Genetic Regulation of Physiological Reproductive Lifespan and Female Fertility

McGrath, Isabelle M; Mortlock, Sally; Montgomery, Grant W.

doi:10.3390/ijms22052556

Cited by 26 publications

(24 citation statements)

References 92 publications

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“…Thus, the indicator of the contribution of hereditary factors to the development of endometriosis, obtained on the basis of known GWAS-significant polymorphisms (≈5%), is almost 10 times less than the similar indicator obtained from the twin-based data (47%). These data demonstrate that at this moment, it is clear that genetic factors have a great impact on this trait, and also clear that little is known about specific genetic variants that contribute to the endometriosis variation [11]. Hence, many genetic variants contributing to endometriosis variation have yet to be elicited and further research is needed to understand the genetic complexity underlying endometriosis [11].…”

Section: Introductionmentioning

confidence: 88%

“…These data demonstrate that at this moment, it is clear that genetic factors have a great impact on this trait, and also clear that little is known about specific genetic variants that contribute to the endometriosis variation [11]. Hence, many genetic variants contributing to endometriosis variation have yet to be elicited and further research is needed to understand the genetic complexity underlying endometriosis [11].…”

Section: Introductionmentioning

confidence: 88%

“…The disorder biology is complex (multifactorial), involving multiple hormonal, inflammatory, genetic, immunological and environmental factors as causes [2]. The genetic factors play an important role in endometriosis etiology [6,[8][9][10][11]. A twin-based study showed that genetic influences on the development of endometriosis are quite considerable and amount to 47% [8].…”

Section: Introductionmentioning

confidence: 99%

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Sex Hormone Candidate Gene Polymorphisms Are Associated with Endometriosis

Golovchenko

Aizikovich

Головченко

et al. 2022

IJMS

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The present study was designed to examine whether sex hormone polymorphisms proven by GWAS are associated with endometriosis risk. Unrelated female participants totaling 1376 in number (395 endometriosis patients and 981 controls) were recruited into the study. Nine single-nucleotide polymorphisms (SNPs) which GWAS correlated with circulating levels of sex hormones were genotyped using a TaqMan allelic discrimination assay. FSH-lowering, and LH- and testosterone-heightening polymorphisms of the FSHB promoter (allelic variants A rs11031002 and C rs11031005) exhibit a protective effect for endometriosis (OR = 0.60–0.68). By contrast, the TT haplotype loci that were GWAS correlated with higher FSH levels and lower LH and testosterone concentrations determined an increased risk for endometriosis (OR = 2.03). Endometriosis-involved epistatic interactions were found between eight loci of sex hormone genes (without rs148982377 ZNF789) within twelve genetic simulation models. In silico examination established that 8 disorder-related loci and 80 proxy SNPs are genome variants affecting the expression, splicing, epigenetic and amino acid conformation of the 34 genes which enrich the organic anion transport and secondary carrier transporter pathways. In conclusion, the present study showed that sex hormone polymorphisms proven by GWAS are associated with endometriosis risk and involved in the molecular pathophysiology of the disease due to their functionality.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Sex Hormone Candidate Gene Polymorphisms Are Associated with Endometriosis

Golovchenko

Aizikovich

Головченко

et al. 2022

IJMS

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“…35 Of these genes, the FSHB gene is of particular interest, because the haplotype (genetic region) conferring higher endometriosis risk has also been significantly associated with lower serum testosterone, lower luteinizing hormone, heavier menstruations, shorter menstrual cycles, earlier menarche and earlier menopause, all of which characterize the endometriosis phenotype as noted above. 30,36 This haplotype also confers a lower risk of PCOS. 37 More broadly, Mendelian Randomization analyses using endometriosis GWAS data can be used to help uncover the causal, genetic bases of the clinical correlates of endometriosis.…”

Section: Reduced Androgen Levels As Outcomes Of Genetic and Epigeneti...mentioning

confidence: 99%

Prenatal Origins of Endometriosis Pathology and Pain: Reviewing the Evidence of a Role for Low Testosterone

Crespi¹,

Evans²

2023

JPR

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Endometriosis is a polygenic, estrogen-dependent, inflammatory disorder of uncertain aetiology associated with pain, infertility and reduced quality of life. While the positive association between endometriosis and estrogen is established, a suite of recent studies has demonstrated an inverse association between the presence of endometriosis lesions and levels of testosterone both prenatally and postnatally. The following narrative review provides new insights into the roles of testosterone in the aetiology, diagnosis, and management of endometriosis and associated symptoms, especially pain. A relatively short anogenital distance (AGD) is indicative of lower levels of testosterone during fetal development. A shorter AGD has recently been correlated with both a higher risk of developing endometriosis in adult life, and with known correlates of endometriosis including earlier onset of reproductive cycling, lower ovarian follicle number, lower postnatal testosterone, and premature ovarian insufficiency. During adult life, lower levels of testosterone are positively associated with key comorbidities of endometriosis, including days per month of pelvic pain and increased pain sensitivity. Biochemically, lower levels of testosterone are associated with higher levels of pro-inflammatory IL-1β and lower levels of β-endorphin. In rodents, prenatal administration of testosterone to females reduces their pain sensitivity in adulthood. The emerging convergent links of endometriosis with low prenatal and postnatal testosterone provide evidence of a centrally mediated effect beginning in early prenatal development, and persisting through adult life, with notable effects on pain sensitivity. They generate a novel conceptual framework for understanding, studying and treating this disorder, whereby endometriosis is mediated by a combination of high estrogen in endometrial tissue with low systemic and ovarian testosterone.

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“…For example, a large scale GWAS has identified a genetic component to age at first birth and number of children with 12 loci including a SNP associated with ESR1 (rs4851269) (Barban et al, 2016). There is also evidence from GWAS studies for a shared genetic risk factors between ovarian ageing and premature ovarian failure (McGrath et al, 2021). A preprint article [https://doi.org/10.1101/401448] which has not yet been peer reviewed reported a GWAS of endometriosis-related infertility, including 2,969 cases and 3,770 controls; they did not confirm genome-wide significance for any SNPs associated with endometriosis-related infertility although they recorded 3 SNPs at or near genes implicated in female fertility in model organisms.…”

Section: Genomic Studies Have Revealed Links Between Endometriosis Reproductive Traits and Other Disordersmentioning

confidence: 99%

Insights Gained from Genomic Studies on the Role of Sex Steroids in the Aetiology of Endometriosis

Saunders¹

2021

Preprint

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Endometriosis is a chronic neuro-inflammatory disorder the defining feature of which is the growth of tissue (lesions) that resembles the endometrium in sites outside the uterus. Estimates of prevalence typically quote rates of ~10% of women of reproductive age, equating to ~190 million women world-wide. Three subtypes of endometriosis are usually considered when discussing the aetiology of the disorder - superficial peritoneal, ovarian (endometrioma cysts), and deep (infiltrating). Genetic, hormonal and immunological factors have all been proposed as contributing to risk factors associated with the development of lesions. Twin studies report the heritable component of endometriosis as ~50%. Genome wide association studies (GWAS) have been conducted allowing unbiased scanning of the genome for single nucleotide polymorphisms (SNPs) in many thousands of individuals. These studies have identified SNPs that appear over-represented in patients with endometriosis, particularly those with more extensive disease (stage III/IV). Amongst the larger scale GWAS there has been replication of SNPs near genes involved in oestrogen and other signalling pathways including ESR1 (oestrogen receptor alpha), GREB1, HOXA10, WNT4 and MAPK kinase signalling. The results from patients with endometriosis have also provided an opportunity to make comparisons with GWAS conducted on other patient cohorts including those with reproductive traits (age at menarche) and disorders (fibroids, endometrial and ovarian cancer) and conditions that are reported by women with endometriosis (migraine, depression). These comparative studies have highlighted some shared genetically-controlled biological mechanisms, including hormone-regulated pathways which might explain the co-occurrence of endometriosis with these disorders. In summary, unbiased genetic analysis has provided new insights into the genetic factors that may contribute to increased risk of developing endometriosis. New studies are needed to broaden the range of patients contributing to these datasets and to improve integration with non-genomic and tissue expression data before their full potential for diagnosis and improvements in patient care can be fully realised.

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Genetic Regulation of Physiological Reproductive Lifespan and Female Fertility

Cited by 26 publications

References 92 publications

Sex Hormone Candidate Gene Polymorphisms Are Associated with Endometriosis

Sex Hormone Candidate Gene Polymorphisms Are Associated with Endometriosis

Prenatal Origins of Endometriosis Pathology and Pain: Reviewing the Evidence of a Role for Low Testosterone

Insights Gained from Genomic Studies on the Role of Sex Steroids in the Aetiology of Endometriosis

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