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This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of infertility? ​

Abstract ​

Infertility is a complex condition impacting a significant portion of couples globally, with an estimated prevalence of 12-25%. Understanding the underlying mechanisms is crucial for developing effective diagnostic and therapeutic strategies. This review synthesizes current research on the multifaceted factors contributing to infertility, organized into hormonal, genetic, anatomical, environmental, and psychological categories. Hormonal mechanisms involve disruptions in the hypothalamic-pituitary-gonadal axis, affecting reproductive hormone secretion in both sexes. Genetic factors, including chromosomal abnormalities and specific mutations, significantly influence reproductive capabilities, with implications for genetic testing and personalized treatment. Anatomical abnormalities, such as those associated with endometriosis, can lead to direct fertility challenges through anatomical distortions and hormonal dysregulation. Environmental influences, particularly exposure to endocrine disruptors and lifestyle choices, play a significant role in reproductive health, emphasizing the need for holistic treatment approaches. Psychological factors, including stress and emotional distress, further complicate infertility, highlighting the necessity for integrated mental health support. This review aims to illuminate the complex interplay of these factors and suggest future research directions to enhance reproductive health outcomes.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Hormonal Mechanisms of Infertility
    • 2.1 The Role of the Hypothalamus and Pituitary Gland
    • 2.2 Ovarian Function and Disorders
    • 2.3 Male Hormonal Factors and Spermatogenesis
  • 3 Genetic Factors Influencing Infertility
    • 3.1 Chromosomal Abnormalities
    • 3.2 Genetic Mutations and Their Impact on Reproduction
  • 4 Anatomical Abnormalities and Infertility
    • 4.1 Female Reproductive Tract Anomalies
    • 4.2 Male Reproductive System Disorders
  • 5 Environmental and Lifestyle Factors
    • 5.1 Impact of Endocrine Disruptors
    • 5.2 The Role of Nutrition and Lifestyle Choices
  • 6 Psychological Factors and Infertility
    • 6.1 Stress and Its Effects on Reproductive Health
    • 6.2 The Psychological Impact of Infertility
  • 7 Conclusion

1 Introduction ​

Infertility is a multifaceted condition that affects a significant portion of the global population, with estimates suggesting that approximately 12-25% of couples experience difficulties in conceiving after one year of unprotected intercourse [1]. This complex phenomenon arises from a myriad of biological, environmental, and lifestyle factors, necessitating a comprehensive understanding of its underlying mechanisms. Infertility is not only a personal and social concern but also poses significant public health challenges, influencing emotional well-being and economic stability for affected individuals and couples [2].

The significance of elucidating the mechanisms of infertility cannot be overstated. A thorough understanding of these mechanisms is essential for the development of effective diagnostic tools and therapeutic strategies. As infertility often stems from a combination of factors, including hormonal imbalances, genetic anomalies, anatomical defects, and environmental influences, research in this field has expanded significantly in recent years [3][4]. For instance, hormonal dysregulation involving the hypothalamic-pituitary-ovarian axis has been identified as a key factor affecting both female and male fertility [3]. Additionally, genetic factors, such as chromosomal abnormalities and specific mutations, have been linked to reproductive challenges [5][6].

Current research indicates that anatomical abnormalities, such as those associated with endometriosis or congenital malformations, also play a critical role in infertility [7][8]. Environmental factors, including exposure to endocrine disruptors and lifestyle choices, have been shown to impact reproductive health, highlighting the need for a holistic approach to infertility treatment [5][9]. Furthermore, psychological factors, such as stress and emotional distress, are increasingly recognized as significant contributors to infertility, suggesting that mental health support is an integral component of infertility management [2].

This review aims to explore the multifaceted mechanisms of infertility, structured as follows: Section 2 will delve into hormonal mechanisms, examining the roles of the hypothalamus, pituitary gland, ovarian function, and male hormonal factors. Section 3 will address genetic influences, focusing on chromosomal abnormalities and mutations that affect reproductive capabilities. Section 4 will investigate anatomical abnormalities in both female and male reproductive systems. In Section 5, we will discuss the impact of environmental and lifestyle factors, including nutrition and exposure to toxins. Section 6 will explore psychological aspects and their effects on reproductive health. Finally, the conclusion will summarize key findings and suggest future research directions.

By synthesizing current research findings, this review will provide a comprehensive overview of the complex interplay between various factors contributing to infertility. In doing so, we hope to illuminate potential avenues for targeted interventions and personalized treatment approaches that address both male and female infertility, ultimately enhancing reproductive health outcomes for affected individuals and couples.

2 Hormonal Mechanisms of Infertility ​

2.1 The Role of the Hypothalamus and Pituitary Gland ​

Infertility can arise from various hormonal mechanisms, particularly involving the hypothalamic-pituitary-gonadal (HPG) axis, which plays a critical role in regulating reproductive function. The hypothalamus and pituitary gland are central components of this axis, and their interactions are essential for normal reproductive hormone secretion and fertility.

The hypothalamus produces gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary gland to secrete gonadotropins, namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These hormones are crucial for the regulation of the ovaries in females and the testes in males. In females, FSH promotes ovarian follicle development, while LH triggers ovulation and supports the corpus luteum. In males, FSH is vital for spermatogenesis, while LH stimulates testosterone production, which is necessary for the maintenance of spermatogenesis and overall male fertility [10].

Disruptions in the HPG axis can lead to various forms of hypogonadism, which may result in infertility. For instance, a deficiency in GnRH production can lead to hypogonadotropic hypogonadism, characterized by low levels of FSH and LH, subsequently causing delayed or absent puberty and infertility [10]. Additionally, conditions such as functional hypothalamic amenorrhea, which can occur due to stress, excessive exercise, or significant weight loss, disrupt the normal pulsatile release of GnRH, leading to secondary amenorrhea and infertility [11].

Furthermore, hyperprolactinemia, an elevated level of prolactin in the blood, can also inhibit the secretion of GnRH, thereby affecting the release of FSH and LH. This condition can lead to menstrual irregularities and infertility in women, as well as decreased testosterone levels and fertility issues in men [11].

In summary, the hormonal mechanisms of infertility primarily involve the complex interactions within the hypothalamic-pituitary-gonadal axis. Any perturbation in the function of the hypothalamus or pituitary gland can lead to hormonal imbalances that impair reproductive functions, resulting in infertility. Understanding these mechanisms is crucial for the assessment and management of individuals presenting with infertility-related concerns. Prompt evaluation and treatment are essential to prevent long-term consequences, such as loss of bone mass due to hypoestrogenemia in women or infertility in both sexes [11].

2.2 Ovarian Function and Disorders ​

Infertility, particularly in women, can often be attributed to various hormonal mechanisms that impact ovarian function and result in disorders affecting reproductive capabilities. A comprehensive understanding of these mechanisms is essential for developing effective treatments and interventions.

One of the primary hormonal influences on ovarian function is the hypothalamic-pituitary-ovarian (HPO) axis. Alterations in this axis can lead to abnormal secretion of gonadotropins and steroid hormones, adversely affecting ovulation and implantation processes, thereby resulting in decreased fertility (Qi et al., 2025) [3]. In women with polycystic ovary syndrome (PCOS), for example, there is often a disruption in the typical cyclical release of gonadotropin-releasing hormone (GnRH), which can result in persistent high-frequency stimulation of the pituitary gland. This leads to elevated luteinizing hormone (LH) levels and low follicle-stimulating hormone (FSH) levels, contributing to ovarian hyperandrogenemia and ovulatory dysfunction (McCartney et al., 2022) [12].

Moreover, endocrine disorders such as hyperprolactinemia, thyroid dysfunction, and adrenal gland disorders can significantly impair ovarian function. Hyperprolactinemia, for instance, is known to disrupt normal gonadal function and can be treated effectively with established medical therapies (Unuane et al., 2011) [13]. Thyroid disorders, whether hyperthyroid or hypothyroid, can also have direct effects on ovarian function and may involve autoimmune mechanisms, further complicating the clinical picture (Unuane et al., 2011) [13].

In addition to these hormonal imbalances, the role of oxidative stress (OS) in ovarian dysfunction has gained attention. OS results from an imbalance between the production of reactive oxygen species and the body's ability to counteract their harmful effects. This condition can lead to cellular damage within the ovaries, negatively impacting oocyte quality and overall fertility (Ghantabpour et al., 2025) [14]. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of oxidative homeostasis, and its activation may help improve ovarian function by mitigating the adverse effects of oxidative stress (Ghantabpour et al., 2025) [14].

Furthermore, inflammation and immune responses also play a crucial role in ovarian function. Chronic low-grade inflammation, often observed in conditions like PCOS and endometriosis, can lead to ovulatory and implantation disorders. In these scenarios, dysregulation of cytokines and chemokines can alter the local reproductive environment, making it less conducive to successful conception (Omidvar-Mehrabadi et al., 2024) [15].

Lastly, lifestyle factors such as diet and circadian rhythm disruptions have been shown to influence ovarian health and function. High-fat diets, for instance, have been linked to negative impacts on oocyte and follicular quality, while circadian rhythm disturbances can disrupt hormonal secretion patterns that are vital for fertility (Gonnella et al., 2022; Sciarra et al., 2020) [16][17].

In summary, hormonal mechanisms underlying infertility are multifaceted and involve intricate interactions between various endocrine pathways, oxidative stress, inflammation, and lifestyle factors. A deeper understanding of these mechanisms is critical for the development of targeted therapeutic strategies aimed at restoring ovarian function and enhancing fertility outcomes.

2.3 Male Hormonal Factors and Spermatogenesis ​

Infertility in males is often closely linked to hormonal factors that significantly influence spermatogenesis, the process by which spermatozoa are produced. Central to this process are hormones such as luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone, which work through intricate endocrine and paracrine signaling pathways.

Luteinizing hormone plays a critical role in stimulating Leydig cells to produce testosterone, which is essential for the regulation of spermatogenesis. Testosterone, in turn, is necessary for the proper functioning of Sertoli and germ cells, facilitating their proliferation and differentiation. The relationship between LH and testosterone is crucial, as LH-driven testosterone production activates various inter-related regulatory pathways that are fundamental to spermatogenesis. Studies have shown that exogenous gonadotropins containing LH can restore spermatogenesis in males with hypogonadotropic hypogonadism, indicating LH's importance in male fertility treatment [18].

The hormonal regulation of spermatogenesis is primarily governed by the hypothalamic-pituitary-gonadal (HPG) axis. This axis, which involves the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, subsequently stimulates the secretion of FSH and LH from the pituitary gland. Both gonadotropins are essential for maintaining normal testicular functions and testosterone levels, which are critical for sperm production. Disruptions in this hormonal balance can lead to various reproductive disorders, including hypogonadism, which is characterized by insufficient testosterone production and impaired spermatogenesis [19].

In addition to the direct hormonal influences, environmental factors, genetic predispositions, and epigenetic modifications can also impact hormonal regulation and, consequently, spermatogenesis. Hormonal imbalances can result from various endocrine disorders, which are often reversible causes of male infertility. These include disruptions in the HPG axis, which may be modulated by other hormonal systems, such as the thyroid and adrenal axes [20].

Genetic factors also contribute significantly to male infertility. Genetic disorders that affect gonadotropin secretion or action, chromosomal abnormalities, and specific gene mutations have been implicated in impaired spermatogenesis. For instance, microdeletions in the Y chromosome, which harbor critical genes for spermatogenesis, can lead to infertility [21]. Furthermore, advances in understanding the genetic basis of spermatogenesis have shifted the classification of many cases of idiopathic infertility towards identifiable genetic causes [22].

Overall, the mechanisms underlying male infertility are multifaceted, involving a complex interplay of hormonal regulation, genetic factors, and environmental influences. Further research is essential to elucidate these mechanisms and develop targeted therapies to address male infertility effectively [4].

3 Genetic Factors Influencing Infertility ​

3.1 Chromosomal Abnormalities ​

Infertility is a complex health issue affecting approximately 10-15% of couples globally, with male-related factors accounting for a significant proportion of these cases. Genetic factors play a crucial role in infertility, particularly chromosomal abnormalities, which are one of the key genetic influences. Chromosomal abnormalities can be categorized into various types, including aneuploidies, deletions, and translocations, which can lead to significant reproductive challenges.

Chromosomal abnormalities can affect both male and female fertility, but certain conditions are gender-specific. For example, Klinefelter syndrome, characterized by the presence of an extra X chromosome in males (47,XXY), results in male infertility due to impaired spermatogenesis and hormonal imbalances. Similarly, structural abnormalities, such as translocations, can disrupt the normal function of gametes and lead to infertility in both sexes[23].

In males, specific chromosomal defects, such as deletions of the Y chromosome, are linked to impaired sperm production and quality. These genetic anomalies are implicated in approximately 30-50% of male infertility cases, highlighting the significant impact of genetic factors[24]. Genetic testing for these abnormalities has become routine in andrology practices, allowing for better diagnosis and management of male infertility.

The genetic basis of infertility is not limited to chromosomal abnormalities; it also encompasses single-gene disorders that can disrupt reproductive function. These disorders may lead to various phenotypes, including hypogonadotropic hypogonadism, which affects hormonal signaling and can result in reduced sperm production[25]. Genes such as CFTR, SPATA16, and others have been associated with infertility, indicating that a diverse range of genetic factors contribute to reproductive health issues[25].

Overall, the genetic mechanisms influencing infertility are multifaceted, with chromosomal abnormalities representing a significant area of concern. The understanding of these genetic factors is essential for developing targeted interventions and treatments for affected individuals, ultimately improving reproductive outcomes[26].

3.2 Genetic Mutations and Their Impact on Reproduction ​

Infertility is a multifaceted condition influenced by various genetic factors, which can manifest through numerous mechanisms. Genetic mutations play a crucial role in the etiology of infertility, affecting both male and female reproductive functions.

In males, infertility often presents as decreased sperm count (azoospermia or oligozoospermia), reduced sperm motility (asthenozoospermia), or a higher incidence of morphologically abnormal sperm (teratozoospermia). Approximately 10-15% of severe male infertility cases are attributed to genetic causes, including chromosomal aberrations and single-gene mutations (Ferlin et al., 2007). Notably, loss-of-function mutations in genes critical for spermatogenesis can lead to conditions such as Yq microdeletions, which disrupt normal sperm production and function. Furthermore, idiopathic male infertility, which constitutes about 30% of total infertility cases, often lacks a clear genetic explanation, underscoring the complexity of spermatogenic regulation (Karimian et al., 2021).

In females, genetic factors account for at least 35% of infertility cases, impacting various processes such as ovarian development, oocyte maturation, and fertilization competence. Genetic abnormalities can include large chromosomal alterations, submicroscopic deletions, and mutations in genes governing hormonal signaling and reproductive organ development (Yatsenko & Rajkovic, 2019). Specific genetic conditions, such as premature ovarian insufficiency (POI) and disorders of sex development (DSD), further illustrate the genetic underpinnings of female infertility. For instance, mutations in the follicle-stimulating hormone receptor (FSHR) gene can lead to dysfunctional ovarian responses, thereby impairing fertility (Levallet et al., 1999).

Recent advancements in high-throughput sequencing technologies have significantly enhanced the identification of infertility-associated genetic mutations. These technologies allow for the discovery of novel mutations linked to various forms of infertility, such as multiple morphological abnormalities of the sperm flagella (MMAF) and early embryonic arrest (Jiao et al., 2021). It has been noted that the majority of our current understanding of infertility derives from knockout mouse models, which help elucidate the functional consequences of specific genetic alterations.

Moreover, the interplay between genetic factors and environmental influences, such as lifestyle choices and exposure to toxins, can exacerbate the risk of infertility. Epigenetic modifications, including DNA methylation and histone modifications, are increasingly recognized as significant contributors to fertility regulation. These epigenetic changes can affect gametogenesis and may be influenced by external factors, potentially leading to infertility (Saftić Martinović et al., 2024).

In summary, genetic mutations exert profound effects on reproductive health through various mechanisms that disrupt normal spermatogenesis and oogenesis. Understanding these genetic factors is crucial for developing effective diagnostic and therapeutic strategies for infertility. As research continues to evolve, it is imperative to integrate genetic findings with clinical practices to enhance fertility outcomes.

4 Anatomical Abnormalities and Infertility ​

4.1 Female Reproductive Tract Anomalies ​

Endometriosis is recognized as the most prevalent cause of infertility in women, and its mechanisms are multifaceted, involving anatomical distortions, endocrine abnormalities, and immune dysfunction. The condition leads to significant anatomical changes within the female reproductive tract, including the formation of adhesions and fibrosis, which can directly impact fertility.

Firstly, alterations in the hypothalamic-pituitary-ovarian axis are observed in individuals with endometriosis, resulting in the secretion of gonadotropins and steroid hormones that adversely affect ovulation and implantation. These hormonal changes can lead to a decline in fertility by disrupting the normal cyclical processes essential for conception [3].

Secondly, the presence of endometriosis is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, leading to elevated serum cortisol and prolactin levels. This dysregulation has implications for stress, depression, and anxiety, which may further complicate reproductive outcomes [3].

The immune system also plays a crucial role in the infertility associated with endometriosis. Abnormal interactions between endometrial cells and the immune system can alter the local microenvironment, resulting in inflammation and epithelial-mesenchymal transition. Activated epithelial cells, stromal cells, and immunocytes produce various chemokines, cytokines, and autoantibodies, creating an unfavorable environment for embryo implantation [3].

Moreover, oxidative stress has been identified as another critical factor affecting fertility in women with endometriosis. An unbalanced redox state, characterized by impaired mitochondrial function and dysregulated lipid metabolism, contributes to a pro-oxidative microenvironment. This condition negatively impacts oocyte quality and the viability of sperm and embryos, thereby predicting challenges in conception [3].

In addition to these mechanisms, endometrial receptivity is another significant factor in infertility. Women with endometriosis often exhibit impaired endometrial function, which can lead to implantation failure. Factors such as hormone imbalance, inflammation, and immunoregulatory dysfunction have been implicated in the altered endometrial environment, further contributing to reproductive challenges [27].

The anatomical abnormalities resulting from endometriosis, including the formation of cysts (endometriomas) and adhesions within the pelvic cavity, can also directly interfere with normal reproductive function. These changes can disrupt the peritoneal fluid and intratubal milieu, impacting fertilization processes and overall fertility outcomes [7].

In summary, the mechanisms underlying infertility in women with endometriosis are complex and multifactorial, involving hormonal imbalances, immune dysfunction, oxidative stress, and anatomical changes within the reproductive tract. A comprehensive understanding of these mechanisms is essential for developing effective strategies for managing endometriosis-related infertility [3][7][27].

4.2 Male Reproductive System Disorders ​

Infertility is a complex condition that affects a significant number of couples globally, with male factors contributing to approximately 20-70% of cases. The mechanisms underlying male infertility are multifactorial, involving anatomical abnormalities, genetic factors, hormonal imbalances, and environmental influences.

Anatomical abnormalities can significantly impede fertility. Conditions affecting sperm production, such as testicular cancer, germ cell aplasia, and varicocele, as well as congenital anomalies affecting the reproductive tract, can obstruct sperm transport. These anatomical issues may result in non-obstructive or obstructive azoospermia, where the absence of sperm in the ejaculate is noted. Imaging techniques, particularly scrotal ultrasonography and magnetic resonance imaging, are critical for identifying such abnormalities and assessing the male reproductive system's integrity[28].

Genetic defects also play a crucial role in male infertility. Approximately 30-50% of infertility cases involve male factor abnormalities, many of which are linked to genetic issues. These can include chromosomal disorders, mutations in genes essential for spermatogenesis, and epigenetic modifications that affect sperm quality and function. The discovery of genetic causes has important implications for assisted reproductive technologies, as these defects can potentially be transmitted to offspring[[pmid:12394759],[pmid:40846510]].

Hormonal imbalances, particularly involving the hypothalamic-pituitary-gonadal axis, can disrupt normal spermatogenesis and testosterone production, leading to infertility. Conditions that affect hormone levels, such as hyperprolactinemia or hypogonadism, can further complicate male fertility[29].

Moreover, environmental factors, including exposure to toxins, lifestyle choices (such as smoking and obesity), and chronic health issues, can adversely affect sperm production and quality. These factors may contribute to oxidative stress, which has been shown to impact oocyte quality and embryo viability, thus influencing fertility outcomes[3].

In summary, the mechanisms of male infertility are diverse, encompassing anatomical, genetic, hormonal, and environmental factors. A thorough understanding of these mechanisms is essential for developing effective diagnostic and therapeutic strategies for managing male infertility. Further research into these areas will continue to enhance the ability to address this prevalent health issue.

5 Environmental and Lifestyle Factors ​

5.1 Impact of Endocrine Disruptors ​

Infertility is a multifaceted condition influenced by a variety of factors, including genetic, hormonal, environmental, and lifestyle elements. Among these, environmental endocrine disruptors (EDCs) have emerged as significant contributors to reproductive health issues, particularly infertility.

EDCs are exogenous chemicals that interfere with hormonal systems and can adversely affect reproductive health in both men and women. They mimic or block hormones and disrupt the normal functioning of the endocrine system, which is critical for reproductive processes. For instance, the exposure to EDCs has been linked to various reproductive disorders, including infertility, endometriosis, and reproductive cancers. Studies indicate that EDCs can cause alterations in the hypothalamic-pituitary-ovarian axis, leading to abnormal hormone secretion that adversely affects ovulation and implantation, thus contributing to fertility decline (Qi et al., 2025) [3].

In female infertility, a study identified five genes significantly associated with infertility risk, among which SULT1B1, MASTL, and TTC39C were linked to increased risk, while ESR1 and AKAP13 exhibited a protective effect. This study also highlighted complex interactions between these genes and key EDCs, such as bisphenol A (BPA) and tetrachlorodibenzodioxin (TCDD), underscoring the intricate molecular mechanisms through which environmental exposures can influence fertility (Hong et al., 2025) [30].

In males, EDCs have been shown to impact sperm quality and fertility. Research indicates that exposure to environmental contaminants, including heavy metals and pesticides, can lead to decreased sperm concentration, motility, and morphological abnormalities, ultimately affecting fertility (Ma et al., 2019) [31]. Furthermore, Leydig cells, which are essential for testosterone production and male reproductive health, are particularly vulnerable to EDCs. These chemicals can induce Leydig cell death and senescence, exacerbating male infertility (Yang et al., 2025) [32].

The mechanisms by which EDCs exert their effects on reproductive health are varied. They can interfere with hormone receptor signaling, disrupt normal hormonal feedback loops, and induce epigenetic changes that affect gene expression related to reproductive functions (Martinović et al., 2024) [4]. Additionally, EDCs may alter the microbiota composition in the reproductive tract, which is crucial for embryo implantation and overall reproductive success (Castellanos-Ruiz et al., 2025) [33].

Overall, the impact of environmental endocrine disruptors on infertility underscores the importance of understanding gene-environment interactions and their implications for reproductive health. This knowledge is vital for developing strategies aimed at mitigating the harmful effects of EDCs and improving reproductive outcomes.

5.2 The Role of Nutrition and Lifestyle Choices ​

Infertility is a multifaceted condition influenced by various environmental and lifestyle factors, including nutrition and specific lifestyle choices. The mechanisms through which these factors impact fertility are complex and involve a range of biological and physiological processes.

Firstly, both male and female fertility can be significantly affected by lifestyle habits such as smoking, alcohol consumption, drug use, and poor dietary choices. For instance, in women, lifestyle factors like excessive caffeine intake, stress, and inadequate physical activity can disrupt hormonal balance and ovulation, leading to infertility. A high-fat diet, in particular, has been shown to negatively affect ovulation and the quality of gametes, which can impair embryo implantation and overall reproductive function [16].

In men, the quality and quantity of sperm are critical determinants of fertility. Factors such as obesity, smoking, and exposure to environmental toxins can adversely affect spermatogenesis. Studies indicate that oxidative stress, inflammation, and endocrine disruption due to lifestyle choices and environmental exposures can lead to reduced sperm quality [34]. Additionally, psychological stress has been linked to impaired semen quality, further complicating male fertility issues [35].

Nutritional factors also play a crucial role in reproductive health. For example, diets rich in anti-inflammatory nutrients, such as omega-3 polyunsaturated fatty acids, have been associated with improved fertility outcomes in women [36]. The Mediterranean diet, characterized by high consumption of fruits, vegetables, whole grains, and healthy fats, has been shown to positively influence reproductive health by improving ovulatory function and hormonal balance [37].

Moreover, epigenetic mechanisms are increasingly recognized as important in understanding how environmental factors and lifestyle choices can lead to infertility. Epigenetic modifications, such as DNA methylation and histone modification, can be influenced by dietary habits and stress, potentially affecting gene expression related to reproductive functions [4].

Overall, the interplay between lifestyle choices, nutritional habits, and environmental exposures creates a complex landscape that influences reproductive health. Addressing these factors through lifestyle modifications, including improved diet and stress management, is essential for enhancing fertility outcomes and mitigating infertility risks [38][39]. Understanding these mechanisms provides valuable insights into potential therapeutic strategies for individuals facing infertility challenges.

6 Psychological Factors and Infertility ​

6.1 Stress and Its Effects on Reproductive Health ​

Infertility is a multifaceted condition influenced by a variety of factors, including psychological stress, which has been shown to significantly affect reproductive health in both men and women. The relationship between stress and infertility has garnered considerable attention in recent research, revealing various mechanisms through which psychological factors may disrupt reproductive function.

Psychological stress can lead to significant physiological changes that adversely impact reproductive health. In men, psychological stress has been associated with delayed spermatogenesis, particularly at the spermatogonia and pachytene phases, resulting in reduced sperm production. A study utilizing single-cell RNA sequencing on testes from stressed rats revealed that stress caused molecular alterations, including the down-regulation of anti-oxidation-related genes and the up-regulation of genes that promote reactive oxygen species (ROS) generation. This increase in ROS levels was linked to reproductive damage through apoptosis or inhibition of testosterone synthesis, highlighting the cellular and molecular mechanisms by which psychological stress disrupts spermatogenesis (Li et al., 2024) [40].

In women, the endometrium plays a crucial role in embryo implantation and the maintenance of early pregnancy. Psychological stress can lead to a nonreceptive endometrium and disturbed maternal-fetal interactions, which may result in infertility characterized by repeated implantation failure and recurrent spontaneous abortion. The exact mechanisms remain unclear, but there is evidence that stress adversely affects female reproductive health, contributing to various reproductive disorders (Wu et al., 2021) [41].

Moreover, stress has been implicated in the regulation of reproductive hormones. For instance, it has been suggested that stress may lead to hormonal dysregulation, particularly through the influence of stress hormones on the hypothalamic-pituitary-gonadal axis. Elevated levels of stress hormones can interfere with the normal secretion of gonadotropins, thereby impacting ovulation and spermatogenesis (Sominsky et al., 2017) [42].

The interplay between stress and infertility is further complicated by environmental factors. Research indicates that various environmental influences, including nutrition and exposure to toxins, can exacerbate the effects of stress on reproductive health. For example, undernutrition or nutritional disorders are often associated with stress, contributing to infertility (Negro-Vilar, 1993) [43]. Additionally, emerging evidence suggests that epigenetic changes induced by environmental factors, including stress, may also play a role in fertility regulation, affecting gametogenesis and leading to infertility (Saftić Martinović et al., 2024) [4].

In conclusion, the mechanisms linking psychological stress to infertility are complex and involve a combination of physiological, hormonal, and epigenetic changes. These findings underscore the importance of addressing psychological factors in the assessment and treatment of infertility, as stress management interventions may improve reproductive outcomes and overall well-being for individuals facing infertility challenges.

6.2 The Psychological Impact of Infertility ​

Infertility is a multifaceted condition influenced by various genetic, environmental, and lifestyle factors. Recent advancements in epigenetics have shed light on the mechanisms that underlie infertility, particularly focusing on DNA methylation, histone modification, and non-coding RNAs. These epigenetic changes play a crucial role in the regulation of fertility, especially during gametogenesis, which encompasses spermatogenesis and oogenesis as distinct processes. The review by Saftić Martinović et al. (2024) emphasizes the significance of understanding these epigenetic contributions to infertility, highlighting how environmental factors such as diet, stress, and exposure to toxins can lead to epigenetic alterations that may result in infertility [4].

While the role of psychological factors in infertility is often discussed, evidence supporting the idea that psychological stress directly interferes with conception is limited. Schover (1997) points out that although infertility is frequently attributed to stress, the more pronounced issue is the stress that infertility itself imposes on patients and their relationships. Recognizing this stress is vital, as primary care physicians can play a crucial role in identifying the psychological burden associated with infertility and facilitating appropriate referrals for psychological support [44].

In addition to the psychological stressors, the biological mechanisms of infertility encompass a range of factors. Trantham (1996) defines infertility as the inability to conceive after one year of unprotected, adequately timed intercourse. The causes can include ovulatory dysfunction, tubal factors, peritoneal factors, uterine factors, and male factors, which can contribute to infertility in up to 40% of couples. Management of infertility typically involves patient education, counseling, and pharmacological therapies such as clomiphene, bromocriptine, and progesterone. For more complex cases, referral to a specialist in infertility is recommended [45].

In summary, the mechanisms of infertility are intricate and encompass both biological and psychological dimensions. The exploration of epigenetic factors offers new insights into the regulation of fertility, while the recognition of the psychological impact of infertility highlights the need for comprehensive care that addresses both the physical and emotional challenges faced by individuals and couples experiencing infertility.

7 Conclusion ​

The exploration of infertility mechanisms reveals a complex interplay of hormonal, genetic, anatomical, environmental, and psychological factors that contribute to this multifaceted condition. Key findings indicate that hormonal dysregulation, particularly within the hypothalamic-pituitary-gonadal axis, plays a crucial role in both male and female infertility. Genetic factors, including chromosomal abnormalities and specific mutations, significantly impact reproductive capabilities, highlighting the need for genetic screening in infertility evaluations. Anatomical abnormalities, such as those caused by endometriosis and congenital malformations, further complicate fertility outcomes. Environmental factors, particularly exposure to endocrine disruptors and lifestyle choices, have been shown to adversely affect reproductive health, necessitating a holistic approach to infertility treatment. Psychological factors, including stress and emotional well-being, are increasingly recognized as significant contributors to infertility, underscoring the importance of integrated care that addresses both physical and mental health. Future research should focus on elucidating the interactions between these diverse factors and developing personalized interventions that enhance reproductive health outcomes for affected individuals and couples.

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