Psychological stressors involved in the pathogenesis of premature ovarian insufficiency and potential intervention measures

Abstract

Premature ovarian insufficiency (POI) is a common gynecological endocrine disease, which seriously affects women’s physical and mental health and fertility, and its incidence is increasing year by year. With the development of social economy and technology, psychological stressors such as anxiety and depression caused by social, life and environmental factors may be one of the risk factors for POI. We used PubMed to search peer-reviewed original English manuscripts published over the last 10 years to identify established and experimental studies on the relationship between various types of stress and decreased ovarian function. Oxidative stress, follicular atresia, and excessive activation of oocytes, caused by Stress-associated factors may be the main causes of ovarian function damage. This article reviews the relationship between psychological stressors and hypoovarian function and the possible early intervention measures in order to provide new ideas for future clinical treatment and intervention.

Keywords:

• Premature ovarian insufficiency
• psychological stressors
• apoptosis
• telomeres
• oocyte generation
• ovarian aging
• protective therapies

Introduction

Premature ovarian insufficiency (POI) is the loss of normal ovarian function before the age of 40 years. POI is clinically characterized by oligomenorrhea or amenorrhea with increased gonadotrophins (FSH > 25 IU/L) and decreased estradiol (E₂) [1] with an incidence of 1–2%, and is still increasing year by year [2]. The pathogenesis of POI is highly intricate, with approximately 90% of cases having an unknown etiology. This may be attributed to various factors including genetic and environmental influences, autoimmune disorders, iatrogenic injuries, as well as idiopathic causes [3]. With the development of social economy and science and technology, anxiety, depression and other negative emotions caused by social, life and environmental factors are considered to be important risk factors for POI [4]. According to previous research, most patients with POI have experienced two or more adverse life events prior to diagnosis, suggesting that the cumulative negative effects of psychological stressors may play a role in the development of POI [4]. Long shifts and intense workloads are associated with menstrual disorders [5]. Lim Ym et al. reported that employed women were more likely to experience POI and early menopause than unemployed people [6]. About 43% of patients with POI had a history of depression, of which 26% were diagnosed with depression within the first 5 years of POI diagnosis [7]. Chronic screaming and unpredictable stress can cause reproductive endocrine disorders in mice and causing ovarian reserve decline by accelerating primordial follicle activation and destroying growing follicles [8–10]. These studies have proved that psychological stressors can indeed inhibit and damage female reproductive and endocrine functions, and induce the occurrence and development of POI. However, the mechanism of action of psychological stressors on POI is not fully understood. And there is currently no effective treatment for POI [1] Therefore, early detection and early prevention may be the direction of future treatment. This article reviews the research progress of the mechanism of psychological stressors on POI and its intervention methods.

The relationship between psychological stressors and ovarian function

The main endocrine components involved in the human stress system response include hypothalamic-pituitary-adrenal (HPA) axis and locus coeruleus norepinephrine (LC/NE), autonomic nervous system [11]. When the brain detects a homeostatic challenge, it activates the sympathetic nervous system (SNS) and releases catecholamine epinephrine (E) and norepinephrine (NE), leading to a physiological stress response [12]. Within minutes of stress-induced HPA axis activation, the medial small cell area of the paraventricular nucleus stimulates the terminal buckling point of the median protuberans axon to release corticotropin-releasing hormone (CRH). In turn, it stimulates corticotroph cells in the anterior pituitary to release adrenocorticotropic hormone (ACTH) into the systemic circulation [13,14]. Each stressor in the stress system has the potential to regulate reproductive suppression. Studies have proved that, the abnormal abundance of neurotrophins, steroid hormones, metabolic and/or inflammatory cytokines can lead to changes in neurotransmitters, intracellular signaling, gene transcription and translation, and then directly or indirectly affect ovarian development and regulate apoptosis [15–17] (Figure 1).

Figure 1. Psychological stressors regulates ovarian function through the HPA and HPG axes.

Psychological stressors can cause ovarian damage by interfering with ovarian hormones

Psychological stressors have gradually become a common and important cause of reproductive endocrine disorders [18]. The activation of the HPA axis suppresses the normal function of the HPO axis through endocrine, paracrine, and neurological mechanisms [19]. The GnRH produced by the hypothalamus enters the pituitary portal venous system, stimulating the secretion of FSH and LH. FSH stimulates follicular maturation and estrogen release during the follicular phase, while LH triggers ovulation and promotes the release of progesterone during the luteal phase [20]. The delayed release of gonadotropin-releasing hormone (GnRH) and the LH surge caused by psychological stressors interfere with the release of reproductive hormones during the follicular phase [21]. Studies have shown that psychological stressors are associated with decreased estradiol (E2) and progesterone (P), as well as increased follicle-stimulating hormone (FSH) [22]. Stressors also affects reproductive hormone levels through some other mechanisms. For example, chronic stress will prolong the catabolic state of the whole body, and continuous HPA overactivity will gradually lead to increased visceral fat and insulin resistance, thereby interfering with HPO axis [23]. Catecholamines and β-adrenergic receptors (ADR β) also affect LH and E2 levels in the body [19]. However, the specific mechanisms of stress-induced endocrine changes and reproductive dysfunction still deserve further study and discussion.

Distribution and regulation of psychological stressors-associated factors in ovary

GnRH and GnRH receptors (GnRHRs) are highly expressed in the granulosa cells (GCs) and granulosa luteal cells (GLCs) of preovulatory follicles [24]. In human GCs, GnRH and GnRH-II induce apoptosis by interfering with the IGF-I/AKT signaling pathway and simultaneously activating proteolytic caspase cascades involved in initiating Caspase-8 and effecting caspase-3 and caspase-7 [25]. GnRH-induced granulosa cell apoptosis is not only related to follicular atresia, but also to low oocyte quality. In luteal cells (LCs), the GnRH/GnRHR system has been proposed to be involved in the processes of luteinization/luteolysis. Specifically, GnRH induces structural luteolysis in corpora lutea, through the up-regulation of molecules that are involved in the remodeling of the extracellular matrix, such as thee matrix metalloproteinase MMP-2 and the membrane type MMP-1 [26,27]. Thus the GnRH/GnRHR system is expressed in a specific manner in the human ovary and is involved in follicular development and luteal function.

CRH concentrations in premenopausal ovaries are higher than those in postmenopausal ovaries, suggesting that ovarian CRH may be associated with normal ovarian function during reproductive life. CRH and its receptor (CRHR-1 and CRHR-2) are found in ovarian tissues, mainly in the membrane, stroma, and cytoplasm of follicle and GCs [28] CRH has a strong inflammatory effect. Reproductive-related CRH regulates reproductive functions, such as ovulation, luteolysis, implantation and delivery, through inflammatory components [29,30]. CRH can also act directly on the ovary to regulate steroidogenesis and/or oocyte production [31,32].

Glucocorticoids, In addition to their effects on ovarian periodicity mediated through the hypothalamus and pituitary, glucocorticoids can also affect ovarian physiology by regulating the function of GCs, oocytes, cumulus cells (CCs), and LCs [33]. In mouse studies, the increased glucocorticoid levels caused by restraint stress impair the developmental potential of oocytes [34]. A study on cats found that glucocorticoid treatment led to morphological changes in oocytes after ovarian stimulation [35]. The use of dexamethasone (DEX) can increase pre-ovulatory anti-Müllerian hormone levels, suggesting that dexamethasone can promote the development of preantral follicles, leading to a reduction in the primordial follicle pool [36]. Glucocorticoids can also affect the production of ovarian steroid hormones, DEX decreased E₂ and P production by cultivated ovarian cells during the experiment [37]. Glucocorticoid exposure was also associated with decreased mRNA expression of glucocorticoid receptor (GR) gene (NR3C1) and the ovarian growth factors insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF) in parietal granule cells [38].

BDNF is a regulator of human oocyte maturation and early embryonic development. It is expressed in the ovary [39] and involved in oocyte maturation, early embryo cleavage and blastocyst formation [40]. BDNF regulates the expression of genes related to cell proliferation (CCND1, p21, and Bcl2) and apoptosis (Bax), playing a crucial role in cell proliferation, differentiation, and apoptosis [41,42]. After binding to its specific receptor, BDNF activates its downstream phosphoinositide-3 kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) signaling pathway, participating in the activation of primordial follicles and the meiotic division of oocytes [43,44], Furthermore, studies have shown that the BDNF-activated PI3K-AKT-mTOR signaling pathway play a role in female reproductive diseases such as polycystic and POI caused by chronic unpredictable mild stressors [45].

Nerve growth factor (NGF) and its receptors are expressed in ovarian cells of different species (oocytes, GCs, theca and stromal cells), including humans [46]. NGF promotes follicular development and increases the cellular response to FSH by up-regulating FSH receptors in GCs [47]. NGF is also involved in promoting thecal cells (TC) proliferation, In vitro culture of sinusoidal follicular TC, Plasmid transfection of tyrosine kinase receptor (TrkA) expression in the presence of NGF led to an increase in the proliferation rate of bovine TC cells [48]. NGF is involved in the regulation of steroid hormone production. For example, NGF directly promotes the production of E₂ by activating TrkA (high-affinity tyrosine kinase NGF receptor), and inhibits the differentiation of GCs into LCs by suppressing the production of P in isolated human GCs [47, 49]. When psychological stressors occurs, the levels of these molecules change accordingly, causing persistent damage to the ovary (Table 1).

Table 1. Location and function of stressors on ovary.

Stress-associated factors	Location existence	Potential fuction	Reference
CRH, CRHR	Oocytes, ovarian stroma and theca cells	Follicular maturation, Ovulation, Luteolysis, Suppression of female sex, Regulatory steroid hormone	[50]
BDNF	Oocytes, Cumulus cells (CCs), GCs	Regulates oocyte maturation and early embryonic development, Participates in the differentiation of primitive GCs into specialized cumulus cells and the mechanism of oocyte/follicle selection	[51–53]
NGF	Oocytes, CCs, GCs, Theca cells	Follicular development, Primary follicle activation, Upregulates FSH receptors, Regulatory steroid hormone	[15]
Adrenergic receptors	GCs	Follicular development, ROS generation, Associated with the production and increase of cAMP and steroid	[54,55]
GnRH	GCs, GLCs	Follicular development, corpus luteum function	[56]
Glucocorticoids	GCs, GLCs, Oocytes, CCs,	Anti-inflammatory, Promotes P production, Promotes preantral follicle development	[36, 38]

The mechanism of psychological stressors induces POI

It is well known that the decline of ovarian function is mainly related to follicular atresia and excessive activation of primordial follicles. Due to the unique physiological environment of the ovary and the process of follicular development, the apoptosis of ovarian granulosa cells (GCs) and oocytes is the main cause of follicular atresia. Furthermore, in the process of POI, cell apoptosis and oxidative stress form a ‘vicious cycle’ involving changes in various molecules. POI caused by psychological stress is closely related to these mechanisms (Figure 2).

Figure 2. Mechanism of stress factor involved in ovarian function impairment.

ROS

Reactive oxygen species (ROS) are one of the most effective biological effectors of stress-related endocrine, immune/inflammatory, and metabolic pathways on cell health [57,58], and excessive ROS levels can induce the occurrence of ovarian diseases. Increased ROS beyond the antioxidant capacity can induce oxidative stress (OS), leading to oxidative damage to lipids, proteins, and DNA, as well as chromosomal abnormalities and telomere shortening, ultimately resulting in a decrease in the number and quality of oocytes [59,60]. Lipid peroxidation leads to an increase in the level of maturation-promoting factor (MPF), disrupting follicular development [61]. The activation of ROS mediates the induction of ovarian cell hypertrophy, apoptosis, and fibrosis through the protein kinase pathway activated by advanced glycation end products [62]. Excessive ROS production can directly affect the targets of signaling pathways, and can also interact as a second messenger with intermediate reaction steps, inducing abnormal outcomes [63]. Furthermore, HIF-1α (hypoxia-inducible factor-1α) can cause oxidative damage and apoptosis of GCs through the hypoxia-inducible factor-vascular endothelial growth factor (VEGF) signaling pathway [64]. ROS-mediated granulosa cell apoptosis reduces the communication between granulosa cells and oocytes, affecting the supply of nutrients and the quality of pre-ovulatory oocyte maturation, and disrupting the developing follicle-oocyte complex [65,66]. The formation of these oxidative damage signaling pathways promotes ovarian injury.

Psychological stressors-induced oxidative stress can cause ovarian injury by increasing ROS (reactive oxygen species) levels. The elevated levels of stress-related factors activate various physiological functions that require oxygen consumption, leading to the production of superoxide free radicals [67,68]. The increase in cortisol levels reduces the superoxide anion in leukocytes, weakening the body’s antioxidant capacity [69]. Furthermore, stress can suppress the levels of antioxidant enzymes, and the activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) in the preantral follicles (PF) under stress conditions are significantly reduced [70].

Inflammatory factors

Elevated glucocorticoids can increase the expression of pro-inflammatory genes (iNOS, IL-1β, TNF-α) and reduce the expression of anti-inflammatory genes including IL-1RA, IL-10, and MKP-1 [71]. Dexamethasone up-regulated gene expression of Shelterin complex proteins telomere repeat-binding factor 1 and 2 (TRF1 and TRF2) and protection of telomeres (POT1) in cell lines cultured in vitro. TNF-α up-regulates the expression of telomerase reverse transcriptase (TERT), TRF1, TRF2, and POT1 genes, suggesting that transcriptional regulation of Shelterin complex may be a potential mechanism for stress-related telomere length dynamic changes [72]. Due to the end replication problem, DNA replication machines cannot complete the synthesis of linear chromosome ends, telomere shortens as cells divide. Telomere shortening, collapse of telomere structure or displacement of the Shelterin complex on telomeres cause disruption of telomere structure, which in turn cause DNA damage response and loss of cell proliferation, and finally leads to senescence or apoptosis [73].

Apoptosis

Death receptor and mitochondrial pathways are involved in the process of oocyte apoptosis. In previous studies, total transcriptome analysis of ovaries in depressed mice found significant reductions in genes associated with the mitotic cell cycle. The number of genes related to the regulation of exogenous apoptosis signaling pathway through death domain receptors and the number of genes related to negative regulation of cells increased significantly [74]. Stress signals can activate the tumor necrosis factor-α (TNF-α) system, increase Fas expression, and trigger apoptosis of ovarian cells and oocytes within the ovary by activating the FasL/Fas system [75,76]. Bcl2 protein family members mainly act on mitochondrial membrane, and play an important role in follicular growth/atresia by regulating the apoptosis of germ cells and somatic cells. In the ovary of depression-like mice, more GCs apoptosis occurs and the expression of Bcl2 in GCs mitochondria significantly reduces [77]. BAX expression was abundant in GCs of early atresia follicles, but not in atresia follicles, suggesting that BAX protein expression in early atresia promotes GCs apoptosis [78]. Bcl2-deficient mice exhibit a reduced number of oocytes and primordial follicles [79], whereas Bax-deficient mice exhibit an excess of abnormal follicles [80,81].

Profilin-1(PFN-1)

Profilin-1(PFN-1) is widely present in eukaryotic cells and participates in the regulation of actin skeleton remodeling, cell morphology maintenance, cell adhesion, motility, growth, division and ligand-dependent signal transduction. Long term influence of stressors stimulation significantly increases the expression of PFN-1 [82]. Overexpression of PFN-1 promotes apoptosis of ovarian endothelial cells. Intercellular adhesion molecules up-regulate and vasodilators stimulate phosphorylation of phosphoproteins, mediates endothelial cell dysfunction [83,84]. Extracellular PFN-1 can promote extracellular regulation of protein kinase 1/2(ERK1/2), ribosomal protein S6 kinase, phosphatidylinositol 3 kinase to stimulate the proliferation and migration of ovarian smooth muscle cells, thereby promoting the progression of ovarian dysfunction [85,86]. PFN-1 regulates cytoskeleton-mediated ovarian vascular hypertrophy, increased expression of PFN-1 can directly lead to elongation of sarcoplasmic reticulum, ovarian fiber rearrangement and increased contractile stress, thus activating mechanical stress-related signaling pathways and affecting ovarian physiological function. In addition, PFN-1 may affect the synthesis of nitric oxide in ovarian endothelial cells by binding to actin, causing cytoskeleton remodeling, increasing stress fibers and activating inflammation-related signaling pathways [87,88]. Therefore, PFN-1 induced fibrosis and ovarian cell apoptosis are important pathological processes of ovarian dysfunction.

Adrenergic receptor signaling

Long term influence of stressors can cause an abnormal increase of NE levels, resulting in cell damage or apoptosis, and thus impair ovarian function [89,90]. The activation of adrenergic receptor signaling has an apoptotic effect on cells. Stimulation with NE can significantly enhance the expression of rno-miR-128-3p in GCS and induce apoptosis of rat GCS by inhibiting the expression of Wilms tumor 1 (WT1) [91]. The miR-21/Smad7 pathway mediated by α1A adrenergic receptor activation plays an important role in the occurrence of POI. It has been reported that overexpression of Smad7 in GCs significantly increases apoptosis [92]. α1A adrenergic receptor (α1A-AR), as a negative mediator of Smad7, can regulate the expression of miR-21. Overexpression of Smad7 reduces miR-21 expression, thereby enhancing TGF-β-induced granulosa cell apoptosis and impairs ovarian function [93]. In addition, ROS is produced during the uptake and metabolism of adrenomedullin by GC, which will continue to act even if the receptor is blocked, in turn forming toxic effects through ROS [90, 94].

The early detection of POI and psychological stressors

Ovarian histology is the gold standard for assessing follicular status and ovarian reserve. However, the invasive nature of histological examination precludes its use in the long-term monitoring of premature ovarian insufficiency (POI) progression. Consequently, identifying sensitive biochemical markers to evaluate the residual follicular pool in POI patients is of paramount importance. By utilizing commonly employed ovarian function testing parameters in conjunction with stress-related assessments, it may be possible to identify POI patients whose condition is highly correlated with psychological stressors. Implementing early interventions targeting this specific population could prove to be the most effective strategy for preserving ovarian function.

When ovarian dysfunction commences, markers of ovarian reserve exhibit a marked decline, particularly those with heightened sensitivity, such as Anti-Müllerian hormone (AMH), antral follicle count (AFC), inhibin B, and the follicle-stimulating hormone (FSH) to luteinizing hormone (LH) ratio.

AMH

A glycoprotein secreted by the granulosa cells of large, small preantral, and small antral follicles in the female ovary, exhibits a strong correlation with the primordial follicle pool [95]. Among the various ovarian reserve assessment tools, AMH is widely regarded as the most sensitive and earliest marker of diminishing ovarian reserve. The commonly accepted cutoff value for predicting the onset of premature ovarian insufficiency (POI) is 1.211 ng/mL (AUC 0.932, 95%, CI 0.918–0.945) [96].

Antral follicle count (AFC)

AFC represents the total number of antral follicles in both ovaries, as visualized by ultrasonography during the early follicular phase (day 2–4) of the menstrual cycle. AFC is a convenient and practical assessment tool, yielding immediate results and demonstrating good intercycle reliability and interobserver reliability. As ovarian function declines from the stage of normal ovarian reserve (NOR) to the pre-premature ovarian insufficiency (pre-POI) stage, AFC values exhibit an approximately two-fold decrease, from 8 to 4. When employed for the prediction of pre-POI, the recommended cutoff value for AFC is 5 (AUC 0.868, 95% CI 0.848–0.885) [96].

Inhibin B

a glycoprotein hormone secreted by the granulosa cells of developing preantral and early antral follicles, reflects the circulating concentration of the follicular pool responsive to gonadotropins. Its levels peak during the early to mid-follicular phase of the menstrual cycle [97]. Serum Inhibin B concentrations decline with advancing reproductive age, particularly in the early follicular phase [98]. Although low Inhibin B levels (≤31.74 pg/mL) demonstrate high specificity for predicting premature ovarian insufficiency (pre-POI), the sensitivity is suboptimal (AUC 0.704, 95% CI 0.679–0.727) [96]. Consequently, Inhibin B is considered a marker of current ovarian function rather than a reliable predictor of ovarian reserve [98].

FSH/LH ratio

FSH remains the sole ovarian reserve marker currently employed in research for defining premature ovarian insufficiency (POI) and its subgroups. As ovarian function declines from normal ovarian reserve (NOR) to the pre-POI stage, the FSH/LH ratio exhibits a significant increase (1.64 ± 0.66 vs. 2.49 ± 1.22, p < 0.001). The generally recommended cutoff value for the FSH/LH ratio is 2.11 (AUC 0.749, 95% CI 0.726–0.772) [96].

Certain clinical manifestations

Certain clinical manifestations warrant attention, as research has demonstrated that stress-induced Premature Ovarian Failure (POF) in patients may be preceded by alterations in the menstrual cycle, such as oligomenorrhea or menorrhag, prior to the onset oforrhea [99].

In line with our previous discussions, prolonged exposure to high levels of stress may result in compromised reproductive function [100]. The application of psychological assessments (CES-D, BSI-GSI, WHOQOL-Bref) to evaluate the overall psychological state of patients can serve as a basis for the prevention of induced by psychological stressors.

Psychological stressors-associated factors

In a study, the Support Vector Regression (SVR) model was effectively utilized to forecast the nonlinear relationships within the neuroendocrine-immune network of rats with stress-induced POI, thereby presenting a methodological paradigm for evaluating the incidence of POI [18]. Research conducted by Biocycle and Eager discovered that salivary cortisol, apart from its convenience in sampling, can sensitively capture and assess fluctuations in daily stress, making it suitable for measuring both acute and chronic stress [101]. The decrease in biomolecular values within the hypothalamic-pituitary-adrenal (HPA) axis during stress-induced responses leads to a significant decrease in hypothalamic biomolecules (β-EP, IL-1, NOS, and GnRH).

Center for Epidemiologic Studies Depression Scale (CES-D)

The CES-D quantifies the severity of depressive symptomatology and consists of 20 items, which are measured using a scale from 0 to 3. Scores range from 0 to 60, with scores of 16 or higher reflecting clinical relevant depressive symptoms. A value of 22 or more signals a major depression [102].

Brief Symptom Inventory (BSI)

The BSI measures a person’s perceived disturbance by physical and psychological symptoms over a period of seven days. It comprises a total of 53 items, which are grouped into nine scales. These scales describe the areas: somatization, compulsiveness, insecurity in social contact, depression, anxiety, aggressiveness/hostility, phobic anxiety, paranoid thinking and psychoticism [103,104].

The global value Global Severity Index (GSI)

GSI represents the most sensitive indicator of the psychological burden, because it measures the intensity of perceived stress in all 53 items. The response format ranges from 0 (not at all) to 4 (very strong). Higher values mean that the burden is judged to be higher. The standard Global Value BSI GSI value in women is M = 0.35. For the depression scale M = 0.33, for the anxiety scale M = 0.39 and the aggression scale M = 0.37.

WHO Quality of Life Bref (WHOQOL-Bref)

The higher the values of the items in the WHOQOL-Bref, the higher the subjective quality of life is rated to be. The WHOQOL-Bref is a subjective quality of life assessment tool comprising 26 items, including global quality of life, physical well-being, mental well-being, social relationships, and environment. According to the scores of the items in WHOQOL-Bref, the higher the scores, the higher the subjective quality of life is rated to be. The standard value of the WHOQOL Global scale is a total mean (M) of 67.8 with a standard deviation (SD) of 16.7. For women aged 26–35, the mean is 72.49, while for women aged 36–45, the mean is 68.72 [105].

Early intervention of POI caused by psychological stressors

Decreased ovarian reserve may be persistent. Spontaneous premature termination of ovarian function requires a higher level of clinical treatment. Reproductive loss requires multidisciplinary management, including the provision of appropriate counseling and emotional support, nutritional supplementation, hormone replacement therapy, reproductive health care, lifestyle changes, etc [106,107]. Conventional treatment methods for Premature Ovarian Insufficiency (POI) have been widely discussed in other reviews. Here, we will focus exclusively on interventions for stress-induced POI. For POI caused by stress, alleviating stress can restore ovulation, fertility, and improve other neuroendocrine-related symptoms [108]. The hypothalamic-pituitary-adrenal (HPA) axis and the corresponding hypothalamic-pituitary-ovarian (HPO) inhibition are fundamental to the impact of psychological stressors on ovarian function [51]. The response of the HPA axis to stress is dynamic, removing the stressor can quickly halt the action of stress-associated factors, thus preventing damage to the peripheral and central nervous system due to prolonged exposure [109]. Several methods may have a positive impact on improving psychological stressors

Psychological intervention

Substantial evidence suggests that psychotherapy is effective for treating anxiety and depression, including Cognitive Behavioral Therapy (CBT) [110,111], Behavioral Activation Therapy [112], and Interpersonal Psychotherapy (IPT) [113], etc. Psychotherapy is more acceptable than drug therapy [114]. Bahari et al. demonstrated that muscle relaxation and laughter therapy are related to improvements in psychological conditions (trait anxiety and depression) and contribute positively to the treatment outcomes for patients undergoing in vitro fertilization (IVF) (estradiol levels, oocyte retrieval, transfer status, and pregnancy test results). The mechanism may be related to laughter altering the activity of dopamine and serotonin [115], with endorphins released during laughter helping to foster positive emotions and reduce negative feelings such as anxiety and depression [116].

Exercise

Research indicates that exercise has a positive impact on mental health, improving mood, self-esteem, and reducing stress and anxiety levels [117–119]. Exercise combats the pathological effects of stress through physiological effects such as increased endorphin levels [120], improved mitochondrial function [121,122], enhanced production of neurotransmitters [123,124], and a weakened response of the hypothalamic-pituitary-adrenal (HPA) axis [123, 125]to stress. Moderate exercise can improve reproductive health. Boudoures et al. found that voluntary exercise can moderately improve mitochondrial structure in oocytes of mice on a high fat diet (HFD), reducing the number of rose petals and oval mitochondria [126]. Another study demonstrated that exercise ameliorated premature decline in ovarian function at the oocyte level in POLG mice, possibly through mitochondrial localization of p53. Enhanced p53 fidelity mechanisms have been demonstrated in somatic tissues after exercise [127,128], and exercise induces translocation of nuclear p53 to mitochondria. This leads to the up-regulation of peroxisome proliferator-activated receptor γ and coactivator 1α, an important regulator of metabolism and mitochondrial biogenesis [119, 126]. Furthermore, exercise can help alleviate inflammation, thereby combating the aging or apoptosis of ovarian cells caused by inflammatory factors through the destruction of telomere structure [129,130].

Gut microorganism

There is evidence in animal and human studies that probiotics are associated with anxiety, stress, and depression-like behaviors. Studies over the years have shown that gut microorganism can affect stress-related HPA axis, autonomic nervous system and neurobiological functions, which constitute the basic mechanism of microbial influence on the central nervous system. People taking probiotics had decreased scores on the Hopkins Symptom Global Severity Index (HSSCL-90) checklist and improved anxiety and depressive symptoms [127]. A daily dose of probiotics can prevent mood disorder symptoms in people with mild stress caused by low cortisol [128]. Indeed, these studies highlight new approaches for the prevention and treatment of depression and anxiety. However, there is still a lack of direct studies on whether the intestinal action of microorganisms can rescue ovarian function.

Conclusions and future perspectives

We focus on the direct and indirect molecular basis of POI caused by psychological stressors. Stress-associated factors produced by psychological stressors can directly act on ovarian surface receptors and participate in the decline of ovarian function. It can also change endocrine hormone levels and ROS production through the HPA and HPO axes to participate in ovarian or GCs apoptosis. Understanding the molecular mechanism and signaling pathway of psychological stressors changes follicle physiology will help to further understand the specific mechanism of stress-mediated ovarian dysfunction.Psychological interventions for women with POI have the potential to reduce anxiety and depression and may well improve the outcomes of POI. Exercise and gut microbiome regulation may also be remedies for stress-related POI. However, more quantitative studies are needed to verify the exact relationship between the occurrence and development of POI and stress. For example, the regulatory effect of stress-induced adrenaline or glucocorticoid on the nervous system and reproductive system is still unclear, and the signal interaction between the nervous system and reproductive system, as well as how to find more effective intervention means, are questions worth exploring and answering in the future.

Authors’ contributions

YX and JW conceived the idea. YX and JF were involved in drafting the early manuscript, ZH, DZ prepared tables and helped with revision of the article.CG has contributed to the literature search. PL and JW provided a significant expert contribution in the scientific content revision process. YX and JW completed the literature collection. Subsequent drafts were expanded upon by all authors. All authors read and approved of the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by the Natural Science Foundation of Fujian Province [grant number: 2022J01778], the Science and Technology Projects of Quanzhou [grant number: 2021N016S], Second Affiliated Hospital of Fujian Medical University PhD Nursery Project [grant number BS202108] and Startup Fund for scientific research, Fujian Medical University [Grant number:2022QH1472].