JiHong Ding

Abstract: In recent years, domestic and international research has found that patients with polycystic ovary syndrome (PCOS) often have varying degrees of mental disorders, with depression being the most common comorbidity. Depression significantly affects patients’ reproductive fertility, psychological health, and quality of life. To further explore the clinical symptoms of PCOS complicated with depression, identify possible causes and pathogenesis, and choose appropriate treatment methods, this article provides a review of the understanding of PCOS complicated with depression from the perspective of traditional Chinese medicine (TCM), clinical manifestations, relevant pathogenesis, and potential treatment strategies. This aims to provide a scientific basis for the clinical treatment of PCOS complicated with depression.

Background: Polycystic Ovary Syndrome (PCOS) is a common endocrine and metabolic disorder in women of childbearing age, with over 15% of women of childbearing age suffering from PCOS^［1,2］. The American Endocrine Society’s clinical practice guidelines^［3］recommend using the Rotterdam criteria for diagnosis, which states that meeting any two or more of the criteria of excessive androgens, ovulatory dysfunction, and ovarian cystic changes can diagnose PCOS. Clinical manifestations of PCOS often include abnormal hair growth (hirsutism or hair loss), menstrual irregularities, pregnancy complications, and metabolic syndrome (such as obesity or insulin resistance). The occurrence of these symptoms increases the risk of depression in patients with PCOS; in fact, over 60% of PCOS patients are diagnosed with at least one mental disorder^［2,4］.

Recent research has found an association between PCOS and mental health issues, with depression being a major concern^［5］and considered one of the significant risk factors for PCOS. A 15-year follow-up study found that psychological distress is more common among reproductive-age and premenopausal women with PCOS^［6］. Several studies have shown that women with PCOS have an increased risk of depression and negative body image compared to those without PCOS^［7-9］.

On the other hand, patients with polycystic ovary syndrome (PCOS) have a higher risk of developing depression and face significant economic burdens. The risk of depression in PCOS patients is more than 2.5 times higher than in healthy women^［10］, and another study indicated that the incidence of depression in PCOS patients is 3 to 8 times higher compared to the control group^［11］, further highlighting the significantly increased risk of depression symptoms in women with PCOS. A domestic study pointed out that the prevalence of depression among PCOS patients in China is 30%, showing an increasing trend^［12］. As of 2021, the direct annual medical costs associated with the most common mental health disorders related to PCOS (depression, anxiety, or eating disorders) in the US population alone exceeded $4 billion^［13］. This demonstrates that the risk of depression caused by PCOS and the related mental health care costs continue to rise.

Therefore, this study, through databases such as China National Knowledge Infrastructure (CNKI) and PubMed, comprehensively analyzes relevant research on PCOS complicated with depression from domestic and international sources. The study will review four aspects: understanding of PCOS complicated with depression from the perspective of traditional Chinese medicine, clinical manifestations, possible related mechanisms, and potential treatment strategies. This is aimed at providing theoretical support for the treatment of PCOS complicated with depression.

Understanding of Polycystic Ovary SyndromeComplicated with Depression in Traditional Chinese Medicine

Based on the clinical manifestations of polycystic ovary syndrome (PCOS) complicated with depression, it can be categorized as “Yu Zheng,” “Zang Zao,” or “Baihe Bing” in traditional Chinese medicine (TCM) terms. The medical case records of Wang Mengying^［14］state: “The liver governs the qi of the whole body, and diseases related to the seven emotions must start from the liver.” Emotional disturbances are most likely to impair qi and blood; women primarily use blood, and stagnation of liver qi and stasis of qi and blood can lead to abnormalities in physiological functions such as menstruation and fertility. For instance, the Wan family’s Obstetrics and Gynecology^［15］describes: “Worrying, overthinking, anger, and resentment can lead to stagnation of qi and blood, resulting in irregular menstruation.” The Essentials of Gynecology^［16］mentions: “If the seven emotions harm the body, it can lead to menstrual disorders and infertility.” Thus, emotional imbalance is considered a significant etiological factor in menstrual irregularities and infertility in women, making liver depression syndrome one of the common clinical patterns in PCOS complicated with depression.

TCM theory suggests that the occurrence and development of PCOS complicated with depression are closely related to emotional factors, with depressive emotions or stressful life events being risk factors for liver depression syndrome. The Secret Essentials of Gynecology^［17］states: “Generally, women with strong emotions, stubbornness, anger, jealousy, and suspicion often damage liver qi.” According to TCM theory, women primarily rely on the liver for congenital essence; when the liver’s regulation and expression are affected by pathological emotions, and qi stagnation occurs, it can impair the functions of the liver, spleen, and kidneys. This, in turn, affects the kidney-Jing (essence)-chong (thoroughfare)-ren (conception)-bao (uterus) reproductive axis, leading to menstrual or pregnancy abnormalities and the development of this condition. The Essentials of the Yin School^［18］states: “Female servants often have depression, leading to irregular menstruation and difficulty in conception.”

From the perspective of TCM differential diagnosis and treatment, patients with PCOS often exhibit liver dysfunction in regulating and expressing qi, qi stagnation, blood stasis, or phlegm-dampness obstruction, leading to dysfunction of organ physiology and clinical manifestations such as obesity, hirsutism, or menstrual irregularities. For example, the Jisheng Formula^［19］states: “The essence of human qi lies in smooth flow; if it flows smoothly, there will be no phlegm or fluid-related disorders.” The Medical Canon^［20］explains: “Emotional disturbances can lead to phlegm.” Prolonged liver dysfunction in regulating and expressing qi, abnormal spleen-stomach ascending and descending functions, improper distribution of body fluids, internal accumulation of phlegm turbidity, and the generation of greasy fats can lead to obesity. The Yellow Emperor’s Inner Canon: Basic Questions^［21］records: “The lungs govern the skin and hair; they nourish the hair.” Prolonged liver depression can generate heat, and wood (liver) overacts on metal (lung), scorching the lung yin and affecting the head and face, leading to clinical signs such as hirsutism.

Common Clinical Manifestations of Polycystic Ovary Syndrome Complicated with Depression

Menstrual Irregularities

Polycystic ovary syndrome (PCOS) is one of the common endocrine disorders in women, characterized by changes in biochemical indicators such as sex steroids and neuroactive steroids^［22］, leading to an increased risk of depression and occurrences of menstrual irregularities or infertility^［23］. The clinical manifestations of menstrual abnormalities can exacerbate negative perceptions among PCOS patients, lower self-esteem, and have a negative impact on emotions^［11］.

Among the related symptoms of PCOS, menstrual cycle irregularities are one of the most common^［24］, such as anovulation, amenorrhea, or oligomenorrhea. A study by Syeda Sidra et al.^［25］surveyed the clinical presentations, health risks, and impact on quality of life among 440 PCOS patients, finding that 71.8% of PCOS patients experienced menstrual irregularities and that depression was the primary cause of reduced quality of life. Similarly, domestic scholars have found a high incidence of emotional disorders among PCOS patients, with mental health issues (depression or anxiety) being the primary factors affecting quality of life^［26］. Reproductive-age PCOS patients are prone to depression or anxiety, with menstrual irregularities being a risk factor for anxiety and depression symptoms, and infertility being a major source of stress leading to anxiety symptoms among reproductive-age PCOS patients^［27］. Overall, both domestic and international studies confirm that menstrual abnormalities in PCOS patients can mutually influence depression, thereby reducing patients’ quality of life.

Infertility or Pregnancy Abnormalities

Polycystic ovary syndrome (PCOS) is considered a complex condition with psychological, reproductive, and metabolic manifestations, affecting women’s health throughout their lifetimes^［28］.

Infertility or pregnancy abnormalities are among the primary clinical presentations of PCOS complicated with depression.

Recent research has found that PCOS is associated with an increased risk of pregnancy and childbirth complications among pregnant women^［29］, and a longer duration of infertility is closely related to higher levels of clinically relevant depressive symptoms^［5］.

Studies indicate that compared to infertile women without PCOS, infertile women with PCOS often experience higher levels of psychological stress^［30］and have difficulty describing their feelings^［31］.

These negative emotions may play a role in the progression of PCOS. Research by Li Sijiao et al. similarly shows that infertile PCOS patients have a higher incidence of depression and are more sensitive in interpersonal relationships compared to non-PCOS infertile patients.

Furthermore, PCOS patients with secondary infertility are more likely to experience anxiety or somatization disorders^［32］. The prevalence of depression among women with PCOS causing infertility is significantly higher^［33］, indicating that multiple complex etiological factors intertwine and may even be mutually reinforcing, exacerbating abnormalities in pregnancy function among PCOS patients.

Therefore, it is evident that the negative emotions of PCOS complicated with depression patients mutually influence the disease, affecting or exacerbating clinical characteristics, hormone levels, and metabolic disorders, leading to infertility and adverse effects on pregnancy outcomes^［34］.

Possible Related Mechanisms of PolycysticOvary Syndrome Complicated with Depression

Neuroendocrine Mechanisms

Patients with polycystic ovary syndrome (PCOS) complicated with depression often experience endocrine and metabolic disturbances or chronic inflammation, leading to long-term chronic stressors (such as elevated androgens^［35］, menstrual irregularities^［36］, or changes in body composition^［37］serving as chronic stressors), keeping them in a prolonged state of emotional stress^［38］, resulting in symptoms of depression and other adverse emotions.

At the neuroendocrine level, PCOS complicated with depression may be associated with abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis^［39］, neurotransmitter deficiencies or abnormalities^［40］, or vitamin D deficiency^［41,42］.

The hypothalamus plays a dual role in regulating reproductive function and emotional centers^［43］. Studies suggest that the occurrence of PCOS complicated with depression may be related to abnormalities in the HPA axis^［39］, indicating that PCOS may disrupt the HPA axis in some way leading to the onset of depression^［44］.

On one hand, emotional stress can act on the hypothalamus, stimulating gonadotropin-releasing hormone secretion, thereby activating the HPA axis, leading to increased secretion of adrenocorticotropic hormone and cortisol^［45］, affecting glucose and lipid metabolism processes, and may also induce insulin resistance or hyperinsulinemia^［46］, forming a vicious cycle of intertwined factors.

On the other hand, negative emotions such as depression or anxiety in PCOS patients can affect hypothalamic endocrine function, leading to increased secretion of ovarian androgens^［35,47］, inhibiting follicular development, thereby affecting the occurrence and development of PCOS.

Changes in neurotransmitters may be one of the causes of gonadotropin-releasing hormone secretion disorders, leading to PCOS complicated with depression. There is substantial evidence that alterations occur in catecholamine metabolism and brain serotonin or opioid activity among PCOS patients^［48］.

Additionally, fluctuations in neurotransmitter and neuropeptide levels among PCOS patients may lead to mood swings. Research by Nirja Chaudhari et al. demonstrates that increased gonadotropin-releasing hormone and luteinizing hormone levels among PCOS patients may be due to cumulative effects of changes in gonadotropin-releasing hormone and inhibitory neurotransmitters in the hypothalamic-pituitary system, which may also be a contributing factor to depressive and anxiety-like mood disorders in women with PCOS^［49］.

Therefore, the abnormal levels of gonadotropin-releasing hormone and luteinizing hormone in PCOS complicated with depression, leading to enhanced production of ovarian androgens and changes in cortisol metabolism resulting in increased adrenal androgen production, and mood swings affecting the release of these neurotransmitters, may help explain the clinical diversity observed in patients with PCOS complicated with depression.

Gut Microbiota Mechanisms

The dysregulation of gut microbiota plays a crucial role in the development of polycystic ovary syndrome (PCOS) complicated with depression. The gut microbiota, also known as the host’s “second genome,” is closely associated with chronic metabolic diseases. In recent years, the connection between PCOS and gut microbiota has garnered increasing attention^［50］.

The dysbiosis of gut microbiota is related to hyperandrogenism, insulin resistance, chronic inflammation, and metabolic disorders associated with PCOS^［51,52］, making it a potential contributing factor to PCOS complicated with depression.

Depression, as an inflammatory disorder, is characterized by elevated levels of inflammatory markers. On the other hand, PCOS is also considered a pro-inflammatory state, characterized by increased levels of pro-inflammatory markers^［53］.

Meanwhile, the chronic low-grade inflammation seen in PCOS may interact with certain neuroregulators, leading to the onset of depression^［54］. The imbalance in gut microbiota in PCOS patients may be characterized by a decrease in bacteria producing short-chain fatty acids and metabolizing bile acids, indicating a shift in gut microbiota balance that promotes the proliferation of pro-inflammatory bacteria, thus exacerbating inflammation levels in PCOS patients^［55］.

There are alterations in the α-diversity of gut microbiota and the relative abundance of Proteobacteria in women with PCOS. Numerous studies indicate that Proteobacteria could be potential biomarkers of gut microbiota in PCOS complicated with depression^［56］and may even have diagnostic value^［57］.

On the other hand, many dietary components can impact the onset and progression of diseases by targeting gut microbiota^［58］. PCOS patients often have vitamin D deficiency^［59］, and it has been reported that inadequate vitamin D intake can lead to an increase in Proteobacteria^［60］.

This has been indirectly supported by basic experiments, where animal models with imbalanced gut microbiota exhibited typical PCOS symptoms, including menstrual cycle disturbances, elevated testosterone levels, and ovarian morphological changes^［61］.

Potential Treatment Strategies for Polycystic Ovary Syndrome (PCOS) Complicated with Depression

Lifestyle Management

A healthy lifestyle should be a primary focus of care for women with polycystic ovary syndrome (PCOS)^［62］. Research by Natalia Ligocka et al. indicates that adopting a healthy lifestyle, balanced diet, and regular physical activity can help control PCOS symptoms, thereby improving overall quality of life for patients^［63］. Evidence suggests that lifestyle management is a frontline intervention in the hierarchy of PCOS interventions, with multidimensional lifestyle interventions including diet, exercise, and behavioral strategies being core elements of PCOS management^［64］.

Simultaneously, a commentary in The Lancet specifically points out^［65］that the treatment of PCOS should combine lifestyle changes with medical management.

Lifestyle optimization includes maintaining a healthy balanced diet and regular exercise to prevent excessive weight gain. Medical management strategies involve using metformin to improve insulin resistance and abnormal metabolic features, along with combined oral contraceptives to regulate menstrual cycles and manage hyperandrogenism.

Additionally, the“2023 International Evidence-Based Guidelines for the Assessment and Management of Polycystic Ovary Syndrome” emphasizes the need for broader awareness and education about PCOS (such as metabolic risk factors, high prevalence of mental health issues, and adverse outcomes during pregnancy), along with continuous adjustment of lifestyle and emotional health to cope with changes in body weight and other physical characteristics^［66］.

Therefore, recommending a healthy lifestyle to women with PCOS can optimize overall health, quality of life, body composition, and weight control. It may also promote improvement in emotional and mental well-being, thereby enhancing their quality of life as clinical features of PCOS lessen or improve.

Emotional Management and Regulation

Over the past decade, the risk of psychological health issues in PCOS patients has increased, particularly depression and anxiety, extending to other aspects of mental health such as body image concerns and eating disorders^［67］.

Therefore, the treatment of PCOS must include assessment and treatment of psychological health symptoms.

Cognitive Behavioral Therapy (CBT) is a frontline psychological treatment method for clinical depression. CBT has significant advantages in alleviating depression and anxiety in PCOS patients, improving hirsutism, or increasing pregnancy rates^［68］.

Most psychological interventions using CBT can effectively reduce depression scores in PCOS patients^［69］.

Sheida Majidzadeh et al.’s study, using 8 sessions of 60-90 minutes each of cognitive behavioral training (including skill practice and cognitive challenges), found significant reductions in depression and anxiety symptoms in PCOS patients, along with improved quality of life^［70］. Therefore, healthcare providers are advised to use this approach to improve the psychological health and quality of life of PCOS patients.

Aerobic exercise can also effectively alleviate the distress associated with depressive symptoms of polycystic ovary syndrome (PCOS). Aerobic exercise has been shown to improve clinical symptoms in patients with PCOS and also has some efficacy in reducing the incidence of depression and anxiety^［71,72］. A study by Isis K. Santos et al.^［73］employed a 12-week high-intensity interval training (HIIT) program with three sessions per week and 40-60 minutes per session. The PCOS patients in the HIIT group showed significant improvements in quality of life and depressive symptoms. Another large-sample study found that 16 weeks of exercise training, whether continuous aerobic exercise, interval aerobic exercise, or progressive resistance training, could improve depression scores in patients with PCOS. Moreover, among these three exercise types, interval aerobic exercise was found to be the most effective in improving quality of life and depressive symptoms in patients with PCOS^［74］. Therefore, it is not difficult to see the potential of aerobic exercise in improving the mental health and quality of life of patients with PCOS. Aerobic exercise may be a feasible strategy to reduce depressive symptoms in patients with PCOS.

Acupuncture has significant advantages and remarkable efficacy in the treatment of PCOS comorbid with depression. Acupuncture may regulate hormone secretion, affect ovulation or menstrual cycles, thereby improving ovulation rates and pregnancy rates, reducing miscarriage rates, and reducing the production of negative stress; acupuncture can also effectively alleviate insulin resistance, regulate lipid metabolism, adjust body shape, and promote the physical and mental health development of patients with PCOS comorbid with depression; and acupuncture has few side effects and is relatively safe^［75-77］. A study by Zhang Haolin et al.^［78］found that electroacupuncture can effectively relieve patients’ depressive mood, and its mechanism may be related to the regulation of serum endorphin and androgen levels. Another study found that electroacupuncture treatment can reduce depression scores in patients with PCOS, has a mind-body coordination effect, and the therapeutic effect of electroacupuncture is superior to the drug Diane-35^［79］. Therefore, acupuncture has a positive effect on the treatment of the main symptoms of PCOS (whether reproductive, metabolic or mental health). The action of acupuncture in the treatment of PCOS is related to the regulation of sex hormones, the improvement of ovulation and pregnancy rates, the regulation of insulin resistance and lipid metabolism, and the rebalancing of negative emotions.

It’s worth noting that some polycystic ovary syndrome (PCOS) patients in low-income countries may delay seeking professional help and treatment, leading to a delay in managing their condition^［80］. The importance of support and acceptance from family and friends cannot be overlooked when PCOS patients experience emotional disturbances^［63］. Therefore, timely diagnosis, cultural education related to lifestyle and weight management, and improving psychological and emotional support are crucial areas to address in clinical practice and future research for PCOS patients with comorbid depression.

The comorbidity of polycystic ovary syndrome (PCOS) and depression in Traditional Chinese Medicine (TCM) treatment and differentiation may be closely related to depressive patterns. Characteristic clinical manifestations such as menstrual irregularities or pregnancy complications may be closely associated with neuroendocrine abnormalities or disruption of intestinal microbiota balance. Alternatively, multiple complex factors may intertwine. In future research, it is necessary to delve deeper into the mechanisms between these factors. In treatment protocols, lifestyle management and emotional regulation should be the preferred treatment options for PCOS patients with comorbid depression, aiming to improve their overall health status and enhance their quality of life.

Author information:

Jihong Ding，Ph.D. candidate of FuJian University of Traditional Chinese Medicine.

參考文獻

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