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POI Culprit Is POSSIBLY Gene Mutation: A Literature Review

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02 June 2024

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03 June 2024

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Abstract
This review article delves into the multifaceted nature of primary ovarian insufficiency (POI), a condition marked by diminished ovarian function before age 40, underscoring the complexity of its aetiology encompassing genetic, autoimmune, infectious, and environmental factors. A significant focus is placed on the potential role of single-gene mutations, such as those in FMR1, BMP15, and GDF9, in the pathogenesis of POI, highlighting the intricate interplay between genetics and ovarian health. The article also explores innovative therapeutic avenues, including the activation of dormant follicles in vitro, offering hope for fertility restoration in affected individuals. Despite the prevalence of traditional treatments, such as Chinese medicine and hormone therapy, in China, these approaches often need to meet therapeutic needs, underscoring the urgency for advanced research and tailored treatment strategies. The discovery of a pituitary tumour-associated POI case further complicates the diagnostic landscape, suggesting a broader diagnostic lens and more in-depth research to unravel the complex underpinnings of POI and enhance patient care.
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Subject: Medicine and Pharmacology  -   Obstetrics and Gynaecology

Introduction

Primary ovarian insufficiency (POI) is a complex condition characterised by diminished ovarian function before the age of 40, causing symptoms such as irregular menstruation or amenorrhea, and has profound implications for fertility and overall health [1]. The prevalence of POI in Finland aged 15-19 has increased from 7‰ to 10‰ [1]. These symptoms affect at least 17.4 million women worldwide [2], and these young women suffering from irregular menstruation seldom regularly go to the hospital for female reproductive health evaluation. According to the group diagnosed with menstrual disorders, this group has gradually begun to affect young people since 2007 [2]. For young people who come suddenly with irregular menstruation or amenorrhea as the main complaint, clinicians will let their guard down on the grounds of youth. A cohort study showed that women under 45 years old had a higher mortality rate with POI than those over 45 years old, and the mortality rate for POI (37.1%) was almost 18% higher than the mortality rate for non-POI (19.3%) [3]. The global prevalence of POI suggests a significant public health concern, affecting approximately 1% of women under 40 and 0.1% under 30 [4]. The onset of POI is often insidious, causing delayed diagnosis and management. Early detection and intervention are crucial, as POI not only impacts reproductive health but is also associated with increased risks of osteoporosis, cardiovascular diseases, and psychological distress [5]. This statistic underscores the importance of early diagnosis and effective management strategies for affected individuals.
Genetic factors are pivotal in the pathogenesis of POI, with various gene mutations implicated in its development. Notably, mutations in the FMR1 gene, which causes Fragile X syndrome when fully mutated, are linked to POI in its premutation state [6]. Other genes, such as bone morphogenic protein 15 (BMP15), GDF9, and FOXL2, have also been associated with POI, pointing to the role of these genes in folliculogenesis and ovarian function [7,8]. The genetic landscape of POI suggests a heterogeneity of causes, necessitating personalised approaches to diagnosis and treatment and highlighting the importance of genetic testing.
Beyond genetics, autoimmune disorders represent a significant etiological factor, with autoantibodies targeting ovarian tissue, leading to follicular damage and impaired steroidogenesis [9]. The interplay between genetic predisposition and autoimmune processes highlights the complexity of POI pathophysiology.
Lifestyle factors, including smoking, drinking, low energy diet and environmental factors, such as chemotherapy and radiation, also contribute to the risk of developing POI [10]. Understanding these risk factors is essential for preventing or delaying the onset of POI in susceptible individuals.
The diagnosis of POI involves a combination of clinical presentation, elevated gonadotropin levels, and reduced ovarian reserve, as indicated by low anti-Müllerian hormone levels or diminished antral follicle count [11]. However, the approach to diagnosis must be comprehensive, considering the potential underlying causes, including genetic mutations and autoimmune conditions. Genetic testing, particularly for known POI-associated mutations, can provide invaluable insights into the aetiology and guide management decisions.
Effective management of POI requires a multifaceted approach, addressing not only the hormonal deficiencies and infertility but also the long-term health risks associated with the condition. Hormone replacement therapy (HRT) is standard for alleviating menopausal symptoms and reducing the risk of osteoporosis. At the same time, fertility treatment options may include assisted reproductive technologies, with the use of donor oocytes being an option for women with severely diminished ovarian reserve [12].
For clinicians encountering young patients with irregular menstruation or amenorrhea, a thorough evaluation is imperative. Beyond assessing the restoration of menstruation, clinicians should consider genetic testing and evaluate for autoimmune disorders, lifestyle factors, and other potential causes of POI. This comprehensive approach can significantly improve treatment outcomes and quality of life for those affected by this condition.
This review aims to provide a comprehensive overview of the current knowledge on POI, emphasising the importance of a personalised approach to care and the need for ongoing research to unravel the complexities of this condition.

Methods

1. Search Strategy and Selection Criteria

The search strategy for this literature review identified studies investigating the genetic underpinnings of POI. Databases such as PubMed, Scopus, Web of Science, and Google Scholar were utilised, targeting publications up to 2024. Keywords used in the search included “primary ovarian insufficiency,” “POI,” “gene mutations,” “genetic basis of POI,” and related terms. Our selection criteria emphasised articles significantly contributing to understanding the genetics, pathophysiology, and therapeutic interventions relevant to POI. The inclusion of studies was determined based on their provision of substantial genetic evidence, elucidation of disease mechanisms, or presentation of novel treatment modalities.

2. Data Extraction and Analysis

Essential information was systematically gathered regarding genetic mutations, associated pathophysiological mechanisms, and potential or existing treatment strategies. The analysis focused on synthesising these findings to identify common genetic factors implicated in POI, the impact of these mutations on ovarian function, and the effectiveness of various therapeutic approaches. The selection process was meticulously documented to ensure reproducibility and to provide a comprehensive overview of the current state of research in the field, including epidemiological data [1], clinical management strategies [2,13], genetic correlations [7,14], and cutting-edge treatments [15,16].

Results

1. POI Overview

POI Patients present with amenorrhea induced by metabolic disorders and mental abnormalities (Figure 1). However, only hormonal disturbances occur in mild cases, such as elevated gonadotropins. Studies have shown that rare chromosomal mutations can cause POI [17]. A good selection of POI treatment during the first phase of the POI process prevents the deterioration of the patient’s quality of life, reduces the risk of long-term sequelae due to the disease and improves fertility [18].
According to epidemiological statistics, the prevalence of POI among people under 20 years old is 0.1% [1]. However, the incidence rises sharply to 4.8% in females under 40 [15], while average women will experience menopause at 50-52 [2], standing for the decline of ovarian function in women. The incidence of POI increases with age and presents a younger trend.
Recent medical technology has focused on improving survival for women with POI [5]. However, researchers have not paid enough attention to supporting short-term quality of life and avoiding long-term sequelae of premature menopause [13]. The care plan for patients with POI should be multifaceted and include counselling, suggestions on diet and nutritional supplementation, different therapeutic approaches, reproductive healthcare, and mental support [19].
Although there is no specific treatment for POI patients, POI treatment options vary globally, with a blend of traditional Chinese medicine (TCM) in China, including acupuncture and Kuntai capsules, and Western approaches in Europe, such as HRT, oocyte or embryo donation, ovarian tissue cryopreservation, and stem cell therapy [13,20]. Oocyte or embryo donation is commonly recommended for POI patients due to the dormancy of their oocytes, making in vitro fertilisation (IVF) unsuitable [21]. Recently, In Vitro Activation (IVA) has emerged as a promising technique by employing physical and chemical methods to activate dormant follicles, potentially enabling them to develop into mature follicles [15]. Research has primarily concentrated on the phosphatidylinositol-3-kinase (PI3K) signalling pathway among the fundamental mechanisms for activating primordial follicles, alongside the Hippo and Mammalian Target of Rapamycin (mTOR) pathways [22]. Despite its potential, IVA research and application still need to be improved in China. With the clinical needs and the deepening of related mechanism research, it is helpful to summarise IVA's treatment mechanism and methods systematically. The diagnosis and management strategies in Europe and the US contrast the TCM prevalent in China, indicating a significant need to bridge the treatment gap for POI patients.

2. Activating the Mechanism of Dormant Follicles

2.1. pfGCs’ Function

Primordial Follicle Granulosa Cells (pfGCs) are essential components of primordial follicles, which remain quiescent until they are activated to develop into primary follicles. The interaction between pfGCs and oocytes via paracrine signalling is pivotal for follicle activation. Recent studies have highlighted the critical role of the mTOR pathway in pfGCs, where the activation of mTORC1 in these cells stimulates the production and secretion of growth factors that promote oocyte activation and follicular development [23]. Moreover, the mTOR1-KIT ligand (KITL) signalling pathway has been identified as a critical mediator in the communication between pfGCs and dormant oocytes, triggering the progression of oocytes from dormancy to active development into primordial follicles [22].

2.2. PI3K Pathway

The PI3K pathway plays a crucial role in the activation of primordial follicles. The proto-oncogene KIT, encoding a tyrosine kinase receptor, interacts with its ligands to stimulate PI3K activity. This activation leads to the phosphorylation of PIP2 into PIP3, which then activates PDK1 and AKT (Figure 2). AKT phosphorylation results in the nuclear exclusion and degradation of the dormancy factor FOXO3a, thereby promoting the activation of basal follicles [24,25]. PTEN is a feedback inhibitor, dephosphorylating PIP3 back to PIP2 and regulating the pathway's activity. This mechanism's significance in follicle activation has been demonstrated through gene knockout studies in mice, highlighting the essential role of the PI3K/PTEN/AKT/FOXO3a pathway [24].

2.3. mTOR Pathway

The mammalian target of the rapamycin (mTOR) pathway, especially mTORC1, found in granulosa cells, is pivotal for cell growth and the activation of primordial follicles. AKT-mediated inhibition of the TSC complex leads to mTORC1 activation, phosphorylating S6K1 and rps6, stimulating ribosome production in primary oocytes [25]. This sequence of events promotes the development of primordial follicles [25]. The mTOR1-KIT ligand (KITL) signalling pathway plays a critical role in signalling from primordial granulosa cells (pfGCs) to dormant primary oocytes, encouraging their development into primordial follicles (Figure 2).

2.4. Hippo Pathway

The Hippo signalling pathway inhibits tissue overgrowth and controls tissue organ size, homeostasis, and regeneration by regulating cell proliferation and apoptosis [16]. In the ovary, the disruption of Hippo signalling in pfGCs leads to the dephosphorylation and nuclear translocation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), transcriptional coactivators that promote the expression of growth factors and genes involved in cell proliferation and survival [26].
Mature pfGCs send signals to primary oocytes through the mTORC1-KITL pathway, and then primary oocytes secrete growth differentiation factor 9 (GDF9) and bone morphogenic protein 15 (BMP15) [7]. These two proteins can combine with YAP in pfGCs to promote the phosphorylation of SMAD2/3 protein [26]. The phosphorylated SMAD2/3 protein combines with SMAD4 and YAP to form a complex and enter the nucleus, thereby enabling the maturation of pfGCs and the activation and development of dormant follicles [24]. The interplay between the Hippo pathway and other signalling pathways, such as the PI3K and mTOR pathways, illustrates the complexity of the regulatory network governing follicular activation and highlights potential therapeutic targets for POI treatment.

3. Underlying Genetic Mechanism

The genesis of POI is multifaceted, involving a combination of genetic predispositions, environmental factors, and possibly lifestyle choices, which contribute to the premature depletion or dysfunction of ovarian follicles.
Emerging research underscores the significant role of single-gene mutations in developing POI. For instance, mutations in genes like BMP15, DIAPH2, and INHA have been implicated in the condition, suggesting a genetic basis for at least a subset of POI cases [7]. Moreover, structural chromosomal abnormalities, particularly involving the X chromosome, have been identified as another critical factor contributing to POI [24]. This factor is further corroborated by studies demonstrating that specific genotypic profiles, such as a 46, XX karyotype, are associated with an increased risk of developing POI in individuals with concurrent emotional disorders [24].
The impact of gene mutations extends beyond the mere occurrence of POI to influence the clinical presentation and management of affected individuals. Nelson highlighted a case of POI induced by external stressors such as contraceptives and work pressure in a 30-year-old woman, illustrating the complex interplay between genetic predispositions and environmental factors [5]. Furthermore, specific mutations in essential regulatory genes can significantly influence the clinical manifestations of POI. For example, NR5A1, a pivotal gene in the hypothalamic-pituitary-steroidogenic axis, has been linked to POI when mutated. Mutations at codon 222 (c.666delC) of the NR5A1 gene can lead to a loss of secondary sexual characteristics and gonadal tissue fibrosis, as observed under light microscopy [18,27]. Similarly, the c.877G→A mutation in NR5A1 may result in pronounced masculinisation features due to abnormal p. Asp293Asn amino acid function in metabolism [18].
Interestingly, mutations in the NR5A1 gene, such as c.390delG, can lead to a highly masculinised appearance in individuals with 46, XX POI, highlighting the gene’s role in sexual differentiation and reproductive organ development [28]. Additionally, research by Dr Zhe has identified HFM1 mutations, such as c.1686-1 G→C and c.2651 T→G, as contributors to recessive forms of POI, suggesting a broader genetic landscape influencing this condition [29].
Recent studies have also focused on the molecular mechanisms underpinning POI, with particular attention to genes involved in DNA repair and ovarian follicle activation. For instance, BRCA2, known primarily for its role in breast and ovarian cancer predisposition, has been implicated in ovarian development and function. Dr Weinberg-Shukron’s work highlights the essential role of BRCA2 in ovarian health, where mutations like c.7579delG can lead to POI, underscoring the critical need for genetic screening in individuals with unexplained primary amenorrhea [30,31].
Lifestyle influences, including stress, weight fluctuations, and exercise levels, have been recognised for impacting the hypothalamic-pituitary-ovarian axis, leading to conditions like functional hypothalamic amenorrhea [32]. Due to the lack of genetic testing, only characteristic variables were shown in serum hormone levels: low oestradiol levels, soft or low to normal levels of luteinising hormone and follicle-stimulating hormone, gonadotropins remained unchanged in response to GnRH stimulation change [33]. This condition underscores the interaction between environmental factors and genetic predispositions, where stress-induced alterations in hormone levels can exacerbate the underlying genetic susceptibility to POI [34].
The autoimmune-associated endocrine syndrome is another perspective that explains POI. Thanks to the rapid development of single genes, genetic testing and autoantibody analysis only require simple high-throughput DNA sequencing to obtain results [35]. For POIs who come to the outpatient clinic for consultation, having a team of endocrinology, obstetrics, and gynaecology experts who specialise in endocrinology and hormones records the consultation history is best and follow-up patients individually according to the differences in disease data [35]. Autoantibody-related screening should also be considered to assess the risk of diseases that cannot be explained by common blood test evidence, even if these tests are expensive. With the development of genomics and pathology, more early-stage lesions can be diagnosed individually through refined immunopathology and single genes to achieve early treatment [35].
Medical staff should adopt a comprehensive approach to preserving reproductive function and treating diseases in patients with POI. Except for cancers induced by BRCA2 gene mutations, all others can utilise genetic information to launch rebirth through assisted reproductive technology. In vitro follicle maturation techniques have shown promise in helping POI patients achieve oocyte maturation, even though preserving patient fertility is technically challenging. Over the past 15 years, in vitro follicle maturation technology has undergone significant advancement and is now undergoing clinical trials in Europe and the United States, demonstrating positive results in animal experiments. This technology holds potential for female cancer patients and those with POI. Although the success rate of in vitro follicle maturation technology is low, it poses fewer risks and provides a novel assisted reproductive technology option that can benefit POI patients [36]. The goal in treating POI is to develop fertility-sparing methods that allow patients a range of options linked to a multidisciplinary treatment plan until complete disease recovery or fertility needs are met [36].

4. The Role of Ovarian Laparoscopic Biopsy in POI Diagnosis and Research

In the context of diagnosing and investigating POI, ovarian laparoscopic biopsy stands out as a pivotal procedure. This minimally invasive technique involves extracting a small ovarian tissue sample for subsequent histopathological and genetic analysis, offering profound insights into the condition’s underlying mechanisms [37]. The procedure’s value extends to exploring the ovarian microenvironment, particularly concerning growth factors and gene expression crucial for ovarian functionality.
Research utilising ovarian laparoscopic biopsy has illuminated alterations in gene expression related to growth factors, providing a clearer understanding of the pathophysiological pathways leading to POI [38]. Moreover, this approach facilitates the identification of specific gene mutations or dysregulations directly within ovarian tissue, offering a more nuanced view of the genetic landscape associated with POI [38].
Ovarian laparoscopic biopsy contributes significantly to the development of targeted therapies and personalised treatment strategies for POI by enabling a direct examination of gene expression patterns and the detection of novel genetic variations [38], which underscores the procedure's indispensable role in the diagnosis and the broader research landscape of POI.

5. Whole Ovary Laparoscopic Incision

In recent years, the Whole Ovary Laparoscopic Incision (WOLI) procedure has emerged as a novel approach to managing POI. This minimally invasive surgical method stimulates ovarian function by enhancing growth factor circulation and potentially altering gene expression within the ovarian microenvironment. According to Dr Sun, the WOLI procedure has been associated with increased serum levels of ovarian growth factors, such as VEGF and GDF-9, which are crucial for follicular development and ovarian function [39]. Furthermore, Dr Chang reported preliminary findings suggesting that WOLI may induce changes in ovarian gene expression, contributing to improved follicular response in POI patients [40]. These studies indicate that while WOLI represents a promising avenue for POI treatment, further research is necessary to understand its mechanisms and long-term efficacy fully.

Discussion

1. Key Gene Mutations

POI is a multifactorial syndrome with genetic mutations playing a critical role. Studies have identified mutations in the FOXL2 gene, which are associated with blepharophimosis-ptosis-epicanthus inversus syndrome and POI [8]. FMR1 premutation is the most known genetic cause of POI, leading to Fragile X Associated Primary Ovarian Insufficiency (FXPOI) [6]. The genetic landscape of POI is complex, with numerous other genes implicated in its pathogenesis [7].

2. Genetic Testing and Implications

Genetic testing for POI is essential for early diagnosis and management and counselling regarding familial risk [1]. Identifying specific mutations can inform personalised treatment strategies and provide insight into the potential for associated conditions, such as autoimmune disorders [9].

3. Limitations

Genetic testing for POI still has limitations. Many cases remain idiopathic, with no identifiable genetic cause [5]. Moreover, the relationship between genotype and phenotype is not always clear, complicating the interpretation of genetic results [4].

4. Future Directions

Future research should focus on uncovering additional genetic factors and their interactions with environmental and lifestyle influences [10]. Longitudinal studies are necessary to understand the natural history of POI and its association with mortality [3]. Furthermore, developing novel biomarkers, such as AMH, may improve the prediction and diagnosis of POI [11]. Ultimately, a better understanding of the genetic basis of POI will enhance our ability to prevent and treat this condition [12].

5. Conclusion

In conclusion, this review underscores the significant role of gene mutations in the aetiology of POI, highlighting the intricate genetic landscape that underpins this condition. Identifying key mutations, such as those in the FOXL2 and FMR1 genes, has shed light on the genetic mechanisms contributing to POI, offering new avenues for diagnosis, management, and familial risk assessment. Despite these advances, the genetic basis of POI still needs to be understood, with many cases eluding explicit genetic characterisation. This gap underscores the necessity for continued research into the genetic underpinnings of POI, including exploring novel genetic contributors and the complex interplay between genetic predispositions and environmental or lifestyle factors.
Pursuing a deeper understanding of POI’s genetic architecture is not merely academic; it holds tangible implications for affected individuals. Enhanced genetic insights promise to refine diagnostic accuracy, facilitate early intervention, and enable personalised treatment approaches. While therapeutic strategies such as IVA and WOLI represent significant advancements in managing POI, the core of our efforts must remain focused on elucidating the genetic origins of this condition. By prioritising genetic research in POI, researchers pave the way for breakthroughs that could transform the prognosis for individuals grappling with this challenging diagnosis, moving closer to a future where POI can be effectively predicted, prevented, or even reversed.

Conflicts of Interest:

The authors declare no competing interests.

References

  1. Silvén H, Savukoski SM, Pesonen P, Pukkala E, Gissler M, Suvanto E, et al. Incidence and familial risk of premature ovarian insufficiency in the Finnish female population. Hum Reprod. 2022;37(5):1030-6. [CrossRef]
  2. Saadedine M, Kapoor E, Shufelt C. Functional Hypothalamic Amenorrhea: Recognition and Management of a Challenging Diagnosis. Mayo Clin Proc. 2023;98(9):1376-85.
  3. Blümel JE, Mezones-Holguín E, Chedraui P, Soto-Becerra P, Arteaga E, Vallejo MS. Is premature ovarian insufficiency associated with mortality? A three-decade follow-up cohort. Maturitas. 2022;163:82-7.
  4. Schmidt PJ, Luff JA, Haq NA, Vanderhoof VH, Koziol DE, Calis KA, et al. Depression in Women with Spontaneous 46, XX Primary Ovarian Insufficiency. The journal of clinical endocrinology and metabolism. 2011;96(2):E278-E87.
  5. Nelson, LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606-14. [CrossRef]
  6. Fink DA, Nelson LM, Pyeritz R, Johnson J, Sherman SL, Cohen Y, et al. Fragile X Associated Primary Ovarian Insufficiency (FXPOI): Case Report and Literature Review. Frontiers in genetics. 2018;9:529-.
  7. Qin Y, Jiao X, Simpson JL, Chen ZJ. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015;21(6):787-808.
  8. Yang XW, He WB, Gong F, Li W, Li XR, Zhong CG, et al. Novel FOXL2 mutations cause blepharophimosis-ptosis-epicanthus inversus syndrome with premature ovarian insufficiency. Molecular genetics & genomic medicine. 2018;6(2):261-7.
  9. Bakalov VK, Gutin L, Cheng CM, Zhou J, Sheth P, Shah K, et al. Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency. Journal of autoimmunity. 2012;38(4):315-21.
  10. Yang Y, Huang W, Yuan L. Effects of Environment and Lifestyle Factors on Premature Ovarian Failure. Environment and Female Reproductive Health. 2021:63-111.
  11. Cameron DA, Anderson R, Clatot F, Demeestere I, Lambertini M, Nelson SM, et al. Anti-Müllerian hormone (AMH) as a marker of ovarian reserve and premature ovarian insufficiency (POI) in children and women with cancer: A systematic review. Journal of clinical oncology. 2021;39(15_suppl):e24057-e. [CrossRef]
  12. Iliodromiti S, Iglesias Sanchez C, Messow C-M, Cruz M, Garcia Velasco J, Nelson SM. Excessive Age-Related Decline in Functional Ovarian Reserve in Infertile Women: Prospective Cohort of 15,500 Women. The journal of clinical endocrinology and metabolism. 2016;101(9):3548-54.
  13. Panay N, Kalu E. Management of premature ovarian failure. Best Pract Res Clin Obstet Gynaecol. 2009;23(1):129-40.
  14. Lourenço D, Brauner R, Lin L, De Perdigo A, Weryha G, Muresan M, et al. Mutations in NR5A1 Associated with Ovarian Insufficiency. The New England journal of medicine. 2009;360(12):1200-10.
  15. Kawamura K, Kawamura N, Hsueh AJ. Activation of dormant follicles: a new treatment for premature ovarian failure? Curr Opin Obstet Gynecol. 2016;28(3):217-22. [CrossRef]
  16. Li Z, Zhang M, Zheng J, Tian Y, Zhang H, Tan Y, et al. Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Improve Ovarian Function and Proliferation of Premature Ovarian Insufficiency by Regulating the Hippo Signaling Pathway. Frontiers in endocrinology (Lausanne). 2021;12:711902-.
  17. Vujovic, S. Aetiology of premature ovarian failure. Menopause Int. 2009;15(2):72-5. [CrossRef]
  18. Panay, N. Progress in understanding and management of premature ovarian insufficiency. Climacteric. 2021;24(5):423-4.
  19. Kalu E, Panay N. Spontaneous premature ovarian failure: management challenges. Gynecol Endocrinol. 2008;24(5):273-9.
  20. Liu FX, Sun Y. Identification of the active ingredients and pharmacological effects of Kuntai capsules in the treatment of primary ovarian insufficiency: A review. Medicine (Baltimore). 2023;102(21):e33884.
  21. De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet. 2010;376(9744):911-21.
  22. Takeuchi A, Koga K, Satake E, Makabe T, Taguchi A, Miyashita M, et al. Endometriosis Triggers Excessive Activation of Primordial Follicles via PI3K-PTEN-Akt-Foxo3 Pathway. J Clin Endocrinol Metab. 2019;104(11):5547-54.
  23. Ernst EH, Grøndahl ML, Grund S, Hardy K, Heuck A, Sunde L, et al. Dormancy and activation of human oocytes from primordial and primary follicles: molecular clues to oocyte regulation. Human reproduction (Oxford). 2017;32(8):1684-700.
  24. Li J, Kawamura K, Cheng Y, Liu S, Klein C, Liu S, et al. Activation of dormant ovarian follicles to generate mature eggs. Proc Natl Acad Sci U S A. 2010;107(22):10280-4.
  25. Ersahin T, Tuncbag N, Cetin-Atalay R. The PI3K/AKT/mTOR interactive pathway. Mol Biosyst. 2015;11(7):1946-54.
  26. Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proceedings of the National Academy of Sciences - PNAS. 2013;110(43):17474-9.
  27. Fabbri-Scallet H, Werner R, Guaragna MS, de Andrade JGR, Maciel-Guerra AT, Hornig NC, et al. Can Non-Coding NR5A1 Gene Variants Explain Phenotypes of Disorders of Sex Development? Sex Dev. 2022;16(4):252-60.
  28. Allali S, Muller JB, Brauner R, Lourenço D, Boudjenah R, Karageorgou V, et al. Mutation analysis of NR5A1 encoding steroidogenic factor 1 in 77 patients with 46, XY disorders of sex development (DSD) including hypospadias. PLoS One. 2011;6(10):e24117.
  29. Zhe J, Chen S, Chen X, Liu Y, Li Y, Zhou X, et al. A novel heterozygous splice-altering mutation in HFM1 may be a cause of premature ovarian insufficiency. J Ovarian Res. 2019;12(1):61.
  30. Weinberg-Shukron A, Rachmiel M, Renbaum P, Gulsuner S, Walsh T, Lobel O, et al. Essential Role of BRCA2 in Ovarian Development and Function. The New England journal of medicine. 2018;379(11):1042-9.
  31. Ludman MD, Philipsborn SL, Hartmajer S, Shwartzman NS, Reinstein E. Recurring pathogenic variants in the BRCA2 gene in the Ethiopian Jewish population. Founder mutations? Fam Cancer. 2022;21(2):121-3.
  32. Kimball A, Sertic M, Saylor PJ, Kamran SC, Boyraz B. Case 38-2022: A 21-Year-Old Woman with Fatigue and Weight Gain. The New England journal of medicine. 2022;387(24):2269-77.
  33. Germain N, Fauconnier A, Klein JP, Wargny A, Khalfallah Y, Papastathi-Boureau C, et al. Pulsatile gonadotropin-releasing hormone therapy in persistent amenorrheic weight-recovered anorexia nervosa patients. Fertil Steril. 2017;107(2):502-9.
  34. Yoshiji S, Shibue K, Fujii T, Usui T, Hirota K, Taura D, et al. Chronic primary adrenal insufficiency after unilateral adrenonephrectomy: A case report. Medicine (Baltimore). 2017;96(51):e9091.
  35. Huhtaniemi I, Hovatta O, La Marca A, Livera G, Monniaux D, Persani L, et al. Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency. Trends Endocrinol Metab. 2018;29(6):400-19.
  36. Machura P, Grymowicz M, Rudnicka E, Pięta W, Calik-Ksepka A, Skórska J, et al. Premature ovarian insufficiency - hormone replacement therapy and management of long-term consequences. Prz Menopauzalny. 2018;17(3):135-8.
  37. Zhang X, Han T, Yan L, Jiao X, Qin Y, Chen Z-J. Resumption of Ovarian Function After Ovarian Biopsy/Scratch in Patients With Premature Ovarian Insufficiency. Reproductive sciences (Thousand Oaks, Calif). 2019;26(2):207-13.
  38. Heddar A, Ogur C, Da Costa S, Braham I, Billaud-Rist L, Findikli N, et al. Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine. EBioMedicine. 2022;84:104246-.
  39. Sun TC, Guo YM, Li DM, Wen YJ, Jiao ZX, Li J, et al. Plasma-derived from human umbilical cord blood restores ovarian function and improves serum reproductive hormones levels in mice with premature ovarian insufficiency (POI) through cytokines and growth factors. Molecular reproduction and development. 2024;91(2):e23731-n/a.
  40. Chang, CL. Facilitation of Ovarian Response by Mechanical Force—Latest Insight on Fertility Improvement in Women with Poor Ovarian Response or Primary Ovarian Insufficiency. International journal of molecular sciences. 2023;24(19):14751.
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Figure 1. shows risk factors in the POI cycle by drawing Fig (in another file).
Figure 1. shows risk factors in the POI cycle by drawing Fig (in another file).
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Figure 2. Shows POI mechanisms involved in the PI3K and mTOR pathways, as shown in Fig Draw (in another file).
Figure 2. Shows POI mechanisms involved in the PI3K and mTOR pathways, as shown in Fig Draw (in another file).
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