The underlying sex differences in neuroendocrine adaptations relevant to Myalgic Encephalomyelitis Chronic Fatigue Syndrome

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex multisystem disease characterised by severe and disabling new-onset symptoms of post-exertional malaise (PEM), fatigue, brain fog, and sleep dysfunction that lasts for at least six months. A broad spectrum of accompanying symptoms are also commonly experienced, including problems with blood pressure regulation, muscle pain, tender cervical or axillary lymph nodes, and neurocognitive disability, resulting in diverse symptom presentations, illness trajectories, and prognosis (Carruthers et al., 2011). Despite the diversity of accompanying symptoms that may present, diagnostic criteria have become more stringent over the decades, ensuring a more homogenous population. The Canadian Consensus Criteria (CCC) (2003) (Carruthers et al., 2003) and the International Consensus Criteria (ICC) (2011) (Carruthers et al., 2011) are now often adopted for research purposes, both of which require PEM as a core symptom and at least one other new onset symptom from neurological, autonomic, or immune domains. Despite high prevalence rate estimates of 0.89- 1.14% (Lim et al., 2020), comparable to the prevalence of multiple sclerosis, which has similar phenomenological and neuroimmune characteristics (Morris and Maes, 2013), ME/CFS remains largely under-researched, poorly resourced, and profoundly stigmatised.

The most common aetiological events reported by patients are a history of infection, stressful incident, and exposure to environmental toxins, but many aetiological triggers or ‘insults’ to the body are believed to be able to initiate and propagate the disease state (Chu et al., 2019). The most widely accepted hypothesis of disease manifestation proposes that such environmental triggers interact with an underlying susceptibility, driving dysfunction in vulnerable cardiovascular, renal, metabolic, gastro-intestinal, neurological, and immune systems. The diversity of physiological systems affected is thought to be responsible for the variable symptom expression patterns observed in different ME/CFS patients. Research has yet to find a pathogen or central dysfunction consistent in all ME/CFS patients or even a significant proportion of ME/CFS patients that could explain the disease or the variable symptom patterns. There also may be no single underlying cause for this illness and ME/CFS may serve as an umbrella term for multiple different diseases associated with overlapping symptoms (Maclachlan et al., 2017).

Even though diagnostic biomarkers have yet to be established for ME/CFS there is a large and accumulating body of evidence demonstrating a wide range of biological abnormalities in ME/CFS patients, most notably in the neuroendocrine, autonomic, neurological, metabolic, and immunological domains. There is also evidence for genetic heritability (Albright et al., 2011, Schlauch et al., 2016). The male / female ratio is approximately 1:3 (Lim et al., 2020), with estimates varying across studies with one study suggesting a ratio of 1:9 (Faro et al., 2014). The prevalence rate of ME/CFS has been challenging to estimate due to a lack of specific diagnostic tests, multiple case definitions, different methodologies, and confusion about diagnostic coding (Lim et al., 2020). Regardless, the female sex is one of the most consistent and credible predictive risk factors of a ME/CFS diagnosis (Lacerda et al., 2019). Assuming equal exposure levels of environmental insults or triggers, including infectious agents and physical stressors, and environmental toxins for all sexes, it can be proposed that genotype coupled with the host response ultimately drive the ME/CFS phenotype (Norris et al., 2017). The host response includes sex and age-specific endocrine hormone mediation, which may explain the sex and age discrepancies, although this has yet to be explored in detail.

This narrative review aims to outline sex differences in ME/CFS, in terms of vulnerability factors and clinical phenotype, and explore the known sex differences in neuroendocrine systems affected in ME/CFS and how this may relate to disease risk, onset, pathophysiology, and potential treatment avenues.

Both biological sex (defined as sex assigned at birth throughout this review, although the necessity of considering gender attributes in all diseases is noted) and age discrepancies are observed regarding ME/CFS onset and diagnosis. A study (Bakken et al., 2014) of 5,809 ME/CFS patients using Norwegian population-based registry data explored the distribution of ME/CFS incidence by sex and age. Incidence rates peaked for both males and females between the ages of 10–19-year-old, suggesting that gonadal sex and stress endocrine systems may be involved in ME/CFS. Adolescence represents a significant developmental period with considerable pubertal endocrine changes and represents a period of substantial psychosocial development. In line with this, an epidemiological study found that females had an increased risk of ME/CFS during late adolescence, while children under 12 were equal between males and females (Bakken et al., 2014). In the Norwegian based study, an additional second age peak between 30-39 years old was observed for females only. For females, the ages between 30 to 39 also often represent periods of rapid hormonal changes, including pregnancy and post-partum periods. Again, the increased incidence in this age group may indicate sex hormone endocrine changes or susceptibility of stressors reflecting the increased responsibilities at both work and home. Further, both adolescence and the 30-39 age bracket represent times of immune event susceptibility as direct exposures to infectious agents peak in adolescents, and subsequent reactivation of latent infections can be triggered by pregnancy or acute or chronic stressors (Faro et al., 2016).

Few studies have comprehensively investigated differences in clinical phenotypes or aetiological triggers between sex (Rubinow, 2018), mainly due to the lack of statistical power, although many studies have noted incidental findings. Differences in muscle symptoms, immunological symptoms and cardiac activity have been noted in the literature with differing rates of reported aetiological triggers between the sexes. Males report a younger onset, and fewer associated comorbidities such as fibromyalgia, osteoporosis, anxiety/ depression, and thyroid disease. 11% of women reported pregnancy or childbirth as their aetiological trigger (Wawrzkiewicz-Jałowiecka et al., 2021).

Endocrinological events, particularly those throughout the female lifespan, feature throughout the ME/CFS literature despite few studies directly investigating the link. Reproductive menstrual cycle fluctuations, pregnancy, post-partum and perimenopause involve rapid changes in gonadal sex hormones which directly and indirectly moderate metabolic and immune physiology, including changes in lipid metabolism, glucose homeostasis, energy metabolism (Bhatia et al., 2014, Gold, 2011), and the number of circulating immune cells and their responses (Panay and Studd, 1998). A prospective qualitative study of 150 ME/CFS females showed a significant percentage (42%) reported pregnancy negatively impacted their ME/CFS symptoms (Allen, 2008) which contrasts with a separate small study in ME/CFS showing 81% of women claimed to have been ‘very well’ during pregnancy, though in this latter study a high incidence of postnatal depression was reported (45% of women) (Harlow et al., 1998). Moreover, US-based ME/CFS specialists published their clinical impression that pregnancy attenuated ME/CFS symptoms to the point of remission (Boneva et al., 2015). The various responses recorded for pregnancy impact on ME/CFS may be due to failing to define symptom severity according to pregnancy stage (eg. first, second, third trimester). Each stage of pregnancy has very different hormonal and physiological environments which could be responsible for driving the change in symptoms (Chu et al., 2019).

Menopause and menstrual cycle fluctuations have also been reported to negatively impact ME/CFS symptomatology, in addition to females citing hormone-based contraception and hormone replacement therapy having a deleterious effect on their ME/CFS symptoms (Allen, 2008). It should be noted that the type of hormonal contraceptive or menopause hormone replacement therapy (oral contraceptive pills, transdermal patches, implants) were not defined, nor were the different synthetic and naturally derived estrogen and progestin formulations available. Considering menopausal and premenstrual cycle symptoms of increased fatigue, hot flushes, insomnia, and cognitive difficulties are similar to symptoms experienced in ME/CFS, it is surprising that the potential link has yet to be well explored. Five published studies have shown an association between an ME/CFS diagnosis and endocrinological and gynaecological conditions including polycystic ovarian syndrome, ovarian cysts, hyperlactatemia, pelvic pain, menstrual cycle abnormalities including amenorrhea, and early/ surgical menopause. One study reported that a third of their ME/CFS female patients reported endometriosis as a comorbidity, a full body condition in which cells like those in the endometrium grow outside of the uterus (Boneva et al., 2011, Boneva et al., 2019, Wolfe et al., 2018, Bakken et al., 2014, Mansfield et al., 2016).

Interestingly, sex differences and associated endocrine events mirror several other conditions that also implicate the central nervous system and also observe a female preponderance, including fibromyalgia (Hoy et al., 2012), chronic pain (Trojano et al., 2012, Petersen et al., 2020) and autoimmune disorders including multiple sclerosis (Ramagopalan et al., 2009). Epidemiological studies show that female/ male sex bias ratios are 3:2 for fibromyalgia (Hoy et al., 2012) and 2:1 for chronic widespread pain disorders (Trojano et al., 2012), both of which share high comorbidity rates with a ME/CFS diagnosis (Wawrzkiewicz-Jałowiecka et al., 2021, Voskuhl and Momtazee, 2017) Multiple sclerosis (MS), the most common autoimmune disease involving the nervous system, shares remarkable levels of similarity to ME/CFS in multiple dimensions, including disease progression, the relapsing-remitting nature of the illness’, the use of ‘pacing’ as an energy conservation strategy and symptomatology that includes disabling fatigue, severe exercise intolerance, orthostatic intolerance cardiac dysrhythmias, and postural hypotension (for review see [5)). The female/ male ratio in MS has been estimated to be 2.7:1 (Ramagopalan et al., 2009). As observed for ME/CFS diagnoses, following the onset of puberty, disparity changes rapidly and pubertal girls are at greater risk of developing MS than pre-pubertal girls (Ngo et al., 2014). Moreover, another major clinical observation is that pregnancy is a ‘naturally occurring disease modifier’ of MS associated with a 70% reduction in relapse rates in the third trimester (Jonsjö et al., 2020). Overall, women with MS who have been pregnant have a better long-term outcome than those who have not been pregnant, and this effect seems cumulative since multiparous women seem to have a better outcome than women with fewer, or who have no pregnancies (Wallis et al., 2016).

Despite sex differences in prevalence rates, comorbidities, and the clinical observation that symptom presentation changes during times of vulnerable endocrine fluctuation, few studies have directly investigated hormone-related events and medications in ME/CFS and the biological mechanisms driving these phenomena. Physiological differences between males and females have critical implications for differential susceptibility and response to various diseases, treatment efficacy and the differences in the way medications are metabolised.

Key physiological systems currently being investigated in ME/CFS have also noted sex differences including the immune system (Shan et al., 2016), gut microbiota (xxxx), and metabolic processes. A major driver of such sex differences is thought to be system modulation via sex hormones, particulary estrogens and testosterones. Although outside the scope of this manuscript, detailed reviews on these broad topics will contribute remarkably to the ME/CFS literature. The following section will summarise the evidence of steroid hormone contribution to ME/CFS susceptibility or disease mediation, and where possible, their contribution to the modulation of biological systems, and how they may give rise to sexual dimorphism.

Dysfunction of the nervous system has been postulated as one the possible causes of ME/CFS (Carruthers et al., 2011), with the World Health Organisation (WHO) classifying it as a neurological disorder. Autonomic dysfunction, including orthostatic intolerance, evidence of macro and microstructural brain changes and neuroinflammation of the brain (Nakatomi et al., 2018, Cvejic et al., 2016, Miller, 2017), in addition to neurocognitive and neuropsychological dysfunction (Kovats, 2015) all indicate involvement of the brain and nervous systems. The hypothalamus-pituitary complex, located in the diencephalon of the brain, has both neural and endocrine functions, producing and secreting many hormones. It continually adjusts according to internal and external environments using feedback mechanisms and represents a key facilitator of homeostatic function. Once the hypothalamus-pituitary signalling cascade is triggered, pituitary hormones stimulate steroidogenesis in target glands and organs.

Steroidogenesis predominately occurs in adrenal and gonadal glands (e.g., cortisol and mineralocorticoids are synthesised in the adrenal glands, estrogens in ovaries and testosterone in testis). It is also well-documented to occur in extra-glandular tissues, including the brain, adipocytes, leukocytes, skin, gut, lung, bone, heart, and thymus (Liao et al., 2015). Newly produced steroid hormones are then released into the blood circulation where they act both on peripheral target tissues and the central nervous system (CNS), consequently affecting diverse bodily functions, including blood pressure and heart rate, metabolic and immune function, body temperature maintenance, cognitive processes, the sleep-wake cycle, and emotional states (e.g. fear, pain), in addition to reproduction. Circulating steroids predominately work in a negative feedback manner, allowing systems to respond appropriately in the biological context and then self-stabilise. As such, the hypothalamus-pituitary endocrine system is one of the most important regulators of physiology across the lifespan and contributes to the vast sex differences observed. These above systems are all implicated in ME/CFS, and as such, the wholly integrated picture of a person's steroid metabolome should be explored in ME/CFS. Figure 1 briefly summarises the broad effects of steroid hormones on the physiological systems and ME/CFS symptomatology.

Thyroid releasing hormone (TRH), Adrenocorticotropic Hormone (ACTH); Follicular stimulating hormone (FSH); Luteinising Hormone (LH); Triiodothyronine (T3), Thyroxine (T4).

Steroid hormone synthesis involves a series of enzymatic steps in the mitochondria and endoplasmic reticulum of steroidogenic tissues that convert the precursor molecule, cholesterol (a cholestane, 27 carbons), to pregnenolone (21 carbons). Pregnenolone is then catalysed into other steroids by a series of oxidative enzymes, with the resultant functional steroids determined by the gland or tissue. Steroids are broadly classified into five groups: glucocorticoids, mineralocorticoids and progestins (21 carbons) predominately synthesised in the adrenal gland, and androgens (19 carbons) and estrogens (18 carbons), predominately synthesised in the testis and ovaries, respectively. Their structures are remarkably similar with minor variations in the number of carbons and functional groups. Figure 2 demonstrates the simplified network of steroidogenesis.

Despite their relatively simple chemical structure, steroids occur in a wide variety of biologically active forms. This variability is not only due to the extensive range of compounds secreted by endocrine glands and organs but also because circulating steroids are extensively metabolised peripherally, notably in the liver and in their target tissues, where conversion to an active form is often required before they can elicit their biological responses. Steroid metabolism is therefore important for both the production of these hormones and the regulation of their cellular and physiological actions.

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