that subjects the central nervous system to chronic activation of the sympathetic nervous system and resultant high levels of cortisol (stress hormone) and adrenaline. This triggers circadian disruptions that perpetuate stress and fatigue in a vicious physiological cycle [16].

Work of all kinds has been moved, as much as possible, to online or teleworking arrangements in light of COVID-19 concerns in crowded offices. For female white collar workers, however, social stress remains a source of stress and fatigue as online meetings may trigger fatigue from overconcentration or oversaturation of interpersonal perception [17]. On the other hand, blue collar service professions, such as janitorial or maid services, are mostly women (up to 61%) and could keep women exposed to COVID-19 risk in addition to fatigue from extended standing or excessive physical effort [18,19]. Additionally, female health care workers of all levels and grades have been pressed into extended hours at the frontlines of the pandemic and may experience additional stress from this, in addition to the usual witnessing of death and stress in patients and co-workers, resulting in burnout syndrome that predominantly affects women [20,21].

Physical fatigue from long hours, exacerbated by staffing issues, shift work, and profit-driven corporate expectations, has been paired together with psychosocial pressure to trap women in a vicious cycle. As layoffs and unemployment continue to mainly affect men, the wives of such laid off workers may have to work to compensate for lost income (an effect that is also part of the cultural evolution) while swing shift or night shift work also contributes to fatigue in women that may affect fertility [22,23]. The ultimate result of this dreadful synergy between psychosocial and physical realms is complete exhaustion. Paradoxically, chronically high levels of stress hormone, while inducing fatigue, may disrupt sleep cycles (especially rapid eye movement) and reduce the restorative effects of sleep [24,25]. Fatigue in this sense is also usually accompanied by aching or stiff muscles, headaches, and heart palpitations that further reduce the ability to enter deep sleep [26].

Women may also suffer from physical ailments such as sleep apnea (up to 13–24% of apnea sufferers are women), chronic fatigue syndrome, postural orthostatic tachycardia syndrome (POTS; predominates in women), neuroimmune (e.g., systemic lupus erythromatosis) diseases, and endocrine (hypothalamic-pituitary-adrenal axis) issues [27,28,29,30,31]. Estrogen has also been found to contribute to muscle weakness in women and premenstrual syndrome/menopause contribute to poor quality sleep [28,32]. Additionally, childbirth alters stress patterns in the body (e.g., cortisol fluctuation during bottle feeding versus lower stress from breastfeeding), requiring adequate maternity leave to recover and adapt to life with an infant [33]. While many national policies around the world follow the International Labour Organization-recommended 12 weeks, women may feel financial or employment pressure to return, especially if their leave is unpaid [13,34]. Along with the overlapping cultural expectation that women are primary caregivers for infants, this could create significant stress, especially in single mothers in the US for whom options are limited since national law does not mandate paid maternity leave (mothers must choose to either care for their child and endure mental/physical stress or pay for childcare and suffer financially) [35]. Indeed, women suffer from postpartum depression, with a Japanese study detailing the peak at 1 month post-delivery, and such depression could synergistically add to financial or other psychosocial strain to add to existing stress and fatigue [36,37].

Cultural expectations of women vary by country but most countries expect women to care for their families as a top priority. Such cultural expectations of childcare have forced working women to either attempt to physically care for their children while working or to pay for licensed childcare, imparting additional financial strain. Additionally, up to 57–81% of all caregivers for the elderly and aged in the world are women and caring for an ailing parent or family member in addition to other expected duties has been associated with higher psychological and caregiver burdens [38,39]. Thus, cultural forces that prevent women from shifting their expected burdens may result in somatization of stress as fatigue and this expression may vary by country due to cultural limitations on the expression of such stress [40].

Chemotherapy, surgeries, and even the common cold can cause fatigue as a main symptom. As women have been found to suffer exhaustion more when recovering from illness or injury, this realm, which ties into the physical cause above, may exacerbate stresses from other areas. Additionally, prescription medications may have side effects with regard to fatigue but studies related to female-specific adverse events are underreported in the literature. The fatigue-causing effect of diseases in women is diverse: the results of cancer therapy on the immune system with regard to body weight and chronic fatigue’s links to the immune system have been reported [41,42]. Additionally, recovering from COVID/viruses causes T-cell depletion in both genders but the effect of menopause on the inflammation status in female COVID patients has not been adequately investigated [43,44]. Moreover, the enhancement of the immune system by estrogen could be causative for neuroimmune inflammation or other autoimmune diseases for which fatigue is a key symptom (the inflammation = fatigue theory) [29,30]. Of more recent concern is COVID-19 since an infection that remains mild tends to run its course over a 2-week period but, for around 10–30% of sufferers, their infections become “long-haul” COVID-19 in which symptoms (such as fatigue, brain fog, muscle aches) persist for weeks or months, even after multiple negative test results, and lower quality of life for up to 44% of long haulers [45]. Women, unfortunately, tend to suffer from this long haul syndrome more frequently than men as their estrogen-boosted immune response may leave immune sequelae after infections are cleared, an effect also thought to explain the excessive burden of vaccine (COVID-19) side effects women under 50 have suffered [46,47].

Of particular importance to women’s health is the prevalence of chronic fatigue syndrome in women, who carry a 17–24% higher chance to suffer from myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) [48]. Classified as an idiopathic brain disorder with an estimated gender ratio of 3:1 (female:male), insomnia, dizziness, joint pain, muscle aches, headaches, sore throats, flu-like feelings, palpitations, and extreme fatigue that prevents even part-time work are common symptoms [49]. No causes have been currently confirmed although viral, hormonal, and immune etiologies have been explored, and treatments only provide minor relief from symptoms.

The financial cost of fatigue is enormous. Estimates of $330 million USD per year in lost productivity, errors, and performance reduction have been reported in the US and treatment of CFS may, according to a UK study, cost $20,000 USD per patient per year while an Australian study estimated 12 doctor’s visits per year per patient at a total cost of $14.5 billion USD [50,51]. Although these are aggregate numbers, research has reported the predominance of certain types of fatigue in women (e.g., ME/CFS) and thus estimates of the financial cost, even in women only, remain high.

Apnea costs roughly $165 billion USD per year and accidents due to fatigue in every sector, from industrial to transportation, also kill or injure an estimated 1550 people per year in the US (NHTSC) and 1003 in China (2011) [52,53,54]. Additionally, burnout and fatigue in the health care fields may cause medical mistakes. In the US, estimates of deaths from medical errors reach as high as 251,000 annually and this is at least partly attributed to fatigue and overwork from ever-increasing caseloads [55,56,57]. Since women are key participants in the medical field (as nurses and physicians), fatigue may contribute to the 50% burnout rate seen in a US study, with estimations of burnout in female physicians to be 20–60% higher than men [58].

Chronic stress and its endocrine effect, namely the release of persistent stress hormones at subclinical thresholds, is thought to be causative or add to the risk of developing a panoply of illnesses/conditions, including cardiovascular disease, neurological disorders (including dementia), diabetes, obesity, depression, and cancer. Women, particularly those suffering from gynecologic issues (such as menopause, excessive menstrual bleeding, or pelvic pain), are especially susceptible to ME/CFS while a study by Song and colleagues in 2017 examined 101,708 male and female Japanese participants (gender ratio 1:1.05) and found a 4–6% increased overall risk of cancer based on perceived stress levels [59,60]. Chronic diseases in women, especially immune-driven conditions such as fibromyalgia or lupus, may also be exacerbated by chronic stress or perceptions of it as a 2004 study of 56 Spanish women with SLE found that, while high-stress life events did not clinically worsen disease symptoms, women reported that their perceptions of exacerbations seemed to coincide with such events and, after 2 days of such stress, clinical biomarkers of SLE did increase [61]. In a study of 100 polycystic ovarian syndrome sufferers, aged 13 to 30 years of age, an Indian study found strong correlation between stress levels (reflected in a 6.64% increase in salivary cortisol in PCOS patients) and overweight status, increasing future risk of insulin resistance and PCOS-related metabolic disruptions [62]. Another Spanish study in 45 SLE patients (all female) found that cognitive behavioral therapy did alleviate somatic symptoms in sufferers compared to controls, highlighting the effect of stress on chronic disease exacerbation [63]. Additionally, immune competence and resistance to disease depends on low levels of stress hormones and sufferers of ME/CFS were found to have higher levels of inflammatory biomarkers while activity of NK cells and CD16+CD56+ lymphocytes were found to be compromised in 57 Japanese shift work nurses suffering from fatigue [20,64]. A similar effect was found in a controlled study of 58 first-year graduate students (47 female) in which CD19+ B lymphocytes decreased in response to perceived stress, along with a blunted cortisol awakening response from an increase in stress-induced glucocorticoids [65]. In women of childbearing age, this phenomenon of prenatal maternal stress is heightened, as a study in 89 women who experienced the Quebec ice storm of 1998 had children (37 participating) with up to a 10% decrease in CD4+ T cells and 0.5-log increase in pro-inflammatory TNF-a levels [66]. This drives home the idea that stress and strain can create a stress-mediated immunodeficient condition, a relevant concern in the age of COVID-19 and especially a concern in frontline nurses caring for infected patients. As fatigue and strain also affects pregnant mothers and those caring for infants and young children, reductions in immune competence from fatigue, coupled with the complex regulation of immunity during and immediately after pregnancy, could have serious healthcare implications [67,68].

Tired women, in general, are less willing to have children and this can send demographic shockwaves through an entire country as birthrates fall, yearly replacement of tax-paying workers drops, and governments suffer under the strain of lower revenues for social and infrastructure programs. Women were found, in a large South Korean study, to have significantly higher odds ratios for self-rated stress and depressive symptoms while a case study from Hong Kong found that women working 50+ hours per week were fatigued and this exhaustion was inversely correlated with the desire to have children [69,70]. Japan, as a technologically advanced nation, is well-reported to suffer from below-replacement birth rates and long work hours, exhaustion, depression, and corporate/legal frameworks to protect working mothers have all been blamed [71]. However, this effect is not homogenous; more rural and less crowded areas of Japan (such as Okinawa with a fertility rate of 1.94) seem to be sustaining the birthrate in the place of large cities such as Tokyo (1.17) [72]. Therefore, urbanization (leading to long commutes), high living costs (necessitating the choice for work over children for young women), and scarce land availability (to create fertility rate-boosting childcare centers and parks) have all been examined; however, these choices indicate that women are forced to make an opportunity cost calculation of their financial stability versus having children with a limited energy budget [72].