Obesity and Polycystic Ovary Syndrome

Ryu K., Park H., Kim M.S., Jeong H.G., Kim T.

AbstractTo investigate the relationship between polycystic ovary syndrome (PCOS) and risk of cardiocerebrovascular disease in Korean women. This longitudinal cohort study using data from the Korean National Health Insurance Service included the women aged 15–44 years diagnosed with PCOS between 2002 and 2019, and the controls were matched 1:3 by age group, income, and region of residence. The endpoint outcomes of this study were the occurrence of ischemic heart disease, cerebrovascular diseases, and combined cardiocerebrovascular diseases in the PCOS and control groups. A stratified Cox proportional hazards regression analysis for matched data was performed to evaluate the relative hazard of events in the PCOS group compared to that in the control group. Among a total of 549,400 participants in the cohort, 137,416 women had a diagnosis of PCOS and 412,118 women did not have it. During a median follow-up of 54 months (interquartile range, 30–78 months), the incidence rates of all cardiovascular, ischemic heart, and cerebrovascular diseases were 6.6, 4.0, and 2.9, respectively, per 1000 person-years for women with PCOS, and 4.8, 2.8, and 2.3, respectively, per 1000 person-years for healthy control women. Women with PCOS had a higher hazard ratio of 1.224 (95% confidence interval, 1.18–1.27) of the composite cardiocerebrovascular diseases than those in the controls after propensity score matching for confounding variables, including body mass index, diabetes mellitus, hypertension, dyslipidemia, physical exercise level, alcohol consumption, current smoking, systolic and diastolic blood pressures, total cholesterol, and triglyceride levels. Hazard ratio for ischemic heart and cerebrovascular diseases was higher in women with PCOS than in the control group (hazard ratio, 1.254; 95% confidence interval, 1.20–1.31 and hazard ratio, 1.201; 95% confidence interval, 1.14–1.27, respectively). PCOS is associated with an increased risk of cardiocerebrovascular diseases in Korean women irrespective of their obesity. Counselling on the management of long-term risk of cardiovascular diseases should be offered to women with PCOS in East Asian countries where PCOS is characterized by a relatively low BMI.

Teede H.J., Tay C.T., Laven J.J., Dokras A., Moran L.J., Piltonen T.T., Costello M.F., Boivin J., Redman L.M., Boyle J.A., Norman R.J., Mousa A., Joham A.E., Arlt W., Azziz R., et. al.

Abstract Study Question What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? Summary Answer International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. What is Known Already The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. Study Design, Size, Duration The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. Participants/Materials, Setting, Methods This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). Main Results and the Role of Chance The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. Limitations, Reasons for Caution Overall, recommendations are strengthened and evidence is improved, but remain generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. Wider Implications of the Findings The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation programme supports the Guideline with an integrated evaluation program. Study Funding/Competing Interest(s) This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and the European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the sponsoring organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.

Ibáñez L., de Zegher F.

Adolescent polycystic ovary syndrome (PCOS) is a highly prevalent, reversible, endocrine-metabolic mode essentially driven by ectopic fat, which, in turn, often results from a mismatch between early adipogenesis and later lipogenesis, or between prenatal and postnatal weight gain. The key features of adolescent PCOS are menstrual irregularity and androgen excess (hirsutism, acne, and/or high testosterone). Adolescent PCOS is frequently preceded by rapid maturation (early variants of adrenarche/pubarche and puberty/menarche, also accelerated by ectopic fat) and is diagnosed between 2 and 8 years after menarche, thus during late adolescence or early adulthood. Treatment of adolescent PCOS should not only focus on symptoms, but also reduce the amount of ectopic fat, thereby aiming for an overall state of preconception health.

Argente J., Dunkel L., Kaiser U.B., Latronico A.C., Lomniczi A., Soriano-Guillén L., Tena-Sempere M.

Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues. Substantial progress towards elucidation of the neuroendocrine networks governing puberty has taken place. However, key aspects of the mechanisms responsible for the precise timing of puberty and its alterations have only recently begun to be deciphered, propelled by epidemiological data suggesting that pubertal timing is changing in humans, via mechanisms that are not yet understood. By integrating basic and clinical data, we provide a comprehensive overview of current advances on the physiological basis of puberty, with a particular focus on the roles of kisspeptins and other central transmitters, the underlying molecular and endocrine mechanisms, and the pathways involved in pubertal modulation by nutritional and metabolic cues. Additionally, we have summarised molecular features of precocious and delayed puberty in both sexes, as revealed by clinical and genetic studies. This Review is a synoptic up-to-date view of how puberty is controlled and of the pathogenesis of major pubertal alterations, from both a clinical and translational perspective. We also highlight unsolved challenges that will seemingly concentrate future research efforts in this active domain of endocrinology.

Burt Solorzano C., DeBoer M., Kim S., Pannone A., McCartney C.

Abstract Background Peripubertal hyperandrogenemia (HA) often represents a forerunner to adolescent/adult polycystic ovary syndrome (PCOS), but risk factors for peripubertal HA are unclear. Studies have associated obesity with HA throughout puberty (e.g., McCartney, JCEM 2007;92: 430-436, Knudsen, Obesity 2010;18: 2118-2124). However, these studies were performed in academic centers and could have been influenced by recruitment bias. We therefore investigated if there was a difference in calculated free testosterone (T) levels between girls with healthy weight and those with obesity in a nationally-representative U.S. sample. Methods We analyzed data for 1,196 girls aged 6–18 years from the National Health and Nutrition Examination Survey (NHANES) 2013-2016 databases, utilizing a cross-sectional study design. We calculated free T from total T and sex hormone-binding globulin (Vermuelen equation). We divided girls into 3 groups by age, based on presumed pubertal stages: "Pre-/Early" (6–9 years), "Middle" (10–14 years), and "Late" (15–18 years). Each individual was also categorized as healthy-weight (BMI-for-age percentile 5-85) or obese (BMI-for-age percentile ≥95). We analyzed mean free T concentrations by weight status (healthy-weight vs. obese) for each age group by calculating population estimates. We also performed survey-weighted regression analysis to assess the relationships between weight status and age category (independent variables) and free T (outcome). Results Among Pre-/Early girls, free T was 0.33 pg/ml (0.28-0.38) [mean (95% CI)] for healthy-weight vs. 0.86 pg/ml (0.67-1.05) for obese. Among Middle girls, free T was 2.53 pg/ml (2.27-2.78) for healthy-weight vs. 4.35 pg/ml (3.75-4.95) for obese. Among Late girls, free T was 3.33 pg/ml (2.96-3.70) for healthy-weight vs. 5.64 pg/ml (4.93-6.36) for obese. (Notably, in each age group, the 95% CIs for free T did not overlap between healthy-weight vs. obese subgroups). Mean free T increased with advancing age in both healthy-weight and obese groups, especially between Pre-/Early and Middle age ranges (Pre-/Early-to-Middle differences were 2.20 pg/ml for healthy-weight and 3.49 pg/ml for obese). Our regression model accounted for 45% of the variance in free T (R2=0.45). Both weight status (obese vs. healthy-weight) and age group were independent predictors of free T concentrations (p<0.0001 for both). When adding an age-in-months-by-BMI-percentile interaction term, the model R2 value was 0.47, with age category, weight category, and the interaction term all being independent predictors of free T (p<0.001 for all). Conclusion We conclude that obesity is associated with higher free T levels in U.S. girls aged 6–18 years. Age also predicts free T, likely reflecting increases related to pubertal maturation, and free T differences according to weight status are more prominent in older girls. This study in a nationally-representative sample of U.S. girls supports previous analyses of girls studied at academic centers, further suggesting an important relationship between obesity and peripubertal androgen excess. Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.

Sánchez-Garrido M.A., García-Galiano D., Tena-Sempere M.

Abstract BACKGROUND According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, environmental changes taking place during early maturational periods may alter normal development and predispose to the occurrence of diverse pathologies later in life. Indeed, adverse conditions during these critical developmental windows of high plasticity have been reported to alter the offspring developmental trajectory, causing permanent functional and structural perturbations that in the long term may enhance disease susceptibility. However, while solid evidence has documented that fluctuations in environmental factors, ranging from nutrient availability to chemicals, in early developmental stages (including the peri-conceptional period) have discernible programming effects that increase vulnerability to develop metabolic perturbations, the impact and eventual mechanisms involved, of such developmental alterations on the reproductive phenotype of offspring have received less attention. OBJECTIVE AND RATIONALE This review will summarize recent advances in basic and clinical research that support the concept of DOHaD in the context of the impact of nutritional and hormonal perturbations, occurring during the periconceptional, fetal and early postnatal stages, on different aspects of reproductive function in both sexes. Special emphasis will be given to the effects of early nutritional stress on the timing of puberty and adult gonadotropic function, and to address the underlying neuroendocrine pathways, with particular attention to involvement of the Kiss1 system in these reproductive perturbations. The implications of such phenomena in terms of reproductive medicine will also be considered. SEARCH METHODS A comprehensive MEDLINE search, using PubMed as main interface, of research articles and reviews, published mainly between 2006 and 2021, has been carried out. Search was implemented using multiple terms, focusing on clinical and preclinical data from DOHaD studies, addressing periconceptional, gestational and perinatal programming of reproduction. Selected studies addressing early programming of metabolic function have also been considered, when relevant. OUTCOMES A solid body of evidence, from clinical and preclinical studies, has documented the impact of nutritional and hormonal fluctuations during the periconceptional, prenatal and early postnatal periods on pubertal maturation, as well as adult gonadotropic function and fertility. Furthermore, exposure to environmental chemicals, such as bisphenol A, and maternal stress has been shown to negatively influence pubertal development and gonadotropic function in adulthood. The underlying neuroendocrine pathways and mechanisms involved have been also addressed, mainly by preclinical studies, which have identified an, as yet incomplete, array of molecular and neurohormonal effectors. These include, prominently, epigenetic regulatory mechanisms and the hypothalamic Kiss1 system, which likely contribute to the generation of reproductive alterations in conditions of early nutritional and/or metabolic stress. In addition to the Kiss1 system, other major hypothalamic regulators of GnRH neurosecretion, such as γ-aminobutyric acid and glutamate, may be targets of developmental programming. WIDER IMPLICATIONS This review addresses an underdeveloped area of reproductive biology and medicine that may help to improve our understanding of human reproductive disorders and stresses the importance, and eventual pathogenic impact, of early determinants of puberty, adult reproductive function and fertility.

de Zegher F., Ibáňez L.

Harbulot C., Lessim S., Simon D., Martinerie L., Storey C., Ecosse E., De Roux N., Carel J., Léger J.

Objective Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP. Design and methods This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years. Results In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance. Conclusion These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.

Tay C.T., Hart R.J., Hickey M., Moran L.J., Earnest A., Doherty D.A., Teede H.J., Joham A.E.

Polycystic ovary syndrome (PCOS) is challenging to diagnose. While the 2003 Rotterdam criteria are widely used for adults, the 2018 international PCOS guideline recommended updated Rotterdam criteria with both hyperandrogenism and oligo-anovulation for adolescents based on evidence-informed expert consensus. This study compared the prevalence of PCOS using updated and original Rotterdam criteria in community-based adolescents and explored long-term body mass index (BMI) trajectories across different diagnostic phenotypes. Overall, 227 postmenarchal adolescent females from the prospective cohort Raine Study undertook comprehensive PCOS assessment at age 14–16 years. Detailed anthropometric measurements were collected from birth until age 22 years. Cross-sectional and longitudinal BMI were analyzed using t tests and generalized estimating equations. PCOS was diagnosed in 66 (29.1%) participants using original criteria versus 37 (16.3%) participants using updated Rotterdam criteria. Using updated criteria, participants with PCOS had higher BMI than participants without PCOS from prepubertal. Only the phenotype meeting the updated criteria was significantly associated with higher long-term BMI gain whereas other PCOS phenotypes had similar BMI trajectories to participants without PCOS (p < 0.001). The use of the 2018 updated Rotterdam criteria reduces over-diagnosis of PCOS in adolescents and identifies those at the greatest risk of long-term weight gain, a key contributor to disease severity and long-term health implications. The BMI trajectories of females with PCOS on updated criteria diverge prepubertally compared to those without PCOS. This work supports targeting adolescents diagnosed with PCOS on the 2018 updated criteria for early lifestyle interventions to prevent long-term health complications.

Kim J.J., Choi Y.M.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women, and ethnic diversity has been reported in its manifestation. This review addressed phenotype and genetic studies in Asian women with PCOS. Generally, East Asians are less hirsute, and the hirsutism score cutoff is lower than the Caucasian counterpart. It is not clear whether there are any significant differences in the prevalence or severity of irregular menstruation (IM) or characteristics of polycystic ovary (PCO) across ethnicities. Interestingly, the IM/PCO subgroup is a relatively common phenotype in East Asian patients but not in Caucasian patients. The prevalence of insulin resistance in PCOS patients varies depending on the index used and the cutoff, but women with PCOS showed a higher degree of insulin resistance than those of controls across ethnicities. Lower body mass index (BMI) and lower prevalence of metabolic syndrome were reported in East Asian patients, but despite lower BMI, a comparative study reported that Asian women with PCOS were more likely to have diabetes compared with Caucasian patients, suggesting they also have metabolic complications. Unlike East Asian patients, South Asian patients showed an increased degree of hirsutism, early onset of symptoms, and severe insulin resistance and metabolic risks compared with Caucasians. Genetic components play important roles in the pathogenesis of PCOS, and genome-wide association studies of PCOS suggest that similar genetic risk factors exist between Asian and Caucasian patients. Continuous comparative studies are needed to standardize the diagnosis and management of PCOS across different ethnicities.

Barber T.M., Hanson P., Weickert M.O., Franks S.

Polycystic ovary syndrome (PCOS) is a common female condition typified by reproductive, hyperandrogenic, and metabolic features. Polycystic ovary syndrome is a genetic condition, exacerbated by obesity. There is a close link between obesity and PCOS based on epidemiological data, and more recently corroborated through genetic studies. There are many mechanisms mediating the effects of weight-gain and obesity on the development of PCOS. The metabolic effects of insulin resistance and steroidogenic and reproductive effects of hyperinsulinaemia are important mechanisms. Adipokine production by subcutaneous and visceral fat appears to play a part in metabolic function. However, given the complexity of PCOS pathogenesis, it is important also to consider possible effects of PCOS on further weight-gain, or at least on hampering attempts at weight-loss and maintenance through lifestyle changes. Possible mediators of these effects include changes in energy expenditure, mental ill health, or physical inactivity. In this brief review, we discuss the main mechanisms that underlie the association between obesity and PCOS, from divergent perspectives of weight-gain contributing to development of PCOS and vice versa. We also consider novel management options for women with obesity and PCOS.

Liimatta J., Utriainen P., Voutilainen R., Jääskeläinen J.

Background: It has been speculated that premature adrenarche (PA) could lead to unfavorable outcome, including shorter adult stature, but longitudinal follow-up data are insufficient. Methods: This prospective case-control study included 30 PA and 42 control females who were born mostly full-term and appropriate for gestational age. They were examined first at the median age of 7.6 years and now at 18.1 years. Main outcome measures were height, body mass index (BMI), age at menarche, and serum dehydroepiandrosterone sulfate (DHEAS) and insulin-like growth factor 1 (IGF-1) concentrations. Results: The PA and control females had comparable mean (standard deviation) adult height (167.2 (6.8) vs 164.5 (5.1) cm, P = 0.059) and median (interquartile range) BMI (22.8 (21.1-28.9) vs 21.6 (19.8-24.3) kg/m2, P = 0.068, respectively). Adult heights were comparable with the mid-parental heights in both study groups. The PA females were taller than the controls until the age of 12 years and they lacked a distinct pubertal growth spurt. Serum DHEAS and IGF-1 concentrations did not differ between the PA and control groups at the age of 18 years. Median (range) age at menarche was significantly lower in the PA than control females (11.5 (9.5-15.0) vs 13.0 (10.0-15.0), P = 0.001). Conclusions: Although PA girls have advanced growth and earlier pubertal development together with a tendency to be more overweight, their height, BMI, and serum DHEAS and IGF-1 concentrations are comparable to those of their peers at the age of 18 years. Our findings indicate a benign outcome of PA in appropriate for gestational age -born females concerning adult height and adrenal androgen secretion.

Elhassan Y.S., Idkowiak J., Smith K., Asia M., Gleeson H., Webster R., Arlt W., O’Reilly M.W.

Androgen excess in women is predominantly due to underlying polycystic ovary syndrome (PCOS). However, there is a lack of clarity regarding patterns and severity of androgen excess that should be considered predictive of non-PCOS pathology.We examined the diagnostic utility of simultaneous measurement of serum dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), and testosterone (T) to delineate biochemical signatures and cutoffs predictive of non-PCOS disorders in women with androgen excess.Retrospective review of all women undergoing serum androgen measurement at a large tertiary referral center between 2012 and 2016. Serum A4 and T were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased serum androgen underwent phenotyping by clinical notes review.In 1205 women, DHEAS, A4, and T were measured simultaneously. PCOS was the most common diagnosis in premenopausal (89%) and postmenopausal women (29%). A4 was increased in all adrenocortical carcinoma (ACC) cases (n = 15) and T in all ovarian hyperthecosis (OHT) cases (n = 7); all but one case of congenital adrenal hyperplasia (CAH; n = 18) were identified by increased levels of A4 and/or T. In premenopausal women, CAH was a prevalent cause of severe A4 (59%) and T (43%) excess; severe DHEAS excess was predominantly due to PCOS (80%). In postmenopausal women, all cases of severe DHEAS and A4 excess were caused by ACC and severe T excess equally by ACC and OHT.Pattern and severity of androgen excess are important predictors of non-PCOS pathology and may be used to guide further investigations as appropriate.

Dawood A., Goyal M.

Onstad M.A., Schmandt R.E., Lu K.H.

In sharp contrast to many other cancer types, the incidence and mortality of endometrial cancer continue to grow. This unfortunate trend is, in no small part, a result of the worldwide obesity epidemic. More than half of endometrial cancers are currently attributable to obesity, which is recognized as an independent risk factor for this disease. In this review, we identify the molecular mechanisms by which obesity and adipose tissue contribute to the pathogenesis of endometrial cancer. We further discuss the impact of obesity on the clinical management of the disease and examine the development of rational behavioral and pharmaceutical interventions aimed at reducing endometrial cancer risk, improving cancer outcomes, and preserving fertility in an increasingly younger population of patients with endometrial cancer.