Estradiol
Introduction
Section titled “Introduction”Estradiol is the most potent and principal form of estrogen, a class of steroid hormones essential for numerous physiological functions in both females and males. While primarily produced by the ovaries in females, it is also synthesized in smaller quantities by the adrenal glands, testes, and other tissues throughout the body.
Biologically, estradiol plays a critical role in the development and maintenance of female reproductive tissues and secondary sexual characteristics. It is fundamental for regulating the menstrual cycle, supporting pregnancy, and maintaining bone density. In males, estradiol contributes to bone health, brain function, and spermatogenesis. Beyond reproductive roles, it influences cardiovascular health, cognitive function, and mood in individuals of all sexes.
The of estradiol levels holds significant clinical relevance for diagnosing and monitoring a wide range of health conditions. These include assessing ovarian function, investigating fertility challenges, determining menopausal status, and managing menstrual irregularities. It is also a crucial biomarker in the evaluation of conditions such as polycystic ovary syndrome (PCOS), precocious or delayed puberty, and certain hormone-sensitive cancers. Estradiol levels are routinely monitored during hormone replacement therapy and in assisted reproductive technologies like in vitro fertilization (IVF).
From a societal standpoint, the understanding and management of estradiol levels have profound implications for public health, reproductive autonomy, and individual well-being. It informs practices related to family planning, contraception, and comprehensive menopausal care. Furthermore, it is a key consideration in gender-affirming hormone therapy and contributes to the ongoing scientific understanding of sex hormone influences across the human lifespan and in diverse health conditions.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The interpretation of genetic associations with estradiol is subject to several methodological and statistical limitations. Mendelian randomization (MR) analyses, while powerful for inferring causality, can be affected by unaddressed heterogeneity among genetic instruments and horizontal pleiotropy, where genetic variants influence the outcome through pathways independent of the exposure.[1] While sensitivity analyses like MR Egger and MR-PRESSO are employed to detect and adjust for these biases, their presence in the data can still lead to inflated or unreliable causal estimates.[2] Furthermore, the use of fixed-effects models in meta-analyses, particularly when heterogeneity is present, can yield biased results.[3] Further statistical considerations include potential sample overlap among the various genome-wide association study (GWAS) datasets utilized, which can artificially inflate the precision of estimates and introduce bias.[4] While primary analyses often apply rigorous multiple testing corrections, exploratory analyses may not, increasing the risk of false-positive findings.[2] Additionally, the imputation of non-genotyped SNPs and gene expression levels introduces a degree of uncertainty and potential error into the analyses, which can affect the accuracy of associations.[3] These factors highlight the need for careful interpretation and validation of findings.
Generalizability and Ancestry Representation
Section titled “Generalizability and Ancestry Representation”A significant limitation in understanding the genetics of estradiol is the predominant reliance on data from individuals of European ancestry. Genetic instrument selection and LD pruning, for instance, are often completed using European population reference panels.[2] Similarly, genetically predicted gene expression analyses, such as those utilizing GTEx samples, are largely derived from European ancestry individuals, which inherently limits the direct applicability and generalizability of findings to non-European populations.[5]This ancestral bias can mask important genetic variations and their effects in diverse populations, potentially leading to an incomplete understanding of estradiol’s genetic architecture across the global population. Although some studies incorporate multi-ancestry analyses, the use of European LD scores for cross-ancestry quality control and underpowered analyses for specific ancestry groups, such as African ancestry, remain challenges.[5] Future research should prioritize the inclusion of more diverse populations and the development of ancestry-specific genetic resources to ensure broader relevance and equitable health outcomes, moving beyond social constructs of “race” towards genetically informed ancestry descriptors.[5]
Phenotypic Characterization and Unaccounted Confounders
Section titled “Phenotypic Characterization and Unaccounted Confounders”The precise characterization of phenotypes and exposures, including estradiol, presents its own set of challenges. While large sample sizes (e.g., n = 206,927 for estradiol instruments) contribute to statistical power.[2]the underlying of estradiol in these broad cohorts may vary, impacting the accuracy of genetic associations. Furthermore, the availability and representation of relevant biological tissues in gene expression models, particularly for female reproductive organs, are often limited, which can restrict the discovery and validation of tissue-specific genetic effects.[5]Beyond genetic factors, a substantial portion of the variability in estradiol levels and its related outcomes may remain unexplained due to missing heritability and unmeasured environmental or gene-environment confounders. Factors such as diet, lifestyle, socioeconomic status, and other exogenous exposures can significantly influence hormone levels and disease risk, yet are often challenging to capture comprehensively in large-scale genetic studies. The interplay between genetic predispositions and these environmental factors represents a crucial knowledge gap, requiring future investigations to integrate richer phenotypic and environmental data to fully elucidate the complex etiology of traits influenced by estradiol.
Variants
Section titled “Variants”Genetic variations play a significant role in individual differences in hormone levels, including estradiol. Several single nucleotide polymorphisms (SNPs) across various genes have been implicated in pathways that directly or indirectly influence estradiol synthesis, metabolism, or regulation. Understanding these variants can provide insights into the genetic underpinnings of endocrine traits.
Variants within or near the CYP19A1 and MIR4713HGgenes are particularly relevant for estradiol. TheCYP19A1gene encodes aromatase, the enzyme responsible for the final step in estrogen biosynthesis, converting androgens into estrogens, including estradiol. Therefore, variations likers7173595 , rs2414095 , rs151006058 , rs28892005 , rs727479 , and rs12591359 in CYP19A1can alter aromatase activity or expression, directly impacting the circulating levels of estradiol.MIR4713HG is a long non-coding RNA (lncRNA) gene, and lncRNAs are known to regulate gene expression, potentially including neighboring genes like CYP19A1. Polymorphisms in MIR4713HG could influence the stability or transcription of CYP19A1mRNA, thereby indirectly affecting aromatase levels and, consequently, estradiol production . Such genetic differences contribute to the variability in estradiol levels observed among individuals, which can have implications for hormone-sensitive conditions.
The immunoglobulin heavy chain variable (IGHV) genes, including IGHV3-7, IGHV3-64D, and IGHV3-6, are essential components of the adaptive immune system, providing diversity to antibodies. While these genes are not directly involved in estradiol synthesis, the immune system and inflammation are intricately linked with endocrine function. Variations such asrs34019140 , rs59839634 , and rs11160915 within these IGHVregions could influence immune responses, potentially affecting systemic inflammation or autoimmune conditions that can, in turn, modulate sex hormone balance and estradiol levels . Similarly,LINC03114 is a long intergenic non-coding RNA, and its variant rs5933688 might play a role in regulating gene expression pathways that indirectly impact metabolic or inflammatory processes, further illustrating the complex interplay between genetics, immunity, and steroid hormones.
Other variants contribute to a broader landscape of genetic influence on endocrine health. The MCM8 gene, involved in DNA replication and repair, contains the variant rs16991615 . Alterations in DNA repair mechanisms can impact cellular integrity and function across various tissues, including those involved in hormone production or metabolism, thereby indirectly affecting estradiol levels. Similarly,HELB (Helicase B) is also critical for DNA replication, and its variant rs75770066 may have similar broad cellular implications . The SRD5A2gene encodes steroid 5-alpha-reductase type 2, an enzyme primarily known for converting testosterone into the more potent dihydrotestosterone; however, its activity can influence the overall steroidogenic pathway and the availability of precursors for estrogen synthesis, with its variantrs112881196 potentially altering this balance. LINC01946 is an lncRNA that might regulate SRD5A2 or other genes in steroid metabolism. Furthermore, TMEM150B (transmembrane protein 150B) with variant rs71181755 and ZNF346 (Zinc Finger Protein 346), a transcription factor with variant rs2454949 , represent genes that, through their roles in cellular transport, signaling, or gene regulation, can exert indirect effects on metabolic and endocrine systems, ultimately influencing the precise and physiological impact of estradiol .
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs7173595 rs2414095 rs151006058 | CYP19A1, MIR4713HG | waist-hip ratio BMI-adjusted waist-hip ratio estradiol osteoporosis Breast hypertrophy |
| rs28892005 rs727479 rs12591359 | MIR4713HG, CYP19A1 | estradiol testosterone bone fracture |
| rs34019140 rs59839634 | IGHV3-7 - IGHV3-64D | estradiol |
| rs5933688 | LINC03114 | androgenetic alopecia estradiol balding testosterone |
| rs11160915 | IGHV3-6 - IGHV3-7 | estradiol |
| rs16991615 | MCM8 | age at menopause uterine fibroid Menorrhagia estradiol breast carcinoma |
| rs112881196 | SRD5A2 - LINC01946 | balding estradiol aging rate etiocholanolone glucuronide X-11444 |
| rs71181755 | TMEM150B | estradiol |
| rs2454949 | ZNF346 | estradiol |
| rs75770066 | HELB | age at menopause estradiol chromosome, telomeric region length follicle stimulating hormone |
Operational Definitions and Contexts
Section titled “Operational Definitions and Contexts”The precise definition and operationalization of hormone measurements are critical in both clinical practice and research, particularly for endocrine traits such as estradiol. While specific details for estradiol are not directly provided, studies consistently apply rigorous methodologies to related endocrine-related traits. For example, analyses of hormones like Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), Thyroid Stimulating Hormone (TSH), and Dehydroepiandrosterone Sulfate (DHEAS) involve extensive multivariable adjustments to ensure accurate interpretation.[6] These adjustments constitute an operational definition of the measured trait, accounting for a range of confounding factors.
These comprehensive adjustments are designed to isolate the true biological signal of the endocrine trait. They include controlling for demographic variables such as age and sex, lifestyle factors like body mass index (BMI) and smoking, and clinical conditions including diabetes, hypertension treatment, and prevalent cardiovascular disease.[6]Furthermore, specific physiological contexts, such as menopausal status and the use of exogenous hormones like thyroid hormone or oral contraceptive pills, are carefully considered and adjusted for or used as exclusion criteria, as seen in the specific analyses for LH and FSH restricted to men and naturally post-menopausal women not on hormone replacement.[6] Such precise operational definitions are fundamental for establishing reliable criteria.
Classification of Physiological States and Analytical Subtypes
Section titled “Classification of Physiological States and Analytical Subtypes”Classification systems are indispensable for contextualizing endocrine measurements, including those relevant to estradiol, by stratifying populations into meaningful analytical subtypes. A primary classification involves physiological states such as menopausal status, which significantly influences hormone profiles. For instance, studies explicitly classify and analyze certain endocrine traits, like LH and FSH, exclusively within populations of “men and post-menopausal women only,” specifically excluding individuals using hormone replacement therapy or oral contraceptive pills.[6]This categorical approach ensures that analyses are conducted within homogenous groups, thereby enhancing the interpretability of hormone levels.
Beyond broad demographic categories, a more granular classification is achieved through multivariable adjustments that define nuanced analytical subtypes. These adjustments incorporate a range of continuous and categorical variables, including systolic and diastolic blood pressure, HDL-cholesterol levels, and alcohol intake.[6] By accounting for these diverse factors, researchers can effectively classify individuals into more precise groups based on their metabolic and clinical characteristics, allowing for a deeper understanding of how these variables interact to influence endocrine trait concentrations.
Terminology and Research Criteria for Endocrine Assessment
Section titled “Terminology and Research Criteria for Endocrine Assessment”Standardized terminology and clearly defined research criteria are essential for the consistent assessment and reporting of endocrine traits, including estradiol. Key terms such as Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), Thyroid Stimulating Hormone (TSH), and Dehydroepiandrosterone Sulfate (DHEAS) form part of the established nomenclature in endocrine research.[6]Research criteria for these endocrine traits are operationalized through comprehensive adjustment models that establish thresholds and cut-off values for interpretation. These criteria incorporate a wide array of covariates, including age, sex, BMI, smoking, diabetes, and prior cardiovascular disease, to define what constitutes a relevant or altered hormone level within a study population.[6]The careful application of such research criteria, alongside considerations of menopausal status and exogenous hormone use, is vital for ensuring the robustness and comparability of findings across different studies investigating endocrine health.
Biological Background of Estradiol
Section titled “Biological Background of Estradiol”Estradiol, the primary and most potent endogenous estrogen, is a critical steroid hormone with wide-ranging effects on human physiology, particularly within the reproductive system, but also extending to bone health, cardiovascular function, and metabolic processes. Its precise regulation and action are fundamental for maintaining homeostasis, and imbalances can lead to various pathophysiological conditions. The of estradiol levels provides crucial insights into reproductive health, endocrine function, and disease risk.
Estradiol Biosynthesis and Endocrine Regulation
Section titled “Estradiol Biosynthesis and Endocrine Regulation”Estradiol is a key biomolecule synthesized primarily in the ovaries in premenopausal women, and in smaller amounts in the adrenal glands, adipose tissue, and other peripheral tissues. Its biosynthesis is a complex molecular pathway involving a series of enzymatic conversions from cholesterol, with androgens serving as immediate precursors. A critical enzyme in this pathway is aromatase, encoded by theCYP19A1 gene, which catalyzes the conversion of androgens into estrogens.[7]The production and secretion of estradiol are tightly regulated by the hypothalamic-pituitary-gonadal (HPG) axis, a complex neuroendocrine regulatory network. For instance, the follicle-stimulating hormone (FSH) plays a pivotal role in accelerating oocyte development, which in turn influences ovarian estrogen production.[8] Disruptions in this delicate endocrine balance, such as mutations in the FSHBgene (encoding the beta-subunit of FSH), can lead to conditions like delayed puberty and hypogonadism.[9]
Molecular Mechanisms of Estradiol Action
Section titled “Molecular Mechanisms of Estradiol Action”At the cellular level, estradiol exerts its biological effects primarily by binding to specific intracellular estrogen receptors (ERs),ESR1(estrogen receptor alpha) andESR2(estrogen receptor beta), which are critical proteins acting as ligand-activated transcription factors.[10]Upon binding, the estradiol-receptor complex translocates to the nucleus, where it interacts with specific DNA sequences, known as estrogen response elements (EREs), to modulate the transcription of target genes. This molecular signaling pathway influences numerous cellular functions, including cell proliferation, differentiation, and apoptosis, thereby regulating diverse physiological processes. For example, the expression of theFOXO1 gene in primary human endometrial stromal cells is regulated by ESR1, illustrating the intricate regulatory networks through which estradiol exerts its influence.[11] Furthermore, other transcription factors like WT1(Wilms tumor 1) can interact with specific genetic variants to influence the expression of genes involved in estradiol-related pathways.[11]
Estradiol’s Role in Tissue Development and Homeostasis
Section titled “Estradiol’s Role in Tissue Development and Homeostasis”Estradiol is fundamental for the normal developmental processes and homeostatic maintenance of various tissues, particularly within the female reproductive system. During puberty, estradiol drives the development of secondary sexual characteristics and maturation of reproductive organs.[12]In the adult menstrual cycle, estradiol promotes the proliferation of the endometrial lining during the follicular phase, preparing the uterus for potential pregnancy.[13]This proliferative effect is crucial for reproductive function, but it must be balanced by other hormones, notably progesterone, which induces glandular and stromal differentiation in the endometrium and counteracts estrogen’s growth-stimulatory effects.[14]Beyond reproductive organs, estrogen also significantly impacts musculoskeletal performance and injury risk.[15]
Pathophysiological Implications of Estradiol Dysregulation
Section titled “Pathophysiological Implications of Estradiol Dysregulation”Disruptions in estradiol levels or its signaling pathways are implicated in several pathophysiological processes and diseases. Prolonged exposure to “unopposed” estrogen, meaning estrogen without sufficient counteracting progesterone, is a significant risk factor for endometrial cancer, as it leads to excessive endometrial mitotic rates and hyperplasia.[16]Progestin therapy can effectively reverse endometrial hyperplasia, highlighting the importance of the estrogen-progesterone balance.[17]Estradiol is also a crucial factor in the development and growth of uterine leiomyomata (fibroids).[11]Additionally, conditions like endometriosis and uterine leiomyomata share common genetic origins and are influenced by hormonal factors.[1]Systemically, estradiol levels are linked to bone health, with endogenous estrogen affecting bone turnover and bone mineral density in postmenopausal women.[18]Obesity is a well-established causal risk factor for endometrial cancer, partly due to altered estrogen metabolism in adipose tissue.[19]Furthermore, circulating estradiol and other sex hormones are relevant to the risk of other cancers, such as breast cancer, where elevated prolactin, insulin, and c-peptide levels are also considered risk factors.[20]
Genetic Influences on Estradiol Pathways and Related Traits
Section titled “Genetic Influences on Estradiol Pathways and Related Traits”Genetic mechanisms play a substantial role in regulating estradiol levels and influencing an individual’s susceptibility to estradiol-related conditions. Genome-wide association studies (GWAS) have identified common genetic variants associated with traits like endometrial cancer.[21]For instance, single nucleotide polymorphisms (SNPs) in genes involved in sex steroid hormone metabolism, such asCYP19A1, have been investigated for their association with endometrial cancer risk.[7] Genetic variants located in regulatory regions, such as rs58415480 and rs71575922 near the ESR1 gene, are strong candidates for regulating ESR1 expression in uterine tissue and are important in the growth of leiomyomas.[11] Another variant, rs117245733 , resides in a regulatory region in uterine tissue and targets the FOXO1 gene, which is regulated by ESR1 in endometrial stromal cells.[11]These genetic predispositions, combined with environmental factors, contribute to the variability in estradiol metabolism and its impact on conditions such as adiposity.[22]The identification of genetic commonalities between uterine leiomyomata and endometriosis further underscores the intricate interplay between genetic background and hormonal pathways.[1]
Genetic Regulation of Estradiol-Related Traits
Section titled “Genetic Regulation of Estradiol-Related Traits”The intricate balance and functional output of endogenous sex hormones, including estradiol, are subject to significant genetic regulation. Genome-wide association studies have elucidated genetic influences on various endocrine-related traits.[6]This indicates that gene regulatory mechanisms play a pivotal role in controlling the physiological processes that determine estradiol levels and activity. Such regulation is fundamental to the overall maintenance of endocrine homeostasis and individual hormonal profiles.
Systemic Integration of Sex Hormones
Section titled “Systemic Integration of Sex Hormones”Estradiol, as a key endogenous sex hormone, participates in extensive systems-level integration throughout the body. Its pathways interact with and influence numerous other biological networks, contributing to a broader hierarchical regulation of physiological functions. This systemic crosstalk is evidenced by research linking endogenous sex hormones to the incidence of cardiovascular disease in men.[23]These broad network interactions underscore estradiol’s multifaceted role beyond its primary endocrine functions.
Pathophysiological Mechanisms and Disease Relevance
Section titled “Pathophysiological Mechanisms and Disease Relevance”Dysregulation within the pathways involving endogenous sex hormones, such as estradiol, can manifest as disease-relevant mechanisms affecting overall health. The observed association between sex hormones and the incidence of cardiovascular disease.[23]highlights how alterations in estradiol signaling or metabolism could contribute to the development or progression of cardiovascular conditions. Understanding these pathway dysregulations is essential for uncovering potential compensatory mechanisms and identifying therapeutic targets for disease management.
Frequently Asked Questions About Estradiol
Section titled “Frequently Asked Questions About Estradiol”These questions address the most important and specific aspects of estradiol based on current genetic research.
1. Could my diet actually change my estradiol levels?
Section titled “1. Could my diet actually change my estradiol levels?”Yes, your diet is one of several environmental factors that can significantly influence your hormone levels. While your genetics contribute to your baseline estradiol, what you eat can interact with these predispositions to affect how your body produces and processes this important hormone. This interplay between diet and genetics is a crucial area of ongoing research.
2. Why do some women struggle with fertility more than others?
Section titled “2. Why do some women struggle with fertility more than others?”Individual differences in hormone levels, including estradiol, are significantly influenced by genetic variations. These genetic factors can contribute to conditions affecting ovarian function or conditions like PCOS, making fertility a greater challenge for some. Your lifestyle and environmental exposures also interact with your genetics to impact reproductive health.
3. Does my ancestry affect my typical estradiol levels?
Section titled “3. Does my ancestry affect my typical estradiol levels?”Yes, your ancestral background can play a role. Much of the research on genetic influences on hormones, including estradiol, has historically focused on individuals of European ancestry. This means important genetic variations and their effects in other populations might be less understood, highlighting the need for more diverse research.
4. Can stress really mess with my hormones, like estradiol?
Section titled “4. Can stress really mess with my hormones, like estradiol?”Absolutely. Stress is a significant environmental factor that can influence your hormone levels. While your genetics provide a baseline for how your body produces and responds to hormones, chronic stress can interact with these predispositions, potentially impacting your mood, menstrual cycle, and overall hormonal balance.
5. If my mom had early menopause, will I too?
Section titled “5. If my mom had early menopause, will I too?”There can be a genetic component to the timing of menopause. While environmental factors and lifestyle choices also play a role, your family history can indicate a predisposition. Understanding these genetic influences helps in assessing your potential menopausal status, though it’s not a definitive prediction.
6. Why are my periods so irregular compared to my friends?
Section titled “6. Why are my periods so irregular compared to my friends?”Individual variations in estradiol levels, often influenced by your unique genetic makeup, can contribute to differences in menstrual regularity. Conditions like Polycystic Ovary Syndrome (PCOS), which has a genetic component, can also lead to irregular periods. Your lifestyle and environment further interact with your genetics to affect your cycle.
7. Does my exercise routine have an impact on my estradiol?
Section titled “7. Does my exercise routine have an impact on my estradiol?”Yes, your lifestyle, including your exercise routine, can influence your hormone levels. While genetics contribute to your body’s baseline, physical activity can interact with your genetic predispositions to affect estradiol production and metabolism. This can impact various aspects of your health, including bone density and reproductive function.
8. I feel moody sometimes; could my estradiol be a factor?
Section titled “8. I feel moody sometimes; could my estradiol be a factor?”Yes, estradiol is known to influence cognitive function and mood in individuals of all sexes. Genetic variations can affect how your body regulates and responds to estradiol, potentially contributing to individual differences in mood stability. Environmental factors and lifestyle also play a role in this complex interaction.
9. Can factors in my environment, like pollution, affect my hormones?
Section titled “9. Can factors in my environment, like pollution, affect my hormones?”Yes, various exogenous exposures in your environment, such as certain chemicals or pollutants, can potentially influence your hormone levels, including estradiol. These environmental factors can interact with your genetic predispositions, creating a complex picture of how your body maintains hormonal balance.
10. Why do some people have stronger bones than others, even in the same family?
Section titled “10. Why do some people have stronger bones than others, even in the same family?”While genetics play a significant role in bone health and density, with estradiol being a key hormone involved, environmental factors and lifestyle choices also contribute. Even within families, individual genetic variations and distinct life habits can lead to differences in bone strength and risk for conditions like osteoporosis.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Gallagher, C. S. et al. “Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.”Nature Communications, 2019.
[2] Sliz, E. et al. “Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata.”Nature Communications, 2023.
[3] Spurdle, A. B. et al. “Genome-wide association study identifies a common variant associated with risk of endometrial cancer.”Nature Genetics, 2011.
[4] Wu, X. et al. “A comprehensive genome-wide cross-trait analysis of sexual factors and uterine leiomyoma.” PLoS Genetics, 2024.
[5] Kim, J. et al. “Genome-wide meta-analysis identifies novel risk loci for uterine fibroids within and across multiple ancestry groups.” Nature Communications, 2024.
[6] Hwang, S. J. “A Genome-Wide Association for Kidney Function and Endocrine-Related Traits in the NHLBI’s Framingham Heart Study.” BMC Medical Genetics, PMID: 17903292.
[7] Setiawan, V. W., et al. “Two estrogen-related variants inCYP19A1and endometrial cancer risk: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium.”Cancer Epidemiology, Biomarkers & Prevention, vol. 18, no. 1, 2009, pp. 242-247.
[8] Demeestere, I., et al. “Follicle-stimulating hormone accelerates mouse oocyte development in vivo.”Biology of Reproduction, vol. 87, no. 4, 2012, pp. 1-11.
[9] Layman, L. C., et al. “Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone beta-subunit gene.”New England Journal of Medicine, vol. 337, no. 9, 1997, pp. 607-611.
[10] Bondesson, M., et al. “Estrogen receptor signaling during vertebrate development.”Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, vol. 1849, no. 2, 2015, pp. 142-151.
[11] Rafnar, T., et al. “Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits.”Nature Communications, vol. 7, 2016, p. 11821.
[12] Wood, C. L., et al. “Puberty: normal physiology (brief overview).” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 33, no. 3, 2019, p. 101265.
[13] Ferenczy, A., et al. “Proliferation kinetics of human endometrium during the normal menstrual cycle.” American Journal of Obstetrics and Gynecology, vol. 133, no. 8, 1979, pp. 859-867.
[14] Clarke, C. L., and R. L. Sutherland. “Progestin regulation of cellular proliferation.” Endocrine Reviews, vol. 11, no. 2, 1990, pp. 266-301.
[15] Chidi-Ogbolu, N., and K. Baar. “Effect of estrogen on musculoskeletal performance and injury risk.”Frontiers in Physiology, vol. 9, 2019, p. 1834.
[16] Key, T. J., and M. C. Pike. “The dose–effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk.”British Journal of Cancer, vol. 57, no. 2, 1988, pp. 205-212.
[17] Ehrlich, C. E., et al. “Cytoplasmic progesterone and estradiol receptors in normal, hyperplastic, and carcinomatous endometria: therapeutic implications.”American Journal of Obstetrics and Gynecology, vol. 141, no. 5, 1981, pp. 539-546.
[18] Huang, A. J., et al. “Endogenous estrogen levels and the effects of ultra-low-dose transdermal estradiol therapy on bone turnover and BMD in postmenopausal women.”Journal of Bone and Mineral Research, vol. 22, no. 11, 2007, pp. 1791-1797.
[19] Masuda, T., et al. “A Mendelian randomization study identified obesity as a causal risk factor of uterine endometrial cancer in Japanese.”Cancer Science, vol. 111, no. 12, 2020, pp. 4646-4651.
[20] Tworoger, S. S., et al. “A prospective study of plasma prolactin concentrations and risk of premenopausal and postmenopausal breast cancer.”Journal of Clinical Oncology, vol. 25, no. 12, 2007, pp. 1482-1498.
[21] De Vivo, I. et al. “Genome-wide association study of endometrial cancer in E2C2.”Human Genetics, 2014.
[22] Maes, H. H., et al. “Genetic and environmental factors in relative body weight and human adiposity.”Behavior Genetics, vol. 27, no. 4, 1997, pp. 325-351.
[23] Arnlov, J., et al. “Endogenous sex hormones and cardiovascular disease incidence in men.”Annals of Internal Medicine, vol. 145, 2006, pp. 176-184.