Natural products for treatment of premature ovarian failure: a narrative review

Abstract

Premature ovarian failure (POF) is a female reproductive system disease caused by many factors and systems, which has seriously affected the quality of life of women of childbearing age. Clinically, the disease is difficult to treat while its incidence rate shows an increasing trend. In recent years, natural products used as multi-pathway, multi-target and efficient drugs, have become the focus of many research and clinical studies in China and abroad, and the effect of phytochemicals derived from edible plants and Chinese medicine herbs on POF were investigated in several papers. Using "premature ovarian failure" or "ovary" and related natural products as keywords, we retrieved and reviewed research articles from China National Knowledge Infrastructure Database, Wanfang, PubMed, Web of Science and other literature databases. Up to October, 2021, natural compounds with prophylactic or interference inhibition effects on POF mainly included flavonoids, polysaccharides, saponins, and polyphenols. Their effect on POF and ovarian function was closely related to their antioxidant, antiapoptotic, antiaging, immunoregulatory and estrogen-like activities.

1. INTRODUCTION

Premature ovarian failure (POF) refers to the phenomenon of ovarian function decline that occurs in a woman before 40 years old and is characterized by high gonadotropin and low estrogen.¹ Clinically, the main manifestations are menstrual cycle disorder, amenorrhea, reduced fertility and even infertility. It is also accompanied by hot flashes, night sweats, insomnia, psychological distress, and sexual dysfunction, which are similar to menopausal symptoms and can increase the incidence of osteoporosis, autoimmune diseases, cardiovascular and neurocognitive disorders in the long run.² The incidence of POF was about 1% in patients over 40 years of age, 0.25% in patients over 35 years of age, and 0.1% in patients over 30 years of age.¹ With the increase of social pressure, the incidence of POF is on the rise, and the age of onset is also younger. At present, the general treatment for premature ovarian failure in western medicine is hormone replacement therapy, which simulates the release of physiological hormones. Although hormone replacement therapy can relieve some clinical symptoms, it has no effect on the recovery of ovarian function and fertility. It may also increase the risk of ovarian cancer, breast cancer, endometrial cancer, thrombotic disease, meningioma and other diseases.² Many natural products derived from plants, especially Chinese medicine and edible plant (such as vegetables and fruits), are now the focus of basic research and disease treatment research. In fact, they have been globally used in the study of a variety of diseases due to their advantages of being multi-pathway, multi-target, highly efficient and having less toxic and side effects. Following this trend, studies on the treatment and prevention of POF have also investigated the effect of Chinese medicine herbs and edible plant-derived natural compounds. Nonetheless, the number of these studies is limited, and they mainly focus on molecules such as flavonoids, polysaccharides, saponins, polyphenols and coumarin, etc. In this paper, the prophylactic and therapeutic effects as well as mechanism of action of these natural products were reviewed, so as to provide reference for subsequent experiments and other studies on POF natural prevention and treatment.

2. FLAVONOIDS

2.1. Total flavonoids from semen cuscutae (TFSC)

TFSC are the main active chemical components of Tusizi (Semen Cuscutae), which can be used in multiple systems of the human body, enhance the body's immunity and supplement nutrition.³ It can reduce the injury of female reproductive system caused by endocrine disorder, oxidation, drugs and stress by anti-oxidation, regulating hormone level and feedback on hypothalamic-pituitary-gonadal axis, and has a reproductive protection effect.⁴ Wang et al ⁵ revealed that TFSC had obvious recovery effect on ovarian function of rats with POF, such as significantly recovering estrous cycle, improving estrogen level, increasing ovarian weight of POF rats, and promoting follicular development at all levels of ovary. They had estrogen-like effect and significant curative effect on POF in rats. Zhang et al ⁶ showed that TFSC could correct the abnormal levels of reproduction-related proteins [anti-mullerian hormone (AMH), tyrosine kinase ligand, steroid synthesis acute regulatory protein, and cytochrome P450family 11subfamily A member 1] and imbalanced expression of apoptosis factor Bcl-2 associated X, apoptosis regulator (Bax)/B cell lymphoma-2 (Bcl-2) caused by bisphenol A in pregnant rats, so as to inhibit apoptosis and alleviate the reproductive system damage caused by exposure to bisphenol A in pregnant rats.

Quercetin (Que) is the main active component of flavonoids in Tusizi (Semen Cuscutae) and belongs to flavanol compounds. It has many pharmacological activities encompassing antioxidation, anti-inflammation, anti-apoptosis, anti-infection, neuroprotection, cardio-vascular protection and reproductive protection.^{7,⇓,⇓,⇓-11} Huang et al ¹² demonstrated that both flavonoids from Tusizi (Semen Cuscutae) and quercetin could improve the ovarian function of POF rat model induced by Tripterygium Glycosides to a certain extent, indicating that quercetin might be one of the main active components in flavonoids from Tusizi (Semen Cuscutae) for the treatment of POF. Li’s research¹³ showed that high dose of quercetin (25 mg/kg) could regulate the estrous cycle of mice, regulate the levels of various hormones in serum to make them tend to be normal, promote the development and maturation of mouse follicles, and improve the symptoms of mice with autoimmune POF established by ZP3^330~342, and it had a significant therapeutic effect on POF. Li et al ¹⁴ showed that intraperitoneal injection of Que (20 and 40 mg/kg) could prevent the loss of mouse primordial follicles caused by cyclophosphamide by inhibiting phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/forkhead box O3 (FOXO3a) signaling pathway. These studies suggest that flavonoids from Tusizi (Semen Cuscutae) and its main components are potential effective natural products for treating premature ovarian failure.

2.2. Soybean isoflavone (SI)

SI is a natural phytoestrogen extracted from soybean and has an estrogen-like effect. Its structure is similar to that of endogenous estradiol, and it can bind to and bidirectionally regulate estrogen receptor, thus exerting the dual effects of estrogen and anti-estrogen, respectively.¹⁵ Besides, it also has significant effects on anti-oxidation, anti-cancer, prevention of osteoporosis and cardiovascular disease.¹⁶ Studies have shown that SI can effectively inhibit mouse anti-zona pellucida antibodies, improve the immune function of mice with immune premature ovarian failure, and effectively prevent the occurrence of autoimmune oophoritis.¹⁷ Appropriate dose of SI exposure (≥ 25 mg/kg) can affect the ovarian follicle development of adult rats by affecting the expression of ovarian cytokines,¹⁸ while continuous exposure of high concentration of SI (200 mg/kg) can interfere with the ovarian development of underage mice.¹⁹ Guan et al ²⁰ showed that SI had estrogen receptor activity and good antioxidant effect on Bashang Long-tailed Chickens, which could maintain a relative balance between antioxidant factors and oxygen-promoting factors. An appropriate dose of (15 mg/kg) SI could exert the effects of estrogen and stimulate the reproductive system of Bashang long-tailed chicken. However, a higher dose (25 mg/kg) of SI could decrease reproductive hormone levels and exert estrogen antagonism. These studies confirmed the dual effects of SI on estrogen and indicated that the protection effect of SI on ovary was dose dependent.

Genistein (Gen), also known as genistein, 4',5,7-genistein, belongs to isoflavone compounds and exists in a variety of beans, especially soybean, which is also one of the most consumed phytoestrogens by human beings.²¹ It also has estrogen-like activity and can bind to estrogen receptor (ER) or peroxisome proliferator-activated receptors (PPARs) to exert reproductive protection ¹³, and also has a variety of pharmacological activities such as antioxidant, anti-inflammatory, anticancer, neuroprotection and regulation of liver lipid metabolism.^22,⇓-24 Li’s research ¹³ showed that high dose (45 mg/kg) of Gen could improve the clinical symptoms of mouse model with autoimmune premature ovarian failure established by ZP3^330~342, regulate the estrous cycle of mice, restore the serum levels of various hormones to normal, and promote the development and maturation of mouse follicles. Wen et al ^25-28 found that genistein can up-regulate the expression of ERα in rat ovarian granulosa cells, promote the expression of downstream liver receptor homologue -1 (LRH-1) and cytochrome P450 family 19 (CYP19), and up-regulate the expression of cyclic adenylate response element-binding protein (CREB) in rat ovarian granulosa cells. The regulation of Gen on the expression of follicle stimulating hormone receptor (FSHR) may be mediated by ERα, but not on CYP19, LRH-1 and CREB.

2.3. Icariin

Icariin, one of the main active components of flavonoids in Yinyanghuo (Herba Epimedii Brevicornus), has the activities of immunoregulation, anti-inflammation, anti-aging, anti-tumor, and so on. It can improve the neurological, immune, endocrine, cardiovascular, bone and other related diseases to a certain extent. At the same time, icariin, as one of the effective active components of the kidney-reinforcing and Yang-assisting Traditional Chinese Medicine Yinyanghuo (Herba Epimedii Brevicornus), can also promote the development and protection of the female reproductive system.²⁹ Studies have shown that icariin may promote the development of ovarian follicles by changing the expression of steroid synthesis related genes (Hsd17b1 and Cyp19a1), growth factor related genes (Ptgs-2, Igf-2 and Egf) and ERα protein, thus affecting the reproductive system of mice.³⁰ Furthermore, one study has shown that Icariin can improve the activity and expression of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in rat follicular cells, and increase the relative expression of apoptosis-related genes Bax/Bcl-2, thus playing the role of anti-oxidation and anti-apoptosis, thus promoting the development and maturity of mouse follicles.³¹ Dong's ³² research concluded that icariin did have antioxidant and antiapoptotic effects. The possible mechanism may have been that the phosphorylation of PI3K/Akt/mechanistic target of rapamycin (mTOR) signaling pathway was activated to inhibit oxidative stress, thereby reducing ovarian cell apoptosis, and finally playing a role in improving the chemotherapy-induced POF in rats.

2.4. Pomiferin

Pomiferin is a kind of isoflavone compound extracted from Maclura pomifera (Raf.) Schneid, which has a strong antioxidant effect.^33,34 It also has phytoestrogen effects, but unlike estrogen in general, pomiferin works by binding to the estrogen receptor ERβ.³⁵ Song's study ³⁶ showed that pomiferin could interfere with autoimmune POF by regulating the immune function of mice with autoimmune POF, restoring reproductive hormone levels, promoting ovarian follicle development, and inhibiting Fas-mediated apoptosis of follicle cells.

2.5. Ginkgo flavonoid

Ginkgo flavonoid, also known as Ginkgo biloba P.E, is a flavonoid substance extracted from Yinxingye (Folium Ginkgo) and one of the most effective components of it that can protect the nervous system and promote blood circulation as well antioxidation, antiaging, antitumor and antifibrosis. Ginkgo flavonoid has been used for the treatment of many diseases in clinic.^37,38 Studies have shown that ginkgo flavonoid can protect human granulosa cell injury caused by cisplatin by up-regulating the expression of cytochrome C (Cyt-c) and apoptotic enzyme activating factor-1, and can also increase the SOD activity and reduce the malondialdehyde (MDA) content to protect the cisplatin-induced ovarian damage in rats. This indicates that ginkgo flavonoid has a protective effect on the cisplatin-induced ovarian damage, and the mechanism may be achieved through the antiapoptotic and antioxidative signaling pathways.^39,40

2.6. Puerariae isoflavones

Puerariae isoflavones are one of the effective medicinal components of Gegen (Radix Puerariae Lobatae) and have the effects of treating cardiovascular and cerebrovascular diseases, reducing inflammation, neutralizing free radicals, balancing estrogen level, improving immunity, regulating glucolipid metabolism and protecting the liver.⁴¹ Clinically, puerariae isoflavones can improve the symptoms of menopause in patients with POF. Sequential treatment with medroxyprogesterone acetate for POF has obvious clinical effect, and is safer than the traditional artificial synthetic hormone treatment.⁴² The mechanism may be that the autoimmune injury in POF patients is eliminated by regulating the function of T lymphocytes, inhibiting the proliferation of B lymphocytes and the autoantibodies related to POF, so as to achieve the effects of protecting the ovary and recovering ovarian function.⁴³

2.7. Citrus flavonoids

Citrus flavonoids are dietary flavonoids compounds derived from Chenpi (Pericarpium Citri Reticulatae), which have the effects of protecting nerves, inhibiting inflammation, halting oxidation, regulating intestinal flora and providing intestinal local immunity.^44,⇓-46 A study ⁴⁷ has shown that citrus flavonoids can protect the ovarian damage caused by cytoxan (CTX) in rats, and its mechanism may be through increasing the expression levels of bone morphogenetic protein 15 and growth differentiation factor 9 in the ovary, balancing the reproductive hormone levels, and maintaining the growth and maturation of follicles in order to repair damaged ovary.

2.8. Hubei Begonia flavone

Hubei Begonia flavone, a flavonoid compound extracted from leaves of Hubei Haitang [Malus hupehensis (Pamp.) Rehder]. Not only does this flavonoid have strong antioxidant function and estrogen activity, but it can also reduce blood sugar and blood lipid levels. Phloretin, its main component, can bind to estrogen receptor to exert estrogen effect.⁴⁸ A study showed that total flavonoids of Hubei Haitang [Malus hupehensis (Pamp.) Rehder] had a certain protective effect on the ovary of rats with POF, and the possible mechanism was that by increasing serum SOD activity of POF rats and decreasing MDA content, they enhanced the antioxidant capacity of rats in vivo, promoted the secretion of estrogen and progesterone, and enhanced the expression of estrogen receptor ERα in ovarian granulosa cells and stromal cells, thus playing a role in protecting the ovary.⁴⁹

2.9. Chrysin

Chrysin is a natural flavonoid product found in mushrooms and honey, which has a wide range of biological activities, such as antibacterial, antioxidant, anti-inflammatory, antitumor, hypoglycemic.^50,⇓-52 Chrysin can improve radiation-induced POF. Its mechanism of action to inhibit γ-radiation-induced POF may be through the down-regulation of transforming growth factor β (TGF-β)/mitogen-activated protein kinase (MAPK) signaling pathway, inhibition of the expression of apoptotic protein Cyt-c and Caspase-3, and the decrease of the expression levels of inflammatory markers nuclear factor kappa-B (NF-κB), tumor necrosis factor α (TNF-α), inducible nitric oxide synthase and cyclooxygenase 2 (COX-2) in ovarian injury.⁵³

3. POLYSACCHARIDE

3.1. Lycium barbarum polysaccharide (LBP)

LBP, the extract of Chinese medicinal Gouqizi (Fructus Lycii), is the main active ingredient of Gouqizi (Fructus Lycii) and has a wide range of pharmacological effects, such as antioxidation, antitumor, anti-inflammation, analgesia, immunity improvement, intestinal flora regulation, lipid and glucose reduction, liver protection, reproductive protection, neural protection, etc.^54,55 Research by Huang et al ⁵⁶ showed that LBP could regulate endocrine, reduce the serum anti-zona pellucida antibody level, and protect the ovarian function of mice with autoimmune POF to a certain extent, which might be related to its immune regulation. Sun et al ⁵⁷ used cisplatin-induced rat POF model to study the protective effect of LBP on ovary. The results showed that LBP could reduce cisplatin-induced ovarian function damage in rats to a certain extent. Liu et al ⁵⁸ believed that LBP could repair the ovarian damage caused by repeated OVX in mice, and the most likely mechanism was through the removal of oxidation products 8-hydroxydeoxyguanosine and lipid peroxide and increasing the expression of AMH protein.

3.2. Dendrobium officinale polysaccharide (DOP)

DOP is one of the effective medicinal components of Shihu (Herba Dendrobii Nobilis), with a variety of pharmacological activities such as antiinflammation, anti-apoptosis, antioxidation, anti-fatigue, immune-oregulation, blood glucose reduction, and liver protection. It can treat a variety of diseases such as diabetes, gastroenteritis, and antitumor.^{59,⇓,⇓,⇓,⇓-64} Wu et al ⁶⁵ demonstrated that DOP could treat natural aging-induced POF in mice, and the mechanism of action may involve the inhibition of NF-κB and p53/Bcl-2-mediated signaling pathways, as well as the improvement of mitochondrial membrane potential and the increase in the number of mitochondria to protect ovarian mitochondria.

3.3. Epimedium polysaccharide (EPS)

EPS, one of the effective active components of Yinyanghuo (Herba Epimedii Brevicornus), not only plays an important antioxidant and immunoregulatory role, but it also possesses anti-inflammatory, antiapoptotic, reproduction protective and other biological activities.^{66,⇓,⇓-69} It is preliminarily found that a certain dose of EPS (4-6 mg/0.1 mL) has a positive effect on the development of ovary and uterus in female mice, but too low dose (2 mg/0.1 mL) may not have a positive effect.^70,71 Later, it was found that 6 mg/0.1 mL EPS for 7 or 14 d could increase the expression of ER protein, decrease the expression of progesterone receptor A (PRA), and increase the expression of growth-related genes Ptgs-2 and Igf-2, thus affecting follicular development.³⁰ Xu³¹ showed that 6 mg/0.1 mL EPS could reduce the early apoptosis of follicular cells, and 8 mg/0.1 mL EPS could reduce the relative expression of Bcl-2/Bax. Zhao et al ⁷² showed that EPS (6 mg/0.1 mL) could effectively inhibit the apoptosis of mouse ovarian follicle cells by regulating the expression of Bcl-2/Bax gene. This shows that EPS can protect ovary through anti-apoptosis pathway.

3.4. Angelica polysaccharide (AP)

AP, one of the indispensable active components in Danggui (Radix Angelicae Sinensis), has many biological activities, such as anti-oxidation, anti-tumor, immune stimulation, hematopoietic, liver protection, and so on. It is closely related to the treatment of chronic anemia, leukemia, diabetes and other diseases.⁷³ A study has shown that AP can improve ovarian function of mice with immune POF to a certain extent. By inhibiting oxidative stress levels and restoring endocrine function through the activation of Akt/FOXO3 pathway, AP may inhibit immune POF.⁷⁴

3.5. Squid ink polysaccharide (SIP)

SIP is a main bioactive component isolated from traditional Chinese medicine squid ink, with antioxidant, anti-tumor, anti-apoptosis, anti-chemotherapy damage, immunoregulation and other biological activities.^75,⇓-77 Studies has shown that CTX can alleviate and protect the immune system and ovary damage of POF mice to a certain extent, and the mechanism may be that by regulating the immune level of the mouse body and stimulating the ovarian nuclear transcription factor (Nrf2)/antioxidant response element (ARE) pathway, it relieves the oxidative damage of ovary caused by CTX in POF mice.⁷⁸

4. SAPONINS

4.1. Ginsenoside

Ginsenoside is one of the main active compounds in Renshen (Radix Ginseng) and belongs to sterol compound, also known as triterpenoid saponin. The compound has a variety of biological activities such as reducing blood lipid, lowering blood glucose, inhibiting inflammation and oxidative stress, inhibiting steatosis, protecting liver and myocardial cells, as well as playing anti-aging and anti-tumor roles. Studies have shown that it may be involved in the treatment of certain diseases, such as cardiovascular disease, alcoholic fatty liver, cancer, diabetes, hyperlipidemia.^{79,⇓,⇓-82} Dai et al ⁸³ showed that long-term administration of ginsenoside Rg₁ could improve the fertility of naturally aging mice, and the mechanism might be related to the obvious antioxidant effect on the ovary and hypothalamus. He et al ⁸⁴ believed that ginsenoside Rg₁ might improve the fertility of D-gal-induced POF mice and reduce the pathological damage of ovary by enhancing the anti-inflammation, anti-oxidation and reducing the expression of aging signaling pathway proteins. Similarly, He ⁸⁵ found that ginsenoside Rg₁ could reduce the pathological damage of ovary and uterus in POF mouse model by resisting oxidation and inflammation, and improve the D-gal-induced reproductive function of POF mice by up-regulating the expression of granulocyte follicle-stimulating hormone receptor (FSHR) and down-regulating the aging signaling pathways P53-P21-P19/stk, P16, and Bax/Bcl-2. Liu et al ^86,87 believed that ginsenoside Rg₁ could also delay POF in the D-gal-induced POF mouse model through PI3K/Akt/mTOR autophagy signaling pathway or the aging regulator Sirtuin1 (SIRT1). Tang’s ⁸⁸ rat experiment proved that ginsenoside Rb₁ had a certain protective effect on ovarian function, and the mechanism was that the estrogen activity of ginsenoside could regulate ovarian function, reverse the disorder of sex hormone levels, reduce the apoptosis of ovarian granulosa cells, and delay ovarian aging. These studies have shown that ginsenoside has a protective effect on ovarian function and can delay ovarian aging through its antioxidant, anti-aging, anti-inflammatory and estrogen activities.

4.2. Total momordicoside

Total momordicoside are one of the main components of Kugua (Fructus Momordicae Charantiae) extract, which has good antioxidant and hypoglycemic ability, can also reduce inflammatory reaction and resist apoptosis.^{89,⇓,⇓-92} Yin’s study ⁹³ showed that total momordicoside had a protective effect on ovarian damage induced by CTX in rats, which might be related to increasing the activity of antioxidant enzymes in mice and enhancing the protein of ovarian Nrf2. Total momordicoside also exert certain therapeutic effects on rats with cisplatin-induced ovarian damage, and can significantly improve the oxidative damage of ovarian tissue in rats, which may be related to their ability to activate the PPARγ.⁹⁴ In addition, total momordicoside can significantly reduce the expression of Caspase-3 protein in ovarian granulosa cells and improve the total antioxidant capacity of the ovarian tissue in rats, thereby improving the ovarian function of the ovulation failure model rats.⁹⁵ These studies have shown that total momordicoside have a protective effect on ovarian function, and their mechanism may be related to its antioxidant and anti-apoptotic capabilities.

5. POLYPHENOLS

5.1. Resveratrol (RES)

RES, a non-flavonoid polyphenol compound, is naturally present in bioflavonoids in grapes, red wine, peanuts and several medicinal plants, and is an indirect activator of the silent information factor SIRT1, with a variety of pharmacological activities such as anti-cancer, antioxidation, anti-aging, anti-bacteria, anti-inflammation, immunoregulation, and liver, cardiovascular system, neural and reproductive protection.^96,⇓-98 Yu et al ⁹⁹ explored the protective effects of RES on premature ovarian failure and proliferation of female germline stem cells (FGSCs) at the tissue and cell levels through in vivo and in vitro experiments, and evaluated the therapeutic effect of RES based on ovarian function, antioxidant stress, inflammation, and FGSCs survival rate, and the results showed that RES effectively protected the number of follicles and the survival of FGSCs through various mechanisms such as antioxidant stress, alleviation of inflammatory response, and participation in Hedgehog signaling pathway activity. Zhou et al ¹⁰⁰ showed that RES could improve the developmental potential of oocyte and regulate oocyte aging by activating mitosis. In this process, RES-mediated mitosis needs FOXO3a. Ibrahim et al ¹⁰¹ demonstrated that RES could protect cisplatin-induced ovarian damage and uterine toxicity in female rats from oxidative stress, inflammation and apoptosis. The research conducted by Wu et al ¹⁰² showed that resveratrol could accelerate the repair of oocyte stem cell injury in the RES/CTX-induced accelerated ovarian aging model. In vivo experiments’ results showed that resveratrol at 30 mg/kg could reduce the loss of oocyte stem cells and attenuate the RES/CTX-induced oxidative apoptosis of mouse ovary. In addition, in vitro experiments showed that RES could protect oocytes from H₂O₂-induced cytotoxicity and oxidative stress injury by activating Nrf2. All these studies have indicated that RES is a potential protective agent for POF.

5.2. Curcumin

Curcumin, a natural polyphenol product, is the most important active ingredient of Jianghuang (Rhizoma Curcumae Longae). It has many pharmacological activities, including antioxidation, anti-inflammation, anti-tumor, anti-diabetes, anti-fibrosis, anti-aging, and myocardial and neuroprotective properties.^103,⇓-105 In addition, it also has a certain reproductive effect.¹⁰⁶ One study ¹⁰⁷ found that high mobility group protein B1 regulated the expression of ovulation-related genes (EGFR, VEGF, St AR, TIMP1/2) and IL-6 secretion in dairy cow ovarian granulosa cells through the toll-like receptor 2 (TLR2)/NF-κB signaling pathway, while curcumin could significantly reverse this process, suggesting that curcumin could regulate mammalian reproduction by interfering with the high mobility group protein 1/TLR2 signaling pathway in follicular granulosa cells. Wang et al ¹⁰⁸ showed that curcumin could reduce the content of reactive oxygen species and MDA in serum, ovary and uterine tissues of mice, indicating that curcumin could protect the ovary of mice from oxidative damage by inhibiting oxidative stress. In addition, curcumin can significantly improve the ovarian function of D-gal-induced aging female mice, and significantly reduce the expressions of SOD2, catalase (CAT) and senescence protein P16.¹⁰⁹ Li et al ¹¹⁰ SOD, GSH-PX and CAT in mouse ovarian tissue, indicating that curcumin could protect the ovarian oxidative damage caused by bisphenol A by regulating the level of oxidative stress. These studies show that curcumin has a certain protective effect on mammalian ovarian function, and its mechanism is related to its strong antioxidant and anti-aging activities.

6. OTHER NATURAL COMPOUNDS

6.1. Osthole

Osthole, also known as methoxyparsimone is the main pharmacological active ingredient in Shechuangzi (Fructus Cnidii) of Umbelliferae and belongs to hydrocarbon-based coumarin compounds. Osthole has a wide range of pharmacological activities, such as oxidation resistance, anti-inflammation, analgesia, anti-tumor, blood lipid reduction, immune regulation, endocrine regulation, neuroprotection, reproductive protection, as well as cardiovascular and cerebrovascular protection, etc.^111,112 A study has found that osthole has an estrogen-like effect, which can increase the expression of ERβ in rat uterus and increase the level of serum estradiol.¹¹³ Lu et al ¹¹⁴ showed that a certain concentration of osthole (80 μg/mL) could reduce the oxidative stress damage of ovarian tissue caused by H₂O₂, enhance the antioxidant capacity of ovarian tissue and protect ovarian tissue.

6.2. Cryptotanshinoneh (CRY)

CRY, a natural quinone compound extracted from the roots and rhizomes of Danshen (Radix Salviae Miltiorrhizae), has a variety of pharmacological effects, including anti-cancer, anti-inflammatory, immune regulation, metabolic regulation, neuroprotection, cardiac protection, reproductive protection, etc.^115,⇓-117 Animal experiments on polycystic ovary syndrome have shown that CRY can reduce the synthesis of androgen in ovarian granulosa cells by reducing the expression of key enzymes for androgen synthesis.^118,119 Huang et al ¹²⁰ showed that CRY could reverse the symptoms of POF induced by CTX, increase the expression of Bcl-2, antigen identified by monoclonal antibody Ki-67 and proliferating cell nuclear antigen proliferating cell nuclear antigen, reduce Bax, reduce granulosa cell apoptosis and restore ovarian function.

6.3. Allicin

Allicin, a volatile oil extracted from garlic bulb, which is one of the main active components of Dasuan (Bulbus Allii), has many pharmacological activities, such as anti-bacteria, anti-inflammation, anti-tumor, anti-oxidation, anti-apoptosis, immunoregulation, liver protection and treatment of cardiovascular diseases.^121,⇓-123 One study has shown that allicin can alleviate H₂O₂-induced oxidative stress damage in porcine ovarian granulosa cells, reduce granulosa cell apoptosis, and improve the endocrine function of granulosa cells.¹²⁴ Yu et al ¹²⁵ showed that allicin had a certain protective effect on D-gal-induced ovarian senescence in mice, and could down-regulate the expression levels of FSHR, LH receptor (LHR) and active Caspase-3, which might be related to its participation in the anti-apoptotic process of ovarian tissue.

7. DISCUSSION

7.1. Antiapoptosis

Apoptosis of ovarian granulosa cells is one of the important mechanisms of POF.¹²⁶ The regulatory mechanism of ovarian granulosa cell apoptosis is very complex and highly coordinated. It is not only regulated by the hypothalamic-pituitary-ovarian axis, but also affected by FSH, LH, E2, P, growth factors and other hormones, and cytokines and gene expression products are also involved in the regulation of this process.^127,128 In addition, mitochondrial DNA deletion may accelerate follicular cell apoptosis and cause POF.¹²⁶ There are a variety of genes involved in the regulation of apoptosis, among which Bcl-2 family plays a decisive role in apoptosis, and Bcl-2 genes can promote cell division and play an anti-apoptotic role.^129,130 Studies have shown that overexpression of Bcl-2 increases the number of primordial follicles at birth and, in the absence of Bcl-2, a significant reduction in the total number of primordial follicles containing healthy oocytes.¹³¹ Bax gene and Bcl-2 gene are homologous and antagonistic, and their expression often forms homodimer or heterodimer to induce or inhibit the apoptosis process.^127,128 Studies have shown that ovarian granulosa cells mediate the expression of Bax through the mitochondrial pathway, induce the release of Cyt-c from the mitochondria, which in turn activates Caspase-3 and Caspase-9, triggering Caspases cascade reaction and eventually leading to cell apoptosis. Bcl-2 prevents the outward release of mitochondrial Ca²⁺ and Cyt-c, and inhibits the apoptosis of granulosa cells.¹³²

Reducing the apoptosis of ovarian granulosa cells is an important mechanism for the treatment of POF. As mentioned previously, TFSC, icariin, pomiferin, DOP, EPS, RES and CRY can regulate the expression of Bcl-2/Bax protein, while chrysin, Total momordicoside and allicin can reduce the expression of Caspase-3 in ovarian tissues and the apoptosis of ovarian granulosa cells, so as to protect ovarian function.

7.2. Antioxidation

Free radicals are the products of normal cell metabolism and have the physiological functions of transmitting signals, maintaining cell function, killing bacteria and parasites, and eliminating toxins in the body. They are in dynamic balance under normal physiological conditions. When the body is stimulated by the external stressors, excessive free radicals will be produced, and the dynamic balance of free radicals will be broken at this time. The excessive free radicals cannot be quickly removed, resulting in a large amount of accumulation and inducing the body to produce a large amount of reactive oxygen species (ROS), which will expose the body to oxidative stress, destroy the integrity of various biological molecules, including lipids, protein and DNA, affect the expression of protein in cells, and post-translational modification of DNA/RNA, and even lead to apoptosis.^133,134 Oxidative stress plays an important role in the occurrence and development of POF. Mammalian oocytes and embryos are very sensitive to oxidative stress, and high levels of ROS may induce mtDNA damage, nuclear DNA fragmentation, and even lead to apoptosis.¹³⁵ In vivo, free radicals act on lipids to undergo peroxidation, and finally produce MDA, which can exacerbate membrane damage and is cytotoxic. Under oxidative stress, lipid peroxidation in the body will produce a large number of lipid peroxidation (LPO), and excessive LPO will destroy the structure and function of cells and cell membrane. 8-OhdG is an oxidative adduct produced by the attack of reactive oxygen radicals on guanosine in DNA molecules, and is the most commonly used indicator of DNA oxidative damage.

Antioxidant is an important means to prevent and treat POF. Current studies have shown that there are a variety of natural antioxidants have significant therapeutic potential for POF. For example, the aforementioned icariin, Ginkgo flavonoid, Hubei Begonia flavone, AP, LBP, RES, curcumin, and osthole can reduce oxidative stress damage in vivo by increasing the content of antioxidant enzymes (SOD/CAT), and reducing lipid peroxidation products (MDA/LPO), in order to protect ovarian function. Studies have shown that Nrf2/ARE, FOXO, NF-κB and SIRT, signaling pathways related to oxidative stress, play important roles in the regulation of POF.^136,137 Icariin activates the PI3K/Akt/mTOR signaling pathway through phosphorylation, AP activates the Akt/FOXO3a signaling pathway, SIP activates the Nrf2/ARE signaling pathway, Total Momordicoside inhibits the expression of oxidative stress by up-regulating Nrf2, and RES reduces oxidative damage through the SIRT1/FOXO1 signaling pathway, FOXO3a, and Nrf2.

7.3. Estrogen-like effect

Phytoestrogen is a compound with weak estrogen effect in plants. Its molecular structure is similar to that of endogenous estrogen, and it can play a similar role as estrogen in the body and directly participate in the endocrine regulation of the body.¹³⁸ Phytoestrogens have dual regulatory effects in the body: (a) A certain amount of phytoestrogens can bind to ER in the body to exert estrogen-like effects. (b) Low-dose phytoestrogen and endogenous estrogen competitively combine with ER to form ER complex, occupy receptor binding site, and prevent estrogen molecule from binding to receptor in vivo, thus exerting anti-estrogen effect.¹³⁹ SI, Gen, Hubei Begonia flavone, EPS, icariin, pomiferin, and osthole all exert estrogen effects to protect ovarian function by regulating ER. Ginsenoside, allicin, Gen and EPS can also exert estrogen effects by regulating the expression of FSHR, LHR or PRA. TFSC regulates estrogen level and improves ovarian function through HPA axis.¹⁴⁰ Clinically, phytoestrogen supplementation can alleviate the ovarian failure and estrogen decline in women before and after menopause. The exploration and medicinal exploitation of phytoestrogens in Chinese medicine and diet are of great significance for the treatment of POF.

7.4. Immunoregulatory and anti-inflammation

Autoimmune factors are considered to be important factors affecting POF. Most patients with POF carry autoantibodies, including anti-ovarian antibody, antinuclear antibody, Anti-zona pellucida antibody.¹⁴¹ Cytokines affect the development and atresia of follicles, and the cytokines that are in charge of POF mainly include interleukin-1 (IL-1), IL-21, IL-6, TNF-α, TGF-β, and interferon-γ (IFN-γ), among which TGF-β plays a key role in the regulation of ovarian function.¹⁴² Studies have shown that inflammatory aging plays an important role in the pathogenesis of POF.¹⁴³ Therefore, immune regulation and anti-inflammation also play an important role in the treatment of POF. SI, PI and LBP can all reduce the level of autoantibodies to improve immune POF. Chrysin, SIP, AP, RES and Cur can inhibit inflammation of ovarian tissue by regulating the secretion of cytokines to protect ovarian function.

The protection of ovarian function and the treatment of POF by natural products described in this paper are mainly carried out from the above four aspects, and the mechanism of action is summarized in Figure 1.

Figure 1. Mechanism of natural products in the treatment of premature ovarian failure.

AP: Angelica polysaccharide; LBP: Lycium barbarum polysaccharide; SIP: Squid ink polysaccharide; TFSC: total flavonoids from semen cuscutae; DOP: dendrobium officinale polysaccharides; EPS: epimedium polysaccharide; CRY: cryptotanshinoneh; SI: soybean isoflavone; SOD: superoxide dismutase; CAT: catalase; MDA/LPO: malondialdehyde/lipid peroxidation; Nrf2/ARE: nuclear transcription factor/antioxidant response element; NF-κB: nuclear factor-κB; SIRT: Sirtuin; FSHR: follicle-stimulating hormone receptor; LHR: luteinizing hormone receptor; PRA: progesterone receptor A; ER: estrogen receptor; AOAb: anti-ovarian antibody; ANA: antinuclear antibody; AZPA: anti-zona pellucida antibody; IL: interleukin; IFN-γ: interferon-γ; TNF-α: tumor necrosis factor alpha; TGF-β: transforming growth factor-beta:; FOXO: forkhead box O.

8. CONCLUSIONS

This paper reviewed almost all kinds of natural products related to POF at present, including flavonoids, polysaccharides, saponins, polyphenols, legumes, quinones and volatile oils, whose mechanism was mainly related to their estrogen-like activity, strong antioxidant capacity and anti-apoptotic function, and immune regulation. These natural products were mainly derived from Chinese herbal medicine, indicating that the extracts or active components of Chinese herbal medicine [Renshen (Radix Ginseng), Danshen (Radix Salviae Miltiorrhizae), Gouqizi (Fructus Lycii), Jianghuang (Rhizoma Curcumae Longae), Shechuangzi (Fructus Cnidii), Danggui (Radix Angelicae Sinensis), Shihu (Herba Dendrobii Nobilis), and Yinyanghuo (Herba Epimedii Brevicornus)] had a broad application prospect in the prevention and treatment of POF, and also confirming the significant efficacy of Traditional Chinese Medicine for POF. Some bioactive components of natural products derived from edible plants [Dasuan (Bulbus Allii), Kugua (Fructus Momordicae Charantiae), soybeans, grapes, peanuts, mushrooms, etc.] also have a positive effect on ovarian function, suggesting that a healthy and scientific diet structure plays an important role in the protection of ovarian function and the prevention of POF. Some of the above natural products have been put into clinical use for the treatment of various diseases and the development of health care products, such as LBP, ginsenoside Rh2, and RES.

In summary, natural products with strong antioxidant capacity, anti-apoptotic effect, immunoregulatory function and estrogen activity can be used for the treatment and prevention of POF and the development of new drugs. In particular, natural products such as RES, icariin, ginsenoside can protect ovarian function through a plurality of ways, and the effect is remarkable. This indicates that they may be potential and effective therapeutic drugs for POF. The natural products have profound significance in research and wide range of applications in prevention and treatment of POF.