Chlorogenic Acid on Polycystic Ovarian Syndrome: Comparison
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Chlorogenic acid (CGA) is a powerful antioxidant polyphenol molecule found in many diets and liquid beverages, playing a preventive and therapeutic role in various diseases caused by oxidative stress and inflammation. Recent research has found that CGA can not only improve clinical symptoms in polycystic ovary syndrome (PCOS) patients but also improve follicular development, hormone status, and oxidative stress in PCOS rats, indicating the therapeutic effect of CGA on PCOS.

  • chlorogenic acid
  • hypoxia inducible factor-1alpha
  • follicular development

1. Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disease, with female infertility, anovulation, and hyperandrogenism, which even affects the quality of life after menopause [1,2,3,4,5][1][2][3][4][5]. The main clinical symptoms include hormonal imbalances, irregular menstrual cycles, dysfunction of follicle maturation, and miscarriage [6,7,8][6][7][8]. It is worth noting that the systemic low-grade inflammation in PCOS patients is closely related to oxidative stress [9,10,11][9][10][11]. While oxidative stress is typically present in PCOS patients, leading to an increase in the number of lipid peroxidation products and other highly toxic products such as malondialdehyde [8], it also plays an important role in infertility [12,13,14][12][13][14]. Therefore, alternative treatment strategies to reduce oxidative stress can improve the reserve and developmental ability of ovarian follicles in PCOS patients [15,16,17,18][15][16][17][18].
At present, in-depth research has been conducted on PCOS pathogenesis and treatment strategies. HIF-1alpha is a regulatory alpha-subunit of heterodimeric transcription factor HIF-1, mainly expressed in granulosa cells, regulated by the hypothalamus-pituitary-gonad axis, and involved in follicular development, ovarian ovulation, and hormone synthesis [20,21,24,25,26][19][20][21][22][23]. HIF-1alpha is indispensable in the dimethyldiguanide (DMBG) treatment of PCOS as a novel therapeutic target [20,27,28,29][19][24][25][26].
In recent years, the importance of food-based alternative drugs and free drugs in the treatment of PCOS has received widespread attention. Phytochemical substances in medicinal plants are the source of effective treatment for diseases such as PCOS [30,31,32,33,34,35,36,37][27][28][29][30][31][32][33][34]. They can improve insulin sensitivity, promote ovulation, and reduce hyperandrogenism without side effects [30,32,34,38][27][29][31][35]. Among them, chlorogenic acid (CGA) is a widely distributed natural compound with many pharmacological activities, mainly extracted from natural plants such as honeysuckle, Eucommia ulmoides, coffee beans, and sunflowers [33,39,40,41][30][36][37][38]. It has been widely used in industries such as medicine, health, and food chemicals. CGA is a polyphenol molecule with a strong antioxidant effect that is widely present in many diets and liquid drinks. It can eliminate free radicals in the body and plays a preventive and therapeutic role in many diseases, such as diabetes, hypertension (HPT), and atherosclerosis (AS) [39,40,42,43,44][36][37][39][40][41]. CGA not only has antioxidant activity but also has a series of biological functions such as liver anti-inflammatory protection and neuroprotection [39,40,41,42,43,44][36][37][38][39][40][41]. Recent studies have found that CGA also has therapeutic effects on PCOS [30,34,35,36,37][27][31][32][33][34]. However, the molecular regulatory mechanism of CGA in the treatment of PCOS still needs to be systematically elucidated.

2. Overviews of Chlorogenic Acid (CGA)

CGA is widely distributed in the plant kingdom as coffee tannic acid, ranging from dicotyledonous plants to ferns, and is mainly present in Lonicera and Artemisia plants [44][41]. A high content of CGA exists in plants such as Eucommia ulmoides, honeysuckle, coffee, and chrysanthemum [45][42]. In addition, vegetables and fruits also contain CGA, such as potatoes, carrots, spinach, and apples [44,45,46][41][42][43]. The chemical name of CGA is 3-O-caffeoylquinic acid, C16H18O9, with a molecular weight of 354.30 [21,47][20][44]. Its semihydrate is a white or yellow needle shaped crystal that becomes an anhydrous compound at 110 °C, with a melting point of 206–208 °C [48][45]. At 25 °C, the solubility in water is relatively low, about 4% [48][45]. In hot water, solubility increases and changes with temperature. CGA is a polar organic acid that is unstable and prone to isomerization during the extraction process [44,47,48][41][44][45]. The catechol hydroxyl contained in the molecular structure of chlorogenic acid is the most suitable reaction substrate for phenolase catalysis (Figure 1). It is easily oxidized under heat and light, which is also the key reason for the browning of many fruits containing CGA, such as peaches and apples [21,45][20][42]. Under alkaline conditions, CGA can undergo hydrolysis to form green quinones. CGA present in plants is often a mixture rather than a single component, including monocaffeioyl quinic acid, dicaffeioyl quinic acid, tricaffeioyl quinic acid, and methyl chlorogenic acid [44,47][41][44].
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Figure 1.
The molecular structure of chlorogenic acid (CGA).
CGA is a kind of phenylpropanoids, which are effective phenolic antioxidants [1,44][1][41]. As we know, CGA can effectively eliminate free radicals, maintain normal functions, and also prevent disease occurrence [43,48][40][45]. For example, CGA can up-regulate the expressions of PPARα and SREBP-1, which are involved in liver lipid metabolism and restore diabetes and oleic acid-induced NAFLD [39,46][36][43]. Similarly, CGA can prevent protein glycosylation by regulating glycogen production and gluconeogenesis, thus participating in glucose metabolism [44][41]. Recently, some studies on CGA have found that CGA not only improves follicular development and oxidative stress in PCOS rats but also improves the inflammatory response in PCOS patients, indicating that CGA also has therapeutic effects on PCOS.

3. Polycystic Ovary Syndrome (PCOS)

In 1935, Stein and Leventhal first described female PCOS [49][46], characterized by ovulatory dysfunction, hyperandrogenism, and polycystic ovary, accompanied by neuroendocrine features such as increased serum luteinizing hormone (LH) concentrations (Figure 2) [5,50,51,52,53,54][5][47][48][49][50][51]. Subsequently, a series of studies were conducted on the etiology, diagnosis, and treatment of PCOS [8,55,56,57][8][52][53][54].
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Figure 2.
An increase in testosterone and LH leads to insulin resistance and anovulation in PCOS.
The etiology of PCOS is very complex, mainly caused by genetic and environmental factors [6,8,58][6][8][55]. Unhealthy lifestyles, dietary habits, and infectious agents all increase the risk of its onset [58][55]. Due to insulin resistance and its elevated levels, ovarian function is disrupted, and androgen levels are elevated, leading to anovulation [8]. GnRH, FSH, LH, and prolactin levels in PCOS patients can also be disrupted [50,51,59][47][48][56]. The severity of PCOS increases with increasing levels of insulin and androgen. On the one hand, hyperinsulinemia can affect the synthesis and secretion of androgen levels in ovarian theca cells, reducing the biosynthesis of liver SHBG and IGFBP-1 [5,8,60][5][8][57]. On the other hand, an increase in androgen levels can stimulate visceral adipose tissue (VAT) and produce free fatty acids (FFA), leading to insulin resistance [5,8,54][5][8][51]. In addition, genetic predisposition, autoimmune disorders, and chronic inflammation are also important pathogenic factors for PCOS [61,62,63,64][58][59][60][61]. The diagnosis of PCOS is currently made according to the phenotypes of PCOS patients as described in the Rotterdam criteria (Table 1), which should be clearly indicated when diagnosing PCOS, including irregular menstrual cycles, elevated androgen levels, and exited cysts. The medical history and examination of suspected PCOS patients will be evaluated, while their hormone concentrations will also be tested to rule out similar diseases [65,66,67][62][63][64]. For example, in anovulatory patients, thyroid hormone is measured to exclude thyroid dysfunction, and prolactin is detected to exclude hyperprolactinemia [7,68][7][65]. Additionally, 17-hydroxyprogesterone is measured during the preovulation phase to confirm adrenal 21-hydroxylase deficiency or ovarian androgen excess [12,69][12][66].
Table 1.
Diagnostic criteria, clinical phenotype, and treatment focus of PCOS.
Items Specific Descriptions
Diagnostic Criteria

(Rotterdam 2003)		 Oligo or anovulation
Hyperandrogenism
Polycystic ovaries
Diagnostic Criteria

(AE-PCOS Society 2006)		 Biochemical and clinical evidence of hyperandrogenism
Dysfunctional ovaries
Polycystic ovary morphology
Clinical Phenotype Hyperandrogenism + Oligo-Anovulation + Polycystic ovaries
Hyperandrogenism + Oligo-Anovulation
Hyperandrogenism + Polycystic ovaries
Oligo-Anovulation + Polycystic ovaries
Treatment Focus Suppressing and counteracting androgen secretion and action
Protecting the endometrium and improving menstrual dysfunction
Improving metabolic status
Improving ovulatory fertility
The treatment of PCOS depends on the phenotype, focus, and goals of these patients. The purpose of PCOS treatment is to normalize the endometrium, counteract the effects of androgen, and reduce insulin resistance [12,17][12][17]. For example, androgen blockade is only related to hirsutism, while androgen inhibition is typically associated with acne [6]. In addition, for patients who do not pursue conception and are not contraindicated by hormone contraception, combined oral contraceptive therapy should be considered as part of the initial treatment [46][43]. Transdermal combination contraceptives or contraceptives containing only progesterone can be considered for patients intolerant to contraceptives, while slimming and fitness should be their first-line treatment for obese patients [46,65,66,67][43][62][63][64]. For PCOS patients with metabolic disorders, insulin sensitizers should also be considered, especially DMBG [28,29,62,70][25][26][59][67]. For patients who wish to have immediate fertility, oral ovulation agents should be considered [71][68]. PCOS treatment usually means lifelong follow-up and multiple treatments, including various treatment methods, depending on the patient’s performance, complications, wishes, and goals [15,16,17,26,72,73][15][16][17][23][69][70].

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