Exploring Stress-Induced Mechanisms in Acne Pathogenesis

doi:10.21203/rs.3.rs-4477781/v1

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Exploring Stress-Induced Mechanisms in Acne Pathogenesis

https://doi.org/10.21203/rs.3.rs-4477781/v1

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Background:

Acne vulgaris affects millions worldwide, with psychological stress emerging as a significant contributor to its development. Stress influences acne via hormonal fluctuations, inflammation, immune modulation, altered skin barrier function, and lifestyle changes. Understanding these mechanisms is crucial for developing effective management strategies. This study aims to elucidate the role of stress in acne pathogenesis to inform more targeted interventions.

Methods:

A comprehensive search encompassing databases such as PubMed, MEDLINE, Google Scholar, open access / subscription-based journals, was conducted to retrieve relevant articles for the investigation of key mechanisms through which stress impacts acne development and exacerbation. Articles were searched without any date restrictions. Utilizing the criteria delineated in the methodology section, studies were systematically reviewed to elucidate the relationship between psychological stress and acne development and exacerbation. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

Results:

Our investigation revealed multiple key mechanisms through which stress impacts acne development and exacerbation. Hormonal fluctuations, including increases in cortisol and androgens, stimulate sebaceous gland activity, leading to excess sebum production. Inflammation, triggered by stress-induced cytokine release, exacerbates acne lesions. Stress also impairs skin barrier function, alters immune responses, and influences lifestyle factors such as diet, sleep, and skincare habits, all of which contribute to acne severity. Additionally, neuropeptides, oxidative stress, insulin resistance, altered skin pH, vascular changes, and changes in the skin microbiome play significant roles in stress-induced acne pathogenesis. These findings highlight the varied nature of stress-acne interactions and underscore the importance of addressing both physiological and psychological factors in acne management strategies.

Conclusion:

Our investigation reveals stress's varied impact on acne through hormonal fluctuations, inflammation, barrier function impairment, immune modulation, behavioral factors, psychological distress, neuropeptides, oxidative stress, insulin resistance, altered skin pH, vascular changes, lifestyle habits, and skin microbiome alterations. Addressing these mechanisms underscores the need for holistic acne management strategies integrating stress reduction techniques with conventional treatments. Understanding stress-acne interplay emphasizes the importance of comprehensive approaches to improve acne outcomes, recognizing the bidirectional relationship between physiological and psychological factors in acne pathogenesis and exacerbation.

Dermatology

Psychology

Immunology

Stress

Acne

Hormonal fluctuations

Inflammation

Skin barrier function

Microbiome

Acne vulgaris is a common skin condition that affects millions of individuals worldwide, with a significant impact on physical appearance, psychosocial well-being, and quality of life. While various factors contribute to acne development, including genetics, hormonal fluctuations, and environmental factors, emerging research suggests that psychological stress may also play a significant role in acne pathogenesis [1, 2, 3].

The association between stress and acne has long been recognized anecdotally, with many individuals reporting worsening of acne during periods of heightened stress. However, the underlying mechanisms through which stress influences acne development and exacerbation have only recently begun to be elucidated. Understanding these mechanisms is crucial for developing more effective acne management strategies that address both the physiological and psychological aspects of the condition [4, 5, 6].

Stress can impact acne through multiple pathways, including hormonal fluctuations, inflammation, immune modulation, altered skin barrier function, and changes in lifestyle habits. Hormonal fluctuations, particularly increases in cortisol and androgens during periods of stress, can stimulate sebaceous gland activity, leading to excess sebum production and acne formation. Inflammation, triggered by stress-induced release of inflammatory cytokines, can exacerbate acne lesions and contribute to acne severity. Additionally, stress-related changes in immune function can impair the skin's ability to combat acne-causing bacteria, further exacerbating the condition [7, 8, 9].

Furthermore, stress can influence lifestyle factors such as dietary habits, sleep patterns, exercise levels, and skincare routines, all of which can impact acne development and severity. Psychological distress associated with acne can also lead to behaviors such as skin picking, which can worsen inflammation and scarring [10, 11].

Given the varied nature of stress-acne interactions, there is a clear need for comprehensive research investigating the role of stress in acne pathogenesis. By elucidating the mechanisms through which stress influences acne, this study aims to inform the development of more targeted and effective acne management strategies that address both the physiological and psychological aspects of the condition [12, 13].

A comprehensive search was conducted across PUBMED, MEDLINE, Google Scholar, and various open access/subscription-based journals without imposing date restrictions to identify relevant articles. We investigated key mechanisms through which stress impacts acne development and exacerbation, including hormonal fluctuations, inflammation, impaired skin barrier function, immune system modulation, behavioral factors, psychological impact, neuropeptides, oxidative Stress, insulin resistance, altered skin pH, vascular changes, lifestyle factors, changes in skin microbiome.

The literature screening process was conducted following the same criteria, and relevant data were extracted. The literature search was initiated in March 2022 and concluded in February 2024. An exhaustive investigation was carried out during this period, adhering to the study parameters defined above. Additionally, during the revision process, further literature was searched and referenced up until May 2024. Multiple checks were performed on the literature search and all sections of the manuscript between March 2024 and May 2024 to ensure the highest level of accuracy.

The primary focus of the literature search was to screen articles based on the eligibility criteria mentioned above, following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Only publications in English were included, with no restrictions on the date of publication. Data extraction was conducted based on these eligibility criteria, and studies were systematically reviewed according to the methods outlined in the study. No unpublished studies were used or included in the analysis.

A total of 2238 articles were identified using database searching, and 2133 were recorded after duplicates removal. 1816 were excluded after screening of title/abstract, 179 were finally excluded, and 5 articles were excluded during data extraction. Finally, 133 articles were included as references.

Study Overview:

This study investigated the varied relationship between stress and acne, aiming to elucidate the underlying mechanisms driving acne pathogenesis. Through a comprehensive analysis, we explored the impact of stress on hormonal fluctuations, inflammation, skin barrier function, immune modulation, and lifestyle factors. Additionally, we uncovered novel findings regarding the role of neuropeptides, oxidative stress, insulin resistance, altered skin pH, vascular changes, and changes in the skin microbiome in stress-induced acne. By integrating these diverse perspectives, our study provides a holistic understanding of how stress influences acne development and exacerbation.

Mechanisms of Stress Impact on Acne Development and Exacerbation:

1. Hormonal Fluctuations:

Hormonal fluctuations due to stress play a significant role in the development and exacerbation of acne through several mechanisms, primarily involving increases in cortisol and androgen levels, which are closely linked to the stress response [14]. Cortisol, often called the "stress hormone," is produced in larger amounts during periods of stress. It directly affects the sebaceous glands, responsible for producing sebum (oil) in the skin [15]. An increase in cortisol levels can lead to an overproduction of sebum, a major factor in acne development, as excess oil can clog pores and provide a breeding ground for bacteria [16]. Additionally, cortisol has a role in regulating inflammation in the body. While it typically works to reduce inflammation initially, chronic elevated cortisol can lead to systemic inflammation, worsening acne by increasing the redness, swelling, and discomfort associated with acne lesions [17].

Androgens, such as testosterone, are male hormones present in both men and women, which increase during times of stress [18]. These hormones exacerbate acne by increasing the size and activity of sebaceous glands in the skin [19]. This results in more sebum production and a greater likelihood of pores becoming clogged. Moreover, androgens influence the lifecycle of cells in the skin, particularly those lining the hair follicles [20]. They can cause these cells to proliferate, leading to an accumulation of dead skin cells mixing with excess sebum, further clogging pores, and exacerbating acne [21].

The relationship between cortisol and androgens is multifarious. Elevated cortisol can lead to increased secretion of androgenic hormones by the adrenal glands, amplifying the effects of each hormone in promoting acne [22]. This interaction between cortisol and androgens contributes significantly to the development and exacerbation of acne during times of stress, highlighting the interconnected nature of hormonal influences on skin health [23].

2. Inflammation:

Inflammation plays a central role in the development and exacerbation of acne, particularly in the context of stress [24]. When the body is under stress, it initiates a series of biochemical responses that can directly impact skin health and inflammation levels [25]. Stress triggers the immune system to release various inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) [26]. These cytokines promote inflammation not only generally within the body but also locally within the skin. Increased levels of these cytokines can exacerbate the inflammatory response associated with acne lesions [27].

Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis is another consequence of stress [28]. This activation leads to increased production of cortisol. While cortisol typically has anti-inflammatory effects initially, chronic elevation can disrupt its normal regulatory functions and contribute to inflammation [29]. Chronic stress can impair cortisol’s ability to regulate the immune system effectively, leading to an overactive inflammatory response in the skin [30].

The inflammatory impact on acne pathogenesis is significant. Inflammatory cytokines can influence sebaceous glands to increase sebum production [31]. Excess sebum can mix with dead skin cells and debris to clog pores, forming comedones (blackheads and whiteheads) and providing an environment conducive to the growth of Propionibacterium acnes, the bacteria that can exacerbate acne [32]. Additionally, inflammation can weaken the skin’s barrier function by disrupting the structure and function of essential lipids and proteins in the skin [33]. A compromised barrier is more susceptible to irritants, pollutants, and pathogens, all of which can aggravate acne [34]. Moreover, inflamed skin can make pre-existing acne more painful and visible. Inflammation can cause acne lesions to become more pronounced, appearing as red and swollen areas around comedones and potentially leading to the development of more severe forms of acne, such as nodules and cysts [35].

Psychological stress and its effect on compulsive behaviors, such as skin picking (acne excoriee), are another important aspect to consider [36]. Stress and anxiety can lead to increased skin picking, which not only spreads bacteria but also physically exacerbates inflammation and can lead to scarring [37]. This compulsive behavior further exacerbates the inflammatory response and can worsen acne symptoms, creating a cycle that is both physiological and psychological in nature [38].

3. Impaired Skin Barrier Function:

Impaired skin barrier function is a crucial factor in the development and exacerbation of acne, particularly under stress [39]. The skin barrier, primarily composed of cells and lipids in the outermost layer of the skin (stratum corneum), serves as the body's first line of defense against environmental aggressors, pathogens, and water loss. Stress can negatively impact this barrier function through several mechanisms [40].

Chronic stress leads to increased cortisol levels, which can alter the lipid content of the skin. Cortisol can decrease the synthesis of ceramides, cholesterol, and fatty acids, essential components of the skin's lipid barrier [41]. A decrease in these lipids weakens the barrier, making the skin more susceptible to irritants and microbial invasion, both of which can contribute to acne [42]. Additionally, impaired lipid production leads to increased transepidermal water loss (TEWL) [43]. Dry, dehydrated skin can lead to the overproduction of sebum as a compensatory mechanism, potentially worsening acne by clogging pores and providing an environment conducive to bacterial growth [44].

Stress-induced release of inflammatory cytokines (e.g., IL-1, TNF-alpha) can directly impair barrier function by affecting the growth and differentiation of keratinocytes, the predominant cell type in the epidermis [45]. Abnormal keratinocyte behavior can lead to improper formation of the skin barrier, enhancing vulnerability to acne-causing factors [46]. Moreover, stress can lead to changes in skin pH, shifting it from its normal acidic range [47]. An altered pH can affect the skin's bacterial flora, possibly increasing the colonization of harmful bacteria, including Propionibacterium acnes [48]. This bacterium plays a significant role in the development of acne by promoting inflammation and further barrier disruption [49].

Stress might lead individuals to neglect regular skincare routines, potentially leading to the buildup of dead skin cells and excessive oil, which can exacerbate acne [50]. Additionally, stress and anxiety can increase behaviors such as skin picking, which physically damages the barrier, leading to inflammation and potentially secondary infections that exacerbate acne [51]. These factors underscore the diverse impact of stress on skin barrier function and its role in the pathogenesis of acne [52].

4. Immune System Modulation:

The immune system plays a fundamental role in the skin’s response to stress, influencing acne development and exacerbation through various mechanisms [53]. Stress can modulate the immune system in ways that affect inflammation, sebum production, and the skin's microbial balance, all of which are key factors in acne pathogenesis [54].

Stress-induced immune changes significantly contribute to the development and exacerbation of acne. Chronic stress activates the immune system to release pro-inflammatory cytokines (such as interleukin-1, interleukin-6, and tumor necrosis factor-alpha), exacerbating the inflammation associated with acne lesions [55]. Moreover, chronic stress can lead to dysregulation of the immune system, impairing the skin's ability to combat acne-causing bacteria like Propionibacterium acnes [56].

In addition to immune modulation, stress impacts skin barrier function and microbial flora, further exacerbating acne. Stress impairs the skin barrier function, allowing easier penetration of acne-causing bacteria and irritants [57]. In addition, stress can disrupt the balance of microorganisms on the skin, promoting the growth of acne-causing bacteria [58].

Stress-induced neuroimmune interactions also play a significant role in acne pathogenesis [59]. Stress leads to the release of various neuropeptides and neurotransmitters that interact with immune cells in the skin, further exacerbating acne by increasing sebum production and inflammation [60].

Moreover, hormonal interactions under stress contribute to acne severity. Increased levels of hormones like cortisol and androgens during stress not only directly affect sebum production but also modulate immune responses, potentially exacerbating inflammatory processes related to acne [61].

5. Behavioral Factors:

Behavioral factors play a significant role in the development and exacerbation of acne, particularly in the context of stress. Stressful periods can lead to changes in behavior that affect skin health, either directly by influencing physiological mechanisms or indirectly through altered lifestyle habits [62].

During stressful periods, individuals might neglect their skincare routines, leading to the accumulation of dead skin cells, excess sebum, and impurities on the skin, which clog pores and exacerbate acne [63]. Stress might also lead individuals to experiment with harsh skincare products or excessive use of treatments in an attempt to quickly address acne, which can strip the skin of essential oils and impair barrier function, leading to worsened skin conditions [63].

Stress often influences dietary choices, leading to increased consumption of high-glycemic-index foods and fatty foods that can exacerbate acne [64]. These foods can trigger hormonal fluctuations and inflammatory responses that contribute to acne development [65]. Stress might also result in reduced consumption of nutrients important for skin health, such as vitamins A, E, and D, zinc, and omega-3 fatty acids, potentially worsening acne [66].

Stress is a well-known cause of sleep disturbances [67]. Poor sleep can lead to increased levels of stress hormones like cortisol, which further exacerbates acne by increasing oil production and inflammation [68]. Lack of sleep can impair the skin’s natural healing processes, making it more difficult for the skin to recover from acne lesions and increasing the likelihood of scarring [69]. Additionally, stress and anxiety can increase compulsive behaviors such as skin picking (acne excoriee), which damages the skin barrier, spreads acne-causing bacteria, and can lead to inflammation and infections [70]. Moreover, psychological stress might lead to a lack of motivation for general self-care, including skincare, which can indirectly exacerbate acne.

High stress levels can lead to decreased physical activity [71]. Regular exercise is beneficial for modulating hormones and improving blood circulation, helping to reduce the severity and frequency of acne breakouts [72]. Conversely, stress can induce sweating (often in conjunction with anxiety), and if the skin is not properly cleaned post-sweat, it can contribute to acne flare-ups [73]. These behavioral factors underscore the complicated interrelationship between stress, lifestyle choices, and acne development [74].

6. Psychological Impact:

The psychological impact of acne is a crucial factor in understanding the complicated relationship between stress and acne. This relationship is bidirectional, while stress can exacerbate acne, the presence of acne can also lead to increased stress and psychological distress, creating a vicious cycle that can worsen the condition [75].

Stress and anxiety can lead to elevated cortisol levels, which in turn can increase sebum production [76]. Sebum is an oily substance that, when overproduced, can contribute to the clogging of pores, thus worsening acne [77]. Psychological stress often leads to behaviors such as compulsive skin picking (acne excoriée), which not only damages the skin but also introduces bacteria into the pores, leading to further inflammation and acne severity [78].

Depression and lowered self-esteem, which can be triggered or exacerbated by the presence of acne, might lead to a neglect of personal hygiene and skincare routines [79]. This neglect can further deteriorate skin health and exacerbate acne. Emotional distress may lead to social withdrawal or reduced physical activity, both of which can increase stress levels and negatively affect overall health, including skin health [80].

Social anxiety and isolation can increase stress, leading again to hormonal imbalances that promote acne exacerbation [81]. People with acne may avoid social interactions, including visits to dermatologists or other healthcare providers due to embarrassment about their skin, leading to delayed or insufficient treatment [82]. These psychological factors contribute significantly to the development and exacerbation of acne under conditions of stress, highlighting the need for comprehensive management strategies that address both the physiological and psychological aspects of the condition [83].

7. Neuropeptides

Neuropeptides, which are small protein-like molecules, enable neurons to communicate and modulate numerous physiological processes, including skin homeostasis. Several key neuropeptides are involved in this process, including Corticotropin-Releasing Hormone (CRH), Substance P (SP), Adrenocorticotropic Hormone (ACTH), Neuropeptide Y (NPY), and Calcitonin Gene-Related Peptide (CGRP). Each of these neuropeptides plays a specific role in the stress response that affects skin physiology [5, 6, 84].

When stress activates the Hypothalamic-Pituitary-Adrenal (HPA) axis, CRH is released from the hypothalamus, stimulating the pituitary gland to secrete ACTH. ACTH prompts the adrenal glands to produce cortisol, a major stress hormone. CRH receptors present in the sebaceous glands bind to CRH, stimulating sebaceous gland activity and increasing sebum production, which can clog pores and contribute to acne formation [5, 58, 84].

Substance P (SP) is another crucial neuropeptide released from nerve endings in the skin under stress. It interacts with neurokinin-1 (NK-1) receptors on sebaceous glands, leading to increased sebum production and stimulating inflammatory cytokines from keratinocytes and sebocytes, exacerbating acne's inflammatory component. Similarly, elevated cortisol levels due to stress increase sebum production and alter skin immune responses, promoting an inflammatory environment that worsens acne [8, 85, 90].

Neuropeptide Y (NPY) and Calcitonin Gene-Related Peptide (CGRP) also play significant roles in stress-induced acne. NPY is released during stress and induces sebaceous gland activity while modulating the immune response, contributing to increased sebum production and inflammation. CGRP, released from sensory nerves in response to stress, causes vasodilation and can increase blood flow to the skin, potentially contributing to the inflammatory process in acne [10, 86, 89].

The combined effects of these neuropeptides lead to increased sebum production, altered keratinization, and heightened inflammation, which are central features in the pathogenesis of acne. Additionally, stress-induced neuropeptides can affect the skin's microbiome, potentially promoting the growth of acne-causing bacteria like Cutibacterium acnes [12, 87, 88].

8. Oxidative Stress:

Oxidative stress is a critical pathway through which stress can influence the development and exacerbation of acne. This process occurs when there is an imbalance between free radicals, known as reactive oxygen species (ROS), and the body's ability to neutralize them with antioxidants [5, 91].

Stress, both psychological and physical, increases the production of ROS through various biochemical pathways. This includes mitochondrial dysfunction, which results in elevated ROS production, and the activation of NADPH oxidase, an enzyme that produces superoxide, a type of ROS. These reactive species initiate a cascade of detrimental effects on the skin, promoting acne development [6, 92].

Lipid peroxidation is one significant consequence of increased ROS levels. The sebaceous glands in the skin produce sebum, which is rich in lipids. ROS can peroxidize these lipids, leading to the formation of lipid peroxides. These peroxides cause hyperkeratinization, leading to clogged pores and the formation of comedones, such as blackheads and whiteheads, which are characteristic of acne [8, 93].

ROS also activate inflammatory pathways by triggering nuclear factor-kappa B (NF-κB) and other transcription factors that increase the production of pro-inflammatory cytokines like IL-1, IL-6, and TNF-α. These cytokines attract inflammatory cells to the site, exacerbating acne inflammation. This inflammatory cascade not only initiates acne formation but also perpetuates and worsens existing lesions [10, 94].

The integrity of the skin barrier and the skin microbiome are compromised under oxidative stress. A weakened skin barrier becomes more susceptible to environmental insults and microbial invasion, while increased ROS can alter the skin microbiome, promoting the growth of acne-causing bacteria such as Cutibacterium acnes. This disruption further exacerbates acne [12, 95, 115].

Chronic stress depletes essential antioxidants like vitamin E, vitamin C, and glutathione in the skin, reducing its ability to neutralize ROS. This depletion creates a vicious cycle where increased ROS leads to more oxidative damage and inflammation, worsening acne. The combination of increased ROS production, lipid peroxidation, inflammatory pathway activation, skin barrier damage, and antioxidant depletion creates an environment highly conducive to acne development and exacerbation [13, 96, 97].

9. Insulin Resistance:

Insulin resistance occurs when cells in the body become less responsive to insulin, leading to elevated levels of insulin and glucose in the blood. This condition significantly impacts skin health, particularly in the context of acne. Stress-induced insulin resistance leads to hyperinsulinemia and elevated androgen levels, promoting sebum production, inflammation, and keratinocyte proliferation, all of which contribute to acne pathogenesis [98, 115].

Hyperinsulinemia, a condition marked by high levels of insulin, is a direct consequence of insulin resistance induced by stress. The pancreas produces more insulin to maintain normal blood glucose levels, which can stimulate sebaceous glands to produce more sebum. Sebum is an oily substance that can clog pores, creating an environment conducive to the growth of acne-causing bacteria such as Cutibacterium acnes [13, 99].

Elevated insulin levels also increase androgen production from the ovaries and adrenal glands. Androgens, like testosterone, are known to stimulate sebaceous gland activity, leading to increased sebum production and acne development. This hormonal imbalance underscores the significant impact of insulin resistance on acne through androgen-mediated pathways [12, 100].

Insulin resistance is associated with the production of pro-inflammatory cytokines, leading to chronic inflammation that exacerbates acne by promoting the formation of inflammatory lesions. Additionally, stress-induced insulin resistance can lead to oxidative stress, further promoting inflammation and worsening acne. This inflammatory response is a critical factor in the pathogenesis of acne [10, 101].

Elevated levels of Insulin-Like Growth Factor 1 (IGF-1) are another consequence of insulin resistance. IGF-1 has similar effects to insulin and enhances sebum production and keratinocyte proliferation. It stimulates the proliferation of skin cells and sebaceous gland cells, contributing to the formation of comedones (clogged pores) and acne lesions. This mechanism further highlights the role of insulin resistance in acne development [8, 102].

Diet and lifestyle factors play crucial roles in modulating insulin resistance and acne. Stress can lead to increased consumption of high-glycemic foods, exacerbating insulin resistance. High-glycemic diets increase blood sugar levels rapidly, prompting higher insulin production. Additionally, chronic stress often results in poor lifestyle choices, such as lack of exercise and inadequate sleep, which can further contribute to insulin resistance and acne [6, 103].

The combined effects of insulin resistance and elevated insulin and IGF-1 levels lead to increased sebum production, keratinization, inflammation, and androgen effects, all contributing to acne formation and exacerbation [5, 104].

10. Altered Skin pH

Stress can influence the development and exacerbation of acne through mechanisms related to altered skin pH. The pH of the skin is a critical factor in maintaining skin barrier function, microbial balance, and overall skin health [5, 105].

Stress activates the sympathetic nervous system, leading to changes in sweat and sebum secretion that can alter the acid mantle, the thin, acidic film on the skin’s surface. Elevated cortisol levels from stress affect the skin’s pH balance by influencing sweat composition and sebum production. These changes in skin pH are fundamental to understanding how stress can disrupt skin homeostasis [8, 106].

An increase in skin pH due to stress disrupts the acid mantle, making the skin more alkaline. The natural pH of the skin is slightly acidic, around 4.5 to 5.5, and a higher pH favors the growth of pathogenic bacteria, including Cutibacterium acnes. An altered pH can also reduce the effectiveness of antimicrobial peptides, weakening the skin's defense against harmful microorganisms and leading to an overgrowth of acne-causing bacteria [12, 107].

An optimal acidic pH is crucial for the integrity and function of the skin barrier. Increased pH can impair the barrier function, leading to increased transepidermal water loss (TEWL) and a more permeable skin barrier. A compromised skin barrier makes the skin more prone to irritation and sensitivity, which can exacerbate acne lesions, highlighting the importance of maintaining pH balance for skin health [108, 115].

An elevated skin pH can promote a pro-inflammatory environment, triggering the release of inflammatory cytokines and contributing to the formation and exacerbation of acne. Altered pH levels can also lead to increased oxidative stress, further promoting inflammation and worsening acne. The interplay between pH imbalance and inflammation underscores a key pathway through which stress impacts acne [6, 109, 110].

Stress can increase sebum production, and an altered pH can change the composition of sebum, making it more prone to oxidation. Oxidized sebum is more comedogenic and can trigger inflammatory responses. An increased pH can also facilitate the peroxidation of sebum lipids, contributing to comedone formation and the inflammatory process in acne. This complicated interaction between sebum changes and pH highlights how stress can directly impact acne pathogenesis [10, 13, 111].

11. Vascular Changes

Stress-induced vascular changes contribute to acne provides a deeper understanding of the underlying physiological processes. These changes involve alterations in blood flow, vascular permeability, and inflammatory responses in the skin [5, 112].

Activation of the sympathetic nervous system is a primary response to stress, leading to the release of catecholamines such as adrenaline and noradrenaline. These hormones cause vasoconstriction, which reduces blood flow to the skin. This reduced blood flow impairs the delivery of oxygen and nutrients to skin cells, negatively impacting skin health and potentially exacerbating acne. The limited blood supply can hinder skin repair and regeneration, creating a more conducive environment for acne development [6, 113].

Elevated cortisol levels during stress further contribute to vasoconstriction. Cortisol narrows blood vessels, diminishing blood flow to the skin and affecting its ability to repair and regenerate. This reduced circulation can make the skin more susceptible to acne and slow the healing of existing lesions. Cortisol's vasoconstrictive effect adds another layer of complexity to the relationship between stress and acne [8, 114].

Stress also increases vascular permeability, leading to the leakage of fluids and immune cells into surrounding tissue. This process results in edema (swelling) and creates a favorable environment for the development of inflammatory acne. Increased permeability allows inflammatory cells, such as neutrophils and macrophages, to infiltrate the skin, contributing to the formation of acne lesions. The presence of these cells can exacerbate inflammation and acne severity [10, 115].

The release of inflammatory mediators like histamine, prostaglandins, and cytokines is another critical aspect of the stress response. These substances cause vasodilation (widening of blood vessels) and increased blood flow to specific areas of the skin, leading to the redness and inflammation commonly seen in acne. The localized increase in blood flow can worsen existing acne lesions and promote the formation of new ones, highlighting the complicated interplay between stress and skin inflammation [12, 115, 116].

Alterations in skin microcirculation due to stress disrupt the balance of pro- and anti-inflammatory factors in the skin. Poor microcirculation can lead to hypoxia (low oxygen levels), stimulating the production of pro-inflammatory cytokines and worsening acne. Additionally, compromised microcirculation impairs the removal of metabolic waste products, further promoting inflammation and acne formation [13, 117, 118].

12. Lifestyle Factors

Stress often leads to changes in dietary habits, including an increased intake of high-glycemic foods and sugary snacks. These foods cause rapid spikes in blood glucose levels, leading to increased insulin production. High insulin levels can promote androgen production and increased sebum production, both of which are key contributors to acne development. Additionally, stress may cause individuals to consume more processed and high-fat foods, which can increase systemic inflammation. Foods high in refined sugars, dairy, and unhealthy fats can exacerbate inflammatory responses in the body, including the skin, leading to the development of inflammatory acne lesions [5, 119].

Stress frequently disrupts sleep patterns, leading to inadequate or poor-quality sleep. Lack of sleep can increase cortisol levels, which in turn can enhance sebum production and inflammation. Chronic sleep deprivation can weaken the skin barrier, making it more susceptible to acne-causing bacteria and environmental irritants. Disrupted sleep can also affect the skin’s natural circadian rhythms, impairing its ability to repair and regenerate. This can lead to increased acne severity and slower healing of existing acne lesions [5, 120].

Stress can lead to a decrease in physical activity, as individuals may feel too fatigued or overwhelmed to engage in regular exercise. Reduced physical activity can negatively affect overall circulation and lymphatic drainage, impairing the removal of toxins from the skin. Exercise helps regulate hormones, and a lack of physical activity can disrupt this balance, contributing to acne. On the other hand, excessive exercise or improper hygiene post-exercise can lead to sweat accumulation on the skin, clogging pores and promoting acne. Stress-related changes in exercise habits can thus either reduce beneficial effects or increase acne risk due to poor skin care post-exercise [8, 115, 121].

Stress can cause individuals to neglect their regular skincare routines. Inconsistent cleansing, moisturizing, and use of acne treatments can lead to the accumulation of dirt, oil, and dead skin cells, clogging pores and exacerbating acne. Conversely, stress might lead some individuals to overuse skincare products in an attempt to control acne, which can irritate the skin, disrupt its pH balance, and impair its barrier function, worsening acne [10, 122]. Psychological factors such as increased touching or picking at the skin due to stress can introduce bacteria, increase inflammation, and lead to scarring, exacerbating existing acne and contributing to new lesions [12, 123].

The combined effects of these lifestyle changes include hormonal imbalance, increased inflammation, and a compromised skin barrier. Poor diet, sleep, and exercise habits can disrupt hormonal balance, increasing androgen levels and sebum production, key contributors to acne. Stress-related dietary habits and sleep deprivation increase systemic and skin-specific inflammation, worsening acne severity. Neglecting skincare routines and improper use of skincare products can damage the skin barrier, making it more susceptible to acne-causing bacteria and environmental irritants [13, 124, 125].

13. Changes in Skin Microbiome:

Stress can influence the development and exacerbation of acne through changes in the skin microbiome. The skin microbiome, a diverse community of microorganisms living on the skin, plays a crucial role in maintaining skin health and preventing disease. Stress-induced alterations in this microbial community can disrupt its balance, leading to acne [57, 126].

Stress activates the sympathetic nervous system, leading to the release of catecholamines such as adrenaline and noradrenaline. These hormones can influence the skin's environment by altering sweat and sebum production, which can impact the composition of the skin microbiome. Changes in sebum production can create a more favorable environment for certain bacteria, such as Cutibacterium acnes, which thrive in lipid-rich environments. This disruption in the balance between commensal and pathogenic bacteria can lead to an overgrowth of acne-causing bacteria [127].

Chronic stress leads to elevated cortisol levels, which can suppress the immune system and alter the skin’s immune responses. This immunosuppression can reduce the skin's ability to control pathogenic bacteria, allowing harmful microbes to proliferate. Altered immune responses further disrupt the skin’s microbial balance, favoring the growth of pathogenic organisms over commensal microbes, which can contribute to acne development [128].

Stress can change the composition of sebum, increasing the levels of certain lipids that can be utilized by acne-causing bacteria. This alteration in lipid profile can support the growth and proliferation of Cutibacterium acnes, enhancing its ability to colonize and cause inflammation in the skin. Increased sebum production under stress provides more nutrients for bacteria, leading to an imbalance in the microbiome and promoting acne [129].

Stress can induce the production of pro-inflammatory cytokines, which alter the skin microbiome by creating an environment that supports the growth of inflammatory bacteria. This inflammatory milieu exacerbates acne by promoting the colonization of pathogenic bacteria and further disrupting microbial balance. Persistent stress-induced inflammation continuously alters the skin microbiome, leading to a long-term imbalance that favors acne development [130].

Stress can impair the production and function of antimicrobial peptides (AMPs) in the skin. AMPs play a crucial role in controlling microbial populations and maintaining a healthy microbiome. Reduced AMP activity weakens the skin’s defense against pathogenic bacteria, allowing acne-causing bacteria to flourish. A weakened antimicrobial defense due to stress can lead to increased bacterial colonization and biofilm formation, particularly by Cutibacterium acnes, which is a major contributor to acne [131, 132].

Stress-induced changes in the skin microbiome play a significant role in the development and exacerbation of acne. By disrupting microbial balance, altering immune responses, changing sebum composition, and reducing antimicrobial peptide activity, stress creates conditions that favor the proliferation of acne-causing bacteria and inflammation [133].

Our investigation into the myriad mechanisms through which stress impacts acne development and exacerbation sheds light on the complicated interplay between physiological and psychological factors in skin health. By elucidating these mechanisms, our findings have several implications for both research and clinical practice.

Understanding the diverse pathways through which stress influences acne underscores the importance of adopting a varied approach to acne management. Integrating stress reduction techniques, such as mindfulness, cognitive-behavioral therapy, and relaxation techniques, alongside conventional acne treatments could enhance therapeutic outcomes by addressing underlying stress-related mechanisms.

Our findings also highlight the need for personalized acne management strategies that consider individual stress levels, lifestyle factors, and psychological well-being. Tailoring treatments to address specific stressors and lifestyle habits could optimize treatment efficacy and improve patient satisfaction and adherence.

Furthermore, our investigation underscores the importance of collaboration between dermatologists, psychologists, and other healthcare professionals in managing acne comprehensively. By addressing both the physiological and psychological aspects of acne, interdisciplinary teams can provide holistic care that addresses the root causes of acne and improves patient outcomes.

Additionally, our findings emphasize the importance of patient education regarding the impact of stress on acne. Educating patients about stress management techniques, the importance of maintaining healthy lifestyle habits, and the bidirectional relationship between stress and acne could empower individuals to take an active role in managing their condition.

Our research highlights the need for further studies investigating the efficacy of stress reduction interventions in acne management. Randomized controlled trials assessing the impact of stress reduction techniques on acne severity, inflammatory markers, and quality of life could provide valuable insights into the effectiveness of integrative approaches to acne care.

Our investigation underscores the complicated relationship between stress and acne and the importance of addressing stress-related mechanisms in acne management. By integrating stress reduction techniques into clinical practice and furthering research in this area, we can improve acne outcomes and enhance the overall well-being of individuals affected by this common skin condition.

Key Findings:

This study explored into the complicated relationship between stress and acne, revealing novel insights into the mechanisms underlying their interaction. Our investigation uncovered the significant role of neuropeptides in stress-induced acne pathogenesis, elucidating how molecules like Corticotropin-Releasing Hormone (CRH), Substance P (SP), and Adrenocorticotropic Hormone (ACTH) contribute to sebum production and inflammation. Additionally, we highlighted the impact of oxidative stress on acne development, emphasizing how imbalances between reactive oxygen species (ROS) and antioxidants exacerbate inflammation and disrupt skin barrier function. Moreover, our research uncovers the influence of insulin resistance on acne severity, shedding light on how elevated insulin levels and insulin-like growth factor 1 (IGF-1) promote sebum production and inflammation. These novel findings deepen our understanding of the complicated interplay between stress and acne, paving the way for more targeted interventions addressing both physiological and psychological aspects of the condition.

Psychological interventions:

Psychological interventions targeting acne development and exacerbation due to stress encompass a range of approaches aimed at addressing both the physiological and psychological aspects of the condition. Cognitive-Behavioral Therapy (CBT) is one such intervention that helps individuals identify and challenge negative thought patterns and behaviors associated with acne-related stress. By teaching coping strategies, relaxation techniques, and problem-solving skills, CBT can reduce anxiety and improve overall psychological well-being, thereby mitigating the impact of stress on acne.

Mindfulness-Based Stress Reduction (MBSR) techniques, such as mindfulness meditation and body scanning, promote present-moment awareness and acceptance of one's thoughts and feelings. By cultivating mindfulness, individuals can better manage stress, reduce emotional reactivity, and cope more effectively with the challenges of acne. Stress Management Workshops are another valuable intervention, providing education and training on stress management techniques like deep breathing exercises, progressive muscle relaxation, and time management strategies. By learning practical skills to manage stress, individuals can minimize its impact on acne development and exacerbation.

Support groups offer a platform for individuals with acne to share experiences, receive validation, and gain emotional support from others facing similar challenges. Peer support can reduce feelings of isolation, improve self-esteem, and foster a sense of community, all of which can help alleviate stress associated with acne. Psychological Counseling, whether individual or group sessions with a qualified therapist, provides a safe space for individuals to explore their feelings about acne, address underlying emotional issues, and develop coping strategies to manage stress more effectively.

Counseling can also help individuals develop a more positive self-image and improve body acceptance, reducing the psychological impact of acne-related stress. By integrating these psychological interventions into acne treatment plans, healthcare providers can offer comprehensive care that addresses the psychological burden of acne alongside its physical manifestations. Ultimately, this approach improves overall outcomes and quality of life for individuals affected by this condition, recognizing the complicated interplay between psychological well-being and dermatological health.

Our investigation into the complicated relationship between stress and acne development has revealed a multitude of key mechanisms through which stress impacts the onset and exacerbation of acne. Stress induces hormonal fluctuations, particularly increases in cortisol and androgen levels, which directly influence sebum production and inflammatory responses, contributing to acne formation. Stress triggers inflammatory pathways, leading to heightened inflammation within the skin. This inflammatory environment exacerbates acne lesions and contributes to their persistence and severity.

Chronic stress disrupts the skin barrier function by altering lipid composition, increasing transepidermal water loss, and compromising the skin's ability to defend against environmental aggressors. This impairment facilitates acne development and worsens existing lesions. Stress dysregulates immune responses, leading to an overactive inflammatory response and impaired immune surveillance against acne-causing bacteria. This modulation contributes to the persistence of acne and its inflammatory manifestations. Stress influences behaviors such as skincare neglect, poor dietary choices, inadequate sleep, and reduced physical activity, all of which can exacerbate acne by promoting sebum production, inflammation, and skin barrier impairment.

The psychological impact of acne and stress forms a bidirectional relationship, where stress exacerbates acne, and acne-induced distress perpetuates stress. Psychological stressors trigger physiological responses that worsen acne symptoms, creating a cycle of exacerbation. Stress-induced neuropeptides, such as CRH, SP, and NPY, interact with various skin components to increase sebum production, inflammation, and bacterial colonization, contributing to acne pathogenesis. Stress-induced oxidative stress disrupts lipid composition, triggers inflammatory pathways, and compromises antioxidant defenses, creating a favorable environment for acne development and progression.

Stress-induced insulin resistance leads to hyperinsulinemia and elevated androgen levels, promoting sebum production, inflammation, and keratinocyte proliferation, all of which contribute to acne pathogenesis. Stress disrupts skin pH balance, favoring the growth of pathogenic bacteria and impairing the skin's barrier function. Altered pH levels exacerbate inflammation and oxidative stress, worsening acne symptoms. Stress-induced vascular changes impair blood flow and increase vascular permeability, leading to tissue edema and enhanced inflammatory responses, thereby exacerbating acne lesions.

Stress influences dietary habits, sleep patterns, physical activity, and skincare routines, all of which impact hormonal balance, inflammation, and skin barrier integrity, contributing to acne development. Stress alters the skin microbiome composition, favoring the growth of pathogenic bacteria and impairing immune defenses, leading to acne exacerbation.

Our comprehensive investigation highlights the varied impact of stress on acne pathogenesis. By elucidating these key mechanisms, our findings underscore the importance of holistic approaches to acne management that address both physiological and psychological factors. Effective acne management strategies should include stress reduction techniques alongside conventional treatments to achieve optimal outcomes for individuals struggling with acne.

HPA: Hypothalamic-Pituitary-Adrenal

TEWL: Transepidermal Water Loss

IL-1: Interleukin-1

IL-6: Interleukin-6

TNF-alpha: Tumor Necrosis Factor-alpha

CBT: Cognitive-Behavioral Therapy

MBSR: Mindfulness-Based Stress Reduction

AMPs: Antimicrobial Peptides

IL-1: Interleukin-1

IL-6: Interleukin-6

TNF-alpha: Tumor Necrosis Factor-alpha

NF-κB: Nuclear Factor-kappa B

IGF-1: Insulin-Like Growth Factor 1

Ethics declarations:
Ethics approval and consent to participate
Not applicable.

Consent for publication:
Not applicable.

Data Availability statement:
All data generated or analyzed during this study are included in this article.

Competing interests:
The authors declare that they have no competing interests.

Funding:
I declare that there was not any source of funding for this research work.

Acknowledgements:
“Not applicable”.

Authors’ Contribution:

Ifrah Siddiqui (IS)* is the author of the study and contributed to its conceptualization, design, and methodology, as well as the literature search and referencing. She was responsible for writing, editing, and revising the manuscript, as well as delineating the findings, results, conclusions, implications, and all other aspects of the study. IS conducted data extraction and analysis, critically evaluated every aspect of the study, ensured adherence to relevant PRISMA guidelines, and addressed study limitations and references. Additionally, she created Figure 1. The author reviewed and approved the manuscript.

She investigated the key mechanisms through which stress impacts acne development and exacerbation, including hormonal fluctuations, inflammation, impaired skin barrier function, immune system modulation, behavioral factors, psychological impact, neuropeptides, oxidative Stress, insulin resistance, altered skin pH, vascular changes, lifestyle factors, changes in skin microbiome.

Ifrah Siddiqui (IS)* holds a Bachelor's Degree with a focus on Psychology from the University of Karachi, Pakistan. She has a passion for investigating the disease mechanisms and psychological aspects of various diseases.

Email address*: [email protected]
Corresponding author: IS
Correspondence to Ifrah Siddiqui

Ubaid Rais (UR) is the co-author of the study and contributed to its literature search and referencing. He was responsible for writing, editing, and revising the manuscript, as well as delineating the findings, results, conclusions, implications, and all other aspects of the study. UR conducted data extraction and analysis, critically evaluated every aspect of the study, ensured adherence to relevant PRISMA guidelines, and addressed study limitations and references. The author reviewed and approved the manuscript.

He contributed to investigating the key mechanisms through which stress impacts acne development and exacerbation, including hormonal fluctuations, inflammation, impaired skin barrier function, immune system modulation, behavioral factors, psychological impact, neuropeptides, oxidative Stress, insulin resistance, altered skin pH, vascular changes, lifestyle factors, changes in skin microbiome.

Ubaid Rais (UR) holds a Doctor of Pharmacy (Pharm.D.) degree from Dow University of Health Sciences, Karachi, Pakistan, and is dual-licensed as a Pharm.D. in both Pakistan and Saudi Arabia. He is currently working as a full-time clinical pharmacist at Dr. Sulaiman Al Habib Medical Group in Saudi Arabia. In his role, he serves nearly 10,000 patients annually in critical care units for neonates and adults. With approximately 8 years of experience in the clinical field, Ubaid's expertise is well-established. His research interests include antimicrobial resistance, the psychological effects of medicines on the human brain, and rare clinical cases.

Mehak Tahir (MT) is the co-author of the study and contributed to its literature search and referencing. She was responsible for writing, editing, and revising the manuscript, as well as delineating the findings, results, conclusions, implications, and all other aspects of the study. MT conducted data extraction and analysis, critically evaluated every aspect of the study, ensured adherence to relevant PRISMA guidelines, and addressed study limitations and references. The author reviewed and approved the manuscript.

She contributed to investigating the key mechanisms through which stress impacts acne development and exacerbation, including hormonal fluctuations, inflammation, impaired skin barrier function, immune system modulation, behavioral factors, psychological impact, neuropeptides, oxidative Stress, insulin resistance, altered skin pH, vascular changes, lifestyle factors, changes in skin microbiome.

Mehak Tahir (MT) holds a Pharm.D. degree from Ziauddin University, Karachi, Pakistan, a Master's in Clinical Pharmacy from AIMST University, Malaysia, and she is currently enrolled in a Master's program in International Business Management from Coventry University, United Kingdom. She focuses her research on KAP (Knowledge, Attitudes, and Practices) studies, Pharmacovigilance, Clinical Sciences, Dermatology, Nutrition, and Food Studies.

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The authors declare no competing interests.

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Exploring Stress-Induced Mechanisms in Acne Pathogenesis

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Abstract

Figures

Background

Methods

Results

Study Overview:

1. Hormonal Fluctuations:

2. Inflammation:

3. Impaired Skin Barrier Function:

4. Immune System Modulation:

5. Behavioral Factors:

6. Psychological Impact:

7. Neuropeptides

8. Oxidative Stress:

9. Insulin Resistance:

10. Altered Skin pH

11. Vascular Changes

12. Lifestyle Factors

13. Changes in Skin Microbiome:

Discussion

Key Findings:

Psychological interventions:

Conclusion

Abbreviations

Declarations

References

Additional Declarations

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