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Farhan M, Seyfi A, Alnuaimi A, Alamour M, Alwarafi S, Elastal H, Nazir MH, Kamaraj B, Putta Nagarajan HD, Delianne D, Ganesan S, Patel T. A narrative review on cutaneous manifestations in polycystic ovary syndrome: pathophysiology, diagnosis, management, and psychosocial impact. Ann Med Surg (Lond) 2025; 87:2804-2811. [PMID: 40337376 PMCID: PMC12055046 DOI: 10.1097/ms9.0000000000003217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/17/2025] [Indexed: 05/09/2025] Open
Abstract
Background Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting 5%-10% of reproductive-aged women. Its diverse clinical spectrum includes reproductive, metabolic, and dermatological abnormalities, with cutaneous manifestations often serving as visible indicators of underlying hormonal and metabolic imbalances. Objective This review explores the pathophysiology, diagnosis, management, and psychosocial impact of the cutaneous manifestations of PCOS, providing an integrated understanding of their clinical significance. Methods A comprehensive analysis was conducted based on existing literature to elucidate the underlying mechanisms, diagnostic approaches, and treatment options for dermatological features associated with PCOS, including acne, hirsutism, acanthosis nigricans, seborrheic dermatitis, and androgenic alopecia. Results The pathophysiology of cutaneous manifestations in PCOS is driven by hyperandrogenism, insulin resistance, and local androgenic effects on the pilosebaceous unit. Acne and hirsutism are among the most common skin findings, followed by androgenic alopecia and acanthosis nigricans. Diagnostic strategies combine clinical evaluation with hormonal assays and imaging. Management requires a multidisciplinary approach encompassing hormonal therapies, lifestyle modifications, and targeted dermatological treatments. Additionally, these manifestations significantly impair psychosocial well-being, necessitating holistic care. Conclusion Cutaneous manifestations are a cosmetic concern and an essential diagnostic and therapeutic focus in PCOS. Addressing these features can enhance patient outcomes by mitigating physical symptoms and improving quality of life. Future research should emphasize personalized treatments and the psychosocial aspects of care to provide comprehensive management for women with PCOS.
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Affiliation(s)
- Muhammad Farhan
- Ajman University, College of Medicine, Ajman, United Arab Emirates
| | - Ariana Seyfi
- Ajman University, College of Medicine, Ajman, United Arab Emirates
| | - Afra Alnuaimi
- Dermatology Department, Sheikh Khalifa Medical Center, Abu Dhabi, United Arab Emirates
| | - Maya Alamour
- Ajman University, College of Medicine, Ajman, United Arab Emirates
| | - Sarah Alwarafi
- Ajman University, College of Medicine, Ajman, United Arab Emirates
| | - Haya Elastal
- Canadian Specialist Hospital, Dubai, United Arab Emirates
| | | | | | | | | | | | - Tirath Patel
- Trinity Medical Sciences University School of Medicine, St. Vincent, Saint Vincent and the Grenadines
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Joseph S, Ubba V, Wang Z, Feng M, dSilva MK, Suero S, Waheed D, Snyder NW, Yang X, Wang H, Richards JS, Ko CJ, Wu S. Ovarian-Specific Cyp17A1 Overexpression in Female Mice: A Novel Model of Endogenous Testosterone Excess. Endocrinology 2025; 166:bqaf071. [PMID: 40208112 PMCID: PMC12006740 DOI: 10.1210/endocr/bqaf071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/13/2025] [Accepted: 04/08/2025] [Indexed: 04/11/2025]
Abstract
Excessive androgen levels can severely affect female health. However, most existing models of androgen excess rely on exogenous androgen administration, which does not fully capture the effect of elevated local ovarian testosterone on reproductive and metabolic functions. Here, we report the development of a novel hyperandrogenic mouse model, Cyp17TM-625, generated by combining CRISPR-Cas9 and a Tet-On doxycycline system to induce Cyp17A1 overexpression in ovarian theca-interstitial cells. As a result, Cyp17TM-625 mice exhibited significantly elevated Cyp17A1 messenger RNA and protein levels, accompanied by increased testosterone concentrations without alterations in basal levels of estradiol, progesterone, luteinizing hormone, or follicle-stimulating hormone. These mice demonstrated subfertility, evident by smaller and fewer litters, prolonged estrous cycles, and an increased number of unhealthy follicles with abnormally shaped oocytes. Despite these marked reproductive changes, body weight and glucose homeostasis remained comparable to Con-625 mice. Notably, withdrawal of doxycycline reversed testosterone overexpression and restored fertility over time. This model recapitulates reproductive dysfunction but not the metabolic disturbances, commonly observed in exogenous androgen models. The Cyp17TM-625 mouse line is a unique model for investigating the effects of local excess androgens on ovarian function. It also serves as a valuable tool for studying fertility restoration following the withdrawal of testosterone.
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Affiliation(s)
- Serene Joseph
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Vaibhave Ubba
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Zhiqiang Wang
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Mingxiao Feng
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Milan K dSilva
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Sofia Suero
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Danielle Waheed
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Nathaniel W Snyder
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Xiaofeng Yang
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Hong Wang
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - JoAnne S Richards
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - CheMyong J Ko
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA
| | - Sheng Wu
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA 19140, USA
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Bauer R, Parker C, Gorsic LK, Hayes MG, Kunselman AR, Legro RS, Welt CK, Urbanek M. Rare variation in LMNA underlies polycystic ovary syndrome (PCOS) pathogenesis in two independent cohorts. J Clin Endocrinol Metab 2024:dgae761. [PMID: 39484826 DOI: 10.1210/clinem/dgae761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/09/2024] [Accepted: 10/29/2024] [Indexed: 11/03/2024]
Abstract
CONTEXT Polycystic ovary syndrome (PCOS) is a common, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive age women. Variants in LMNA cause partial lipodystrophy, a syndrome with overlapping features to PCOS. OBJECTIVE We tested the hypothesis that rare variation in LMNA contributes to PCOS pathogenesis and selects a lipodystrophy-like subtype of PCOS. DESIGN, SETTING, AND PARTICIPANTS We sequenced LMNA by targeted sequencing a discovery cohort of 811 PCOS patients and 164 healthy controls. We then analyzed LMNA from whole-exome sequencing (WES) of a replication cohort of 718 PCOS patients and 281 healthy controls. MAIN OUTCOME MEASURES Variation in the LMNA gene, hormone and lipid profiles of participants. RESULTS In the discovery cohort, we identified 8 missense variants in 15/811 cases, and 1 variant in 1/172 reproductively healthy controls. There is strong evidence for association between the variants and PCOS compared to gnomAD non-Finnish European population controls (χ2=17, p=3.7x10-5, OR=2.9). In the replication cohort, we identified 11 unique variants in 15/718 cases, and 1 variant in 281 reproductively healthy controls. Again, there is strong evidence for association with population controls (χ2=30.5, p=3.4x10-8, OR= 4.0). In both the discovery and replication cohorts, variants in LMNA identify women with PCOS with high triglycerides and extreme insulin resistance. CONCLUSIONS Rare missense variation in LMNA is reproducibly associated with PCOS and identifies some individuals with lipodystrophy-like features. The overlap between this PCOS phenotype and genetic partial lipodystrophy syndromes warrants further investigation into additional lipodystrophy genes and their potential in PCOS etiology.
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Affiliation(s)
- Rosemary Bauer
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Center for Reproductive Science, Northwestern University, Chicago IL 60611
| | - Chloe Parker
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Lidija K Gorsic
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - M Geoffrey Hayes
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Department of Anthropology, Northwestern University, Evanston, IL 60208
| | - Allen R Kunselman
- Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033
| | - Richard S Legro
- Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA 17033
| | - Corrine K Welt
- Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, Utah 84132
| | - Margrit Urbanek
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Center for Reproductive Science, Northwestern University, Chicago IL 60611
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
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Fordham TM, Morelli NS, Garcia-Reyes Y, Ware MA, Rahat H, Sundararajan D, Fuller KNZ, Severn C, Pyle L, Malloy CR, Jin ES, Parks EJ, Wolfe RR, Cree MG. Metabolic effects of an essential amino acid supplement in adolescents with PCOS and obesity. Obesity (Silver Spring) 2024; 32:678-690. [PMID: 38439205 DOI: 10.1002/oby.23988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 03/06/2024]
Abstract
OBJECTIVE Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, insulin resistance, and hepatic steatosis (HS). Because dietary essential amino acid (EAA) supplementation has been shown to decrease HS in various populations, this study's objective was to determine whether supplementation would decrease HS in PCOS. METHODS A randomized, double-blind, crossover, placebo-controlled trial was conducted in 21 adolescents with PCOS (BMI 37.3 ± 6.5 kg/m2, age 15.6 ± 1.3 years). Liver fat, very low-density lipoprotein (VLDL) lipogenesis, and triacylglycerol (TG) metabolism were measured following each 28-day phase of placebo or EAA. RESULTS Compared to placebo, EAA was associated with no difference in body weight (p = 0.673). Two markers of liver health improved: HS was lower (-0.8% absolute, -7.5% relative reduction, p = 0.013), as was plasma aspartate aminotransferase (AST) (-8%, p = 0.004). Plasma TG (-9%, p = 0.015) and VLDL-TG (-21%, p = 0.031) were reduced as well. VLDL-TG palmitate derived from lipogenesis was not different between the phases, nor was insulin sensitivity (p > 0.400 for both). Surprisingly, during the EAA phase, participants reported consuming fewer carbohydrates (p = 0.038) and total sugars (p = 0.046). CONCLUSIONS Similar to studies in older adults, short-term EAA supplementation in adolescents resulted in significantly lower liver fat, AST, and plasma lipids and thus may prove to be an effective treatment in this population. Additional research is needed to elucidate the mechanisms for these effects.
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Affiliation(s)
- Talyia M Fordham
- Department of Nutrition and Exercise Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Nazeen S Morelli
- Department of Pediatrics, Section on Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Yesenia Garcia-Reyes
- Department of Pediatrics, Section on Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Meredith A Ware
- Department of Pediatrics, Section on Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Haseeb Rahat
- Department of Pediatrics, Section on Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Divya Sundararajan
- Department of Pediatrics, Section on Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Kelly N Z Fuller
- Department of Pediatrics, Section on Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Cameron Severn
- Child Health Biostatistics Core, Department of Pediatrics, Section of Endocrinology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Laura Pyle
- Child Health Biostatistics Core, Department of Pediatrics, Section of Endocrinology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA
| | - Craig R Malloy
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- VA North Texas Health Care System, Dallas, Texas, USA
| | - Eunsook S Jin
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Elizabeth J Parks
- Department of Nutrition and Exercise Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Robert R Wolfe
- Department of Geriatrics, Donald W. Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Melanie G Cree
- Department of Pediatrics, Section on Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Center for Women's Health Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Misra S, Gada J, Dhole C, Varthakavi P, Bhagwat N. Comparative Study of Insulin Sensitivity and Resistance and Their Correlation with Androgens in Lean and Obese Women with Polycystic Ovary Syndrome. Reprod Sci 2024; 31:754-763. [PMID: 37848646 DOI: 10.1007/s43032-023-01374-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/01/2023] [Indexed: 10/19/2023]
Abstract
There is a lack of consensus on the optimal screening strategy for insulin resistance (IR), particularly in lean women with polycystic ovary syndrome (PCOS). Therefore, we conducted a cross-sectional study in 80 women with PCOS (28 lean/52 obese) and 80 age- and body mass index (BMI)-matched controls. Using a 5-point 75-g oral glucose tolerance test (OGTT) (0, 30, 60, 90, 120 min), we examined glucose and insulin excursions, IR, insulin sensitivity, beta-cell function (ßF), and the effect of androgens on IR. Lean and obese women with PCOS had similar glucose but higher insulin (except fasting in lean women) and insulin AUC as compared to their respective controls (p < 0.05). Lean women with PCOS were equally insulin-resistant but more hyperinsulinemic than the obese controls (p < 0.05). Although ßF ([1st phase: 481.71 ± 263.53 vs. 430.56 ± 232.37], [2nd phase: 815.16 ± 447.12 vs. 752.66 ± 428.95]) was comparable in lean and obese women with PCOS, lean women had better insulin sensitivity (112.78 ± 66.26 vs. 75.49 ± 55.6) (p < 0.05). Dehydroepiandrosterone sulfate (DHEAS) and androstenedione decreased with increasing BMI in lean women, and this correlated with deteriorating insulin sensitivity and exaggerated hyperinsulinemia. In obese women with PCOS, sex hormone-binding globulin (SHBG) correlated negatively with BMI and hyperinsulinemia, and positively with insulin sensitivity. This data suggests that estimating only fasting insulin may miss IR in lean women with PCOS; hence, additional time points in OGTT will add value to screening for IR. DHEAS and androstenedione may have a beneficial effect on insulin sensitivity and may be used to screen IR in lean women, while SHBG can be used as a predictive marker for IR in obese women with PCOS.
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Affiliation(s)
- Sukirti Misra
- Department of Endocrinology, College Building, Topiwala National Medical College and Bai Yamunabai Laxman (BYL) Nair Charitable Hospital, A.L. Nair Road, Room No. 419, 4Th Floor, Mumbai Central, Mumbai, Maharashtra, 400008, India
| | - Jugal Gada
- Department of Endocrinology, College Building, Topiwala National Medical College and Bai Yamunabai Laxman (BYL) Nair Charitable Hospital, A.L. Nair Road, Room No. 419, 4Th Floor, Mumbai Central, Mumbai, Maharashtra, 400008, India.
| | - Charushila Dhole
- Department of Endocrinology, College Building, Topiwala National Medical College and Bai Yamunabai Laxman (BYL) Nair Charitable Hospital, A.L. Nair Road, Room No. 419, 4Th Floor, Mumbai Central, Mumbai, Maharashtra, 400008, India
| | - Premlata Varthakavi
- Department of Endocrinology, College Building, Topiwala National Medical College and Bai Yamunabai Laxman (BYL) Nair Charitable Hospital, A.L. Nair Road, Room No. 419, 4Th Floor, Mumbai Central, Mumbai, Maharashtra, 400008, India
| | - Nikhil Bhagwat
- Department of Endocrinology, College Building, Topiwala National Medical College and Bai Yamunabai Laxman (BYL) Nair Charitable Hospital, A.L. Nair Road, Room No. 419, 4Th Floor, Mumbai Central, Mumbai, Maharashtra, 400008, India
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Stefanaki K, Ilias I, Paschou SA, Karagiannakis DS. Hepatokines: the missing link in the development of insulin resistance and hyperandrogenism in PCOS? Hormones (Athens) 2023; 22:715-724. [PMID: 37704921 DOI: 10.1007/s42000-023-00487-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023]
Abstract
The liver plays a critical role in several metabolic pathways, including the regulation of glucose and lipid metabolism. Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, is closely associated with insulin resistance (IR) and metabolic syndrome (MetS). Hepatokines, newly discovered proteins secreted by hepatocytes, have been linked to the induction of these metabolic dysregulations. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, has been associated with NAFLD and IR, while hyperandrogenism additionally appears to be implicated in the pathogenesis of the latter. However, the potential role of hepatokines in the development of metabolic disorders in PCOS has not been fully investigated. Therefore, the aim of this review is to critically appraise the current evidence regarding the interplay of hepatokines with NAFLD, hyperandrogenism, and IR in PCOS.
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Affiliation(s)
- Katerina Stefanaki
- Department of Clinical Therapeutics, Medical School of the National and Kapodistrian University of Athens, "Alexandra" Hospital, Athens, Greece
| | - Ioannis Ilias
- Department of Endocrinology, Diabetes and Metabolism, "Elena Venizelou" Hospital, Athens, Greece
| | - Stavroula A Paschou
- Department of Clinical Therapeutics, Medical School of the National and Kapodistrian University of Athens, "Alexandra" Hospital, Athens, Greece
| | - Dimitrios S Karagiannakis
- Academic Department of Gastroenterology, Medical School of the National and Kapodistrian University of Athens, "Laiko" General Hospital, Athens, Greece.
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Çakır Biçer N, Ermiş AA, Baş D. The Role of Different Methods in Defining Cardiometabolic Risk and Metabolic Syndrome in Women with Polycystic Ovary Syndrome. Life (Basel) 2023; 13:1959. [PMID: 37895341 PMCID: PMC10608420 DOI: 10.3390/life13101959] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/31/2023] [Accepted: 09/02/2023] [Indexed: 10/29/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is one of the most frequent endocrine illnesses, often accompanied by visceral adiposity and metabolic syndrome (MetS). Visceral adiposity is an accurate predictor of MetS and cardiometabolic risk. This study aims to evaluate different anthropometric indices that can be used in PCOS and MetS risk assessment. A total of 66 women with PCOS (50%) and 66 controls (50%) were included, and clinical and biochemical parameters were evaluated. The body mass index (BMI), body shape index (ABSI), body roundness index (BRI), dysfunctional adiposity index (DAI), lipid accumulation (LAP) index, and visceral adiposity index (VAI) were calculated. The means of all indices were higher in the PCOS group (p < 0.05). The marker with the lowest discriminatory ability for PCOS and MetS was ABSI (AUC = 0.762 and AUC = 0.714, respectively, p = 0.000). According to the multivariate logistic regression model, the VAI and WC are strong predictors of PCOS (AUC, 98%; accuracy, 92%; sensitivity, 92%; and specificity, 91%), and WC, LAP index, and BRI are strong predictors of MetS (AUC, 0.95%; accuracy, 86%; sensitivity, 83%; and specificity, 88%). The use of different anthropometric indices in the detection of PCOS and MetS may allow for early diagnosis and treatment, and are simple and cost-effective.
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Affiliation(s)
- Nihan Çakır Biçer
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Acıbadem Mehmet Ali Aydınlar University, Icerenkoy Mah., Kayisdagi Cad. No. 32, 34752 Atasehir, Istanbul, Türkiye;
| | - Asime Aleyna Ermiş
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Acıbadem Mehmet Ali Aydınlar University, Icerenkoy Mah., Kayisdagi Cad. No. 32, 34752 Atasehir, Istanbul, Türkiye;
| | - Dilşat Baş
- Department of Nutrition and Dietetics, Faculty of Health Sciences, İstanbul Galata University, Evliya Çelebi Mah., Meşrutiyet Cad. No. 62, Tepebaşı, 34425 Beyoğlu, Istanbul, Türkiye;
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8
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van der Ham K, Koster MPH, Velthuis BK, Budde RPJ, Fauser BCJM, Laven JSE, Louwers YV. Change in Androgenic Status and Cardiometabolic Profile of Middle-Aged Women with Polycystic Ovary Syndrome. J Clin Med 2023; 12:5226. [PMID: 37629271 PMCID: PMC10455407 DOI: 10.3390/jcm12165226] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/01/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Understanding the cardiovascular disease (CVD) risk for women with polycystic ovary syndrome (PCOS) at reproductive age is crucial. To investigate this, we compared the cardiometabolic profiles of different PCOS groups over a median interval of 15.8 years. The study focused on three groups: (1) women with PCOS who were hyperandrogenic at both initial and follow-up screening (HA-HA), (2) those who transitioned from hyperandrogenic to normoandrogenic (HA-NA), and (3) those who remained normoandrogenic (NA-NA). At initial and follow-up screenings, both HA-HA and HA-NA groups showed higher body mass indexes compared to the NA-NA group. Additionally, at follow-up, the HA-HA and HA-NA groups exhibited higher blood pressure, a higher prevalence of hypertension, elevated serum triglycerides and insulin levels, and lower levels of HDL cholesterol compared to the NA-NA group. Even after adjusting for BMI, significant differences persisted in HDL cholesterol levels and hypertension prevalence among the groups (HA-HA: 53.8%, HA-NA: 53.1%, NA-NA: 14.3%, p < 0.01). However, calcium scores and the prevalence of coronary plaques on CT scans were similar across all groups. In conclusion, women with PCOS and hyperandrogenism during their reproductive years exhibited an unfavorable cardiometabolic profile during their post-reproductive years, even if they changed to a normoandrogenic status.
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Affiliation(s)
- Kim van der Ham
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands (J.S.E.L.)
| | - Maria P. H. Koster
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands (J.S.E.L.)
| | - Birgitta K. Velthuis
- Department of Radiology, University Medical Center Utrecht, University of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
| | - Ricardo P. J. Budde
- Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
| | - Bart C. J. M. Fauser
- Department of Reproductive Medicine & Gynecology, University Medical Center Utrecht, University of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
| | - Joop S. E. Laven
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands (J.S.E.L.)
| | - Yvonne V. Louwers
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands (J.S.E.L.)
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Adashi EY, Cibula D, Peterson M, Azziz R. The polycystic ovary syndrome: the first 150 years of study. F S Rep 2023; 4:2-18. [PMID: 36959968 PMCID: PMC10028479 DOI: 10.1016/j.xfre.2022.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
The communities of reproductive medicine and reproductive sciences have been witness to an enormous acceleration of interest in polycystic ovary syndrome (PCO) since the mid-19th century. Although progress has been increasingly palpable, the fundamentals of the etiology and pathophysiology of PCO remain as elusive as ever. Particularly lacking is a requisite understanding of events at the cellular and molecular levels. As we cross the millennial divide, it appears appropriate that an interim progress report be crafted. This treatise is attempting to meet this objective. What follows traces the chronology of the recorded history of PCO in 4 parts.
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Affiliation(s)
- Eli Y. Adashi
- Department of Medical Science, the Warren Alpert Medical School, Brown University, Providence, Rhode Island
- Correspondence: Eli Y. Adashi, M.D., MS, Brown University, 272 George St, Providence, Rhode Island 02906.
| | - David Cibula
- Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University and General University Hospital (Central and Eastern European Gynecologic Oncology Group, CEEGOG), Prague, Czech Republic
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah
| | - Matthew Peterson
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah
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Di Giuseppe G, Ciccarelli G, Soldovieri L, Capece U, Cefalo CMA, Moffa S, Nista EC, Brunetti M, Cinti F, Gasbarrini A, Pontecorvi A, Giaccari A, Mezza T. First-phase insulin secretion: can its evaluation direct therapeutic approaches? Trends Endocrinol Metab 2023; 34:216-230. [PMID: 36858875 DOI: 10.1016/j.tem.2023.02.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/26/2023] [Accepted: 02/01/2023] [Indexed: 03/03/2023]
Abstract
Our work is aimed at unraveling the role of the first-phase insulin secretion in the natural history of type 2 diabetes mellitus (T2DM) and its interrelationship with insulin resistance and with β cell function and mass. Starting from pathophysiology, we investigate the impact of impaired secretion on glucose homeostasis and explore postmeal hyperglycemia as the main clinical feature, underlining its relevance in the management of the disease. We also review dietary and pharmacological approaches aimed at improving early secretory defects and restoring residual β cell function. Furthermore, we discuss possible approaches to detect early secretory defects in clinical practice. By providing a journey through human and animal data, we attempt a unification of the recent evidence in an effort to offer a new outlook on β cell secretion.
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Affiliation(s)
- Gianfranco Di Giuseppe
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Gea Ciccarelli
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Laura Soldovieri
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Umberto Capece
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Chiara M A Cefalo
- Department of Clinical and Molecular Medicine, University of Rome - Sapienza, Rome, Italy
| | - Simona Moffa
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Enrico C Nista
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Michela Brunetti
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Cinti
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Alfredo Pontecorvi
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Giaccari
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Teresa Mezza
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
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11
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Shah D, Rasool S. Ethnicity in polycystic ovary syndrome. Climacteric 2023; 26:15-20. [PMID: 36459492 DOI: 10.1080/13697137.2022.2144211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Polycystic ovary syndrome (PCOS) is the commonest gynecological endocrinopathy. Little is known about the exact etiopathogenesis and cardiometabolic mortality and morbidity in women with PCOS. PCOS is beyond the cosmetic concerns of an adolescent and fertility concerns of an adult and can cause serious unhealthy consequences in perimenopausal and postmenopausal age. This area needs to be assessed and addressed since the majority of these patients are lost to follow-up after completion of their families. Good evidence suggests that there are significant racial and ethnic differences in prevalence, insulin resistance, metabolic syndrome, hyperandrogenemia and the related cardiometabolic risk in women with PCOS.
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Affiliation(s)
- D Shah
- The Center for Women's Health and Fertility, Gynaecworld, Mumbai, India
| | - S Rasool
- Government Medical College, Dr Sabahat's Fertility Center, Srinagar, India
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12
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Dapas M, Dunaif A. Deconstructing a Syndrome: Genomic Insights Into PCOS Causal Mechanisms and Classification. Endocr Rev 2022; 43:927-965. [PMID: 35026001 PMCID: PMC9695127 DOI: 10.1210/endrev/bnac001] [Citation(s) in RCA: 134] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Indexed: 01/16/2023]
Abstract
Polycystic ovary syndrome (PCOS) is among the most common disorders in women of reproductive age, affecting up to 15% worldwide, depending on the diagnostic criteria. PCOS is characterized by a constellation of interrelated reproductive abnormalities, including disordered gonadotropin secretion, increased androgen production, chronic anovulation, and polycystic ovarian morphology. It is frequently associated with insulin resistance and obesity. These reproductive and metabolic derangements cause major morbidities across the lifespan, including anovulatory infertility and type 2 diabetes (T2D). Despite decades of investigative effort, the etiology of PCOS remains unknown. Familial clustering of PCOS cases has indicated a genetic contribution to PCOS. There are rare Mendelian forms of PCOS associated with extreme phenotypes, but PCOS typically follows a non-Mendelian pattern of inheritance consistent with a complex genetic architecture, analogous to T2D and obesity, that reflects the interaction of susceptibility genes and environmental factors. Genomic studies of PCOS have provided important insights into disease pathways and have indicated that current diagnostic criteria do not capture underlying differences in biology associated with different forms of PCOS. We provide a state-of-the-science review of genetic analyses of PCOS, including an overview of genomic methodologies aimed at a general audience of non-geneticists and clinicians. Applications in PCOS will be discussed, including strengths and limitations of each study. The contributions of environmental factors, including developmental origins, will be reviewed. Insights into the pathogenesis and genetic architecture of PCOS will be summarized. Future directions for PCOS genetic studies will be outlined.
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Affiliation(s)
- Matthew Dapas
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
| | - Andrea Dunaif
- Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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13
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Volatilomics as an Emerging Strategy to Determine Potential Biomarkers of Female Infertility: A Pilot Study. Biomedicines 2022; 10:biomedicines10112852. [DOI: 10.3390/biomedicines10112852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/02/2022] [Accepted: 11/04/2022] [Indexed: 11/09/2022] Open
Abstract
Due to its high prevalence, infertility has become a prominent public health issue, posing a significant challenge to modern reproductive medicine. Some clinical conditions that lead to female infertility include polycystic ovary syndrome (PCOS), endometriosis, and premature ovarian failure (POF). Follicular fluid (FF) is the biological matrix that has the most contact with the oocyte and can, therefore, be used as a predictor of its quality. Volatilomics has emerged as a non-invasive, straightforward, affordable, and simple method for characterizing various diseases and determining the effectiveness of their current therapies. In order to find potential biomarkers of infertility, this study set out to determine the volatomic pattern of the follicular fluid from patients with PCOS, endometriosis, and POF. The chromatographic data integration was performed through solid-phase microextraction (SPME), followed by gas chromatography–mass spectrometry (GC-MS). The findings pointed to specific metabolite patterns as potential biomarkers for the studied diseases. These open the door for further research into the relevant metabolomic pathways to enhance infertility knowledge and diagnostic tools. An extended investigation may, however, produce a new mechanistic understanding of the pathophysiology of the diseases.
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14
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Karavanaki K, Paschou SA, Tentolouris N, Karachaliou F, Soldatou A. Type 2 diabetes in children and adolescents: distinct characteristics and evidence-based management. Endocrine 2022; 78:280-295. [PMID: 36029440 DOI: 10.1007/s12020-022-03172-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 08/08/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE Since the dramatic rise of obesity prevalence in childhood and adolescence has contributed to increased rates of type 2 diabetes (T2D) in youth, we sought to explore current evidence-based management options for pediatric T2D patients. METHODS A comprehensive literature search was performed for studies of T2D in childhood and adolescence until September 2021. RESULTS Special pathophysiological and diagnostic characteristics of T2D in this age are presented, while the main focus of the article is on management. Lifestyle interventions with healthy diet and exercise are of great importance for the treatment of T2D in children and adolescents. Metformin and insulin remain the traditional therapeutical means, while liraglutide recently gained indication for children older than 10 years both in USA and Europe. Data on the use, efficacy, safety and therapeutic considerations of other pharmacological treatments in children and adolescents with T2D are critically discussed. CONCLUSION Although many new and promising therapeutic strategies have been introduced during recent years for the management of T2D in adults, available therapeutic options for the management of pediatric T2D remain limited.
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Affiliation(s)
- Kyriaki Karavanaki
- Diabetes and Obesity Unit, 2nd Department of Pediatrics, National and Kapodistrian University of Athens, "P&A Kyriakou" Children's Hospital, Athens, Greece
| | - Stavroula A Paschou
- Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Nicholas Tentolouris
- Diabetes Centre, First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, "Laikon" General Hospital, Athens, Greece
| | - Foteini Karachaliou
- Diabetes and Endocrine Clinic, 3rd Department of Pediatrics, National and Kapodistrian University of Athens, Attikon General Hospital, Athens, Greece
| | - Alexandra Soldatou
- Diabetes and Obesity Unit, 2nd Department of Pediatrics, National and Kapodistrian University of Athens, "P&A Kyriakou" Children's Hospital, Athens, Greece.
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15
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Brinca AT, Ramalhinho AC, Sousa Â, Oliani AH, Breitenfeld L, Passarinha LA, Gallardo E. Follicular Fluid: A Powerful Tool for the Understanding and Diagnosis of Polycystic Ovary Syndrome. Biomedicines 2022; 10:1254. [PMID: 35740276 PMCID: PMC9219683 DOI: 10.3390/biomedicines10061254] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) represents one of the leading causes of anovulatory infertility and affects 5% to 20% of women worldwide. Until today, both the subsequent etiology and pathophysiology of PCOS remain unclear, and patients with PCOS that undergo assisted reproductive techniques (ART) might present a poor to exaggerated response, low oocyte quality, ovarian hyperstimulation syndrome, as well as changes in the follicular fluid metabolites pattern. These abnormalities originate a decrease of Metaphase II (MII) oocytes and decreased rates for fertilization, cleavage, implantation, blastocyst conversion, poor egg to follicle ratio, and increased miscarriages. Focus on obtaining high-quality embryos has been taken into more consideration over the years. Nowadays, the use of metabolomic analysis in the quantification of proteins and peptides in biological matrices might predict, with more accuracy, the success in assisted reproductive technology. In this article, we review the use of human follicular fluid as the matrix in metabolomic analysis for diagnostic and ART predictor of success for PCOS patients.
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Affiliation(s)
- Ana Teresa Brinca
- Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal; (A.T.B.); (Â.S.); (L.B.)
| | - Ana Cristina Ramalhinho
- Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal; (A.T.B.); (Â.S.); (L.B.)
- Assisted Reproduction Laboratory of Academic Hospital of Cova da Beira, 6200-251 Covilhã, Portugal;
- C4-Cloud Computing Competence Centre, University of Beira Interior, 6201-001 Covilhã, Portugal
| | - Ângela Sousa
- Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal; (A.T.B.); (Â.S.); (L.B.)
| | - António Hélio Oliani
- Assisted Reproduction Laboratory of Academic Hospital of Cova da Beira, 6200-251 Covilhã, Portugal;
- São José do Rio Preto School of Medicine, Gynaecology and Obstetrics, São José do Rio Preto 15090-000, Brazil
| | - Luiza Breitenfeld
- Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal; (A.T.B.); (Â.S.); (L.B.)
- C4-Cloud Computing Competence Centre, University of Beira Interior, 6201-001 Covilhã, Portugal
| | - Luís A. Passarinha
- Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal; (A.T.B.); (Â.S.); (L.B.)
- UCIBIO–Applied Molecular Biosciences Unit, Departament of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2819-516 Caparica, Portugal
- Laboratório de Fármaco-Toxicologia, UBIMedical, University of Beira Interior, 6200-284 Covilhã, Portugal
| | - Eugenia Gallardo
- Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal; (A.T.B.); (Â.S.); (L.B.)
- Laboratório de Fármaco-Toxicologia, UBIMedical, University of Beira Interior, 6200-284 Covilhã, Portugal
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16
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Doycheva I, Ehrmann DA. Nonalcoholic fatty liver disease and obstructive sleep apnea in women with polycystic ovary syndrome. Fertil Steril 2022; 117:897-911. [PMID: 35512974 DOI: 10.1016/j.fertnstert.2022.03.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea are frequently associated with polycystic ovary syndrome (PCOS) but remain underrecognized. Women with PCOS have a 2-4 times higher risk of NAFLD independent of body mass index than healthy weight-matched controls. Insulin resistance and hyperandrogenemia together play a central role in the pathogenesis of NAFLD. Timely diagnosis of NAFLD is important because its progression can lead to nonalcoholic steatohepatitis and/or advanced liver fibrosis that can eventually result in liver-related mortality. The presence of NAFLD has also been associated with increased risks of type 2 diabetes, cardiovascular events, overall mortality, and extrahepatic cancers. The treatment of NAFLD in PCOS should include lifestyle interventions. Glucagon-like peptide 1 receptor agonists have shown promising results in patients with PCOS and NAFLD, but future randomized trails are needed to confirm this benefit. Likewise, the use of combined oral estrogen-progestin contraceptives may provide a benefit by decreasing hyperandrogenemia. Sleep disordered breathing is common among women with PCOS and is responsible for a number of cardiometabolic derangements. Obstructive sleep apnea is most often found in overweight and obese women with PCOS, but as is the case with NAFLD, its prevalence exceeds that of women who are of similar weight without PCOS. Left untreated, obstructive sleep apnea can precipitate or exacerbate insulin resistance, glucose intolerance, and hypertension.
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Affiliation(s)
- Iliana Doycheva
- Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois
| | - David A Ehrmann
- Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois.
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17
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Zhou R, Bruns CM, Bird IM, Kemnitz JW, Dumesic DA, Abbott DH. Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques. Int J Mol Sci 2022; 23:ijms23052635. [PMID: 35269778 PMCID: PMC8910161 DOI: 10.3390/ijms23052635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/12/2022] [Accepted: 02/23/2022] [Indexed: 11/16/2022] Open
Abstract
As in women with polycystic ovary syndrome (PCOS), hyperinsulinemia is associated with anovulation in PCOS-like female rhesus monkeys. Insulin sensitizers ameliorate hyperinsulinemia and stimulate ovulatory menstrual cycles in PCOS-like monkeys. To determine whether hyperinsulinemia (>694 pmol/L), alone, induces PCOS-like traits, five PCOS-like female rhesus monkeys with minimal PCOS-like traits, and four control females of similar mid-to-late reproductive years and body mass index, received daily subcutaneous injections of recombinant human insulin or diluent for 6−7 months. A cross-over experimental design enabled use of the same monkeys in each treatment phase. Insulin treatment unexpectedly normalized follicular phase duration in PCOS-like, but not control, females. In response to an intramuscular injection of 200 IU hCG, neither prenatally androgenized nor control females demonstrated ovarian hyperandrogenic responses while receiving insulin. An intravenous GnRH (100 ng/kg) injection also did not reveal evidence of hypergonadotropism. Taken together, these results suggest that experimentally induced adult hyperinsulinemia, alone, is insufficient to induce PCOS-like traits in female rhesus monkeys and to amplify intrinsic PCOS-like pathophysiology.
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Affiliation(s)
- Rao Zhou
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA; (R.Z.); (J.W.K.)
- Endocrinology Reproductive Physiology Training Program, University of Wisconsin, Madison, WI 53715, USA;
| | - Cristin M. Bruns
- Departments of Medicine, University of Wisconsin, Madison, WI 53715, USA;
| | - Ian M. Bird
- Endocrinology Reproductive Physiology Training Program, University of Wisconsin, Madison, WI 53715, USA;
- Departments of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715, USA
| | - Joseph W. Kemnitz
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA; (R.Z.); (J.W.K.)
- Departments of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53715, USA
| | - Daniel A. Dumesic
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
| | - David H. Abbott
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA; (R.Z.); (J.W.K.)
- Endocrinology Reproductive Physiology Training Program, University of Wisconsin, Madison, WI 53715, USA;
- Departments of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715, USA
- Correspondence:
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18
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Livadas S, Anagnostis P, Bosdou JK, Bantouna D, Paparodis R. Polycystic ovary syndrome and type 2 diabetes mellitus: A state-of-the-art review. World J Diabetes 2022; 13:5-26. [PMID: 35070056 PMCID: PMC8771268 DOI: 10.4239/wjd.v13.i1.5] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/30/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) often coexists with a wide spectrum of dysglycemic conditions, ranging from impaired glucose tolerance to type 2 diabetes mellitus (T2D), which occur to a greater extent compared to healthy body mass index-matched women. This concurrence of disorders is mainly attributed to common pathogenetic pathways linking the two entities, such as insulin resistance. However, due to methodological flaws in the available studies and the multifaceted nature of the syndrome, there has been substantial controversy as to the exact association between T2D and PCOS which has not yet been elucidated. The aim of this review is to present the best available evidence regarding the epidemiology of dysglycemia in PCOS, the unique pathophysiological mechanisms underlying the progression of dysglycemia, the most appropriate methods for assessing glycemic status and the risk factors for T2D development in this population, as well as T2D risk after transition to menopause. Proposals for application of a holistic approach to enable optimal management of T2D risk in PCOS are also provided. Specifically, adoption of a healthy lifestyle with adherence to improved dietary patterns, such the Mediterranean diet, avoidance of consumption of endocrine-disrupting foods and beverages, regular exercise, and the effect of certain medications, such as metformin and glucagon-like peptide 1 receptor agonists, are discussed. Furthermore, the maintenance of a healthy weight is highlighted as a key factor in achievement of a significant reduction of T2D risk in women with PCOS.
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Affiliation(s)
| | - Panagiotis Anagnostis
- Unit of Reproductive Endocrinology, 1st Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki 54636, Greece
| | - Julia K Bosdou
- Unit for Human Reproduction, 1st Department of Obstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki 54636, Greece
| | - Dimitra Bantouna
- Department of Pathology and Cytology, University of Patras School of Medicine, Patras 10563, Greece
| | - Rodis Paparodis
- Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, OH 23456, United States
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19
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Sinha P, Bhushan R. Correlation of serum homocysteine levels and hyperinsulinaemia with body mass index in polycystic ovarian syndrome. J Hum Reprod Sci 2022; 15:34-41. [PMID: 35494205 PMCID: PMC9053351 DOI: 10.4103/jhrs.jhrs_147_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 02/27/2022] [Accepted: 02/28/2022] [Indexed: 11/04/2022] Open
Abstract
Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women in reproductive age group. The interrelationship of serum homocysteine, homoeostatic assessment of insulin resistance (HOMA-IR) and body mass index amongst overweight, obese and non-obese PCOS patients is not fully established. Aims: We aimed to study the correlation of serum homocysteine levels and hyperinsulinaemia with body mass index (BMI) in PCOS patients. Study Setting and Design: This was a case–control study in which 35 women with PCOS and 35 non-PCOS women acting as controls were enrolled. Materials and Methods: Cases were identified by Rotterdam's criteria. (IR) indices, HOMA determination and serum homocysteine levels were determined and their correlation with BMI was studied. Statistical Analysis Used: Student's t-test and analysis of variance test were used for statistical analysis. The Pearson correlation coefficient was then used to estimate the correlation. Results: On overall evaluation, a significant positive correlation of fasting insulin, HOMA-IR and serum homocysteine) was observed (P < 0.05), however, on evaluating the correlation of these markers independently in cases and controls, only fasting insulin and HOMA-IR showed a significant correlation. In a multivariate model where PCOS was considered a dependent variable with age, fasting glucose, HOMA-IR, serum homocysteine and body mass index as the independent variables, only serum homocysteine levels were found to be significantly associated with the dependent variable (odds ratio = 1.172; 95% confidence interval = 1.032–1.330). Conclusion: PCOS women had significantly higher mean fasting glucose, fasting insulin, HOMA-IR and homocysteine levels as compared to non-PCOS controls. Mean HOMA-IR, homocysteine and fasting insulin levels showed a significant incremental trend with increasing BMI category in overall evaluation as well as in cases and controls independently.
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20
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Garcia-Hernandez SC, Porchia LM, Pacheco-Soto BT, López-Bayghen E, Gonzalez-Mejia ME. Metformin does not improve insulin sensitivity over hypocaloric diets in women with polycystic ovary syndrome: a systematic review of 12 studies. Gynecol Endocrinol 2021; 37:968-976. [PMID: 33899646 DOI: 10.1080/09513590.2021.1913114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
OBJECTIVE To improve insulin action, most clinicians prescribe Metformin in patients with insulin resistance (IR). Women with polycystic ovary syndrome (PCOS), in which IR is an important physiopathological mechanism, treatment with Metformin and specialized diets have been suggested to reduce the patient's IR. However, numerous studies have demonstrated conflicting results with respect to supplementing a diet with Metformin. Therefore, we conducted a meta-analysis to determine if Metformin provides a benefit in conjunction with hypocaloric diets to improve insulin sensitivity in PCOS women. METHODS PubMed, SCOPUS, LILACS, and EBSCO databases and retrieved studies' bibliographies were searched for prospective studies that investigated the effect between Metformin and hypocaloric diets in PCOS women until April 2020. Pre- and post-intervention values for fasting plasma glucose (FPG), fasting plasma insulin (FPI), and IR indices (HOMA1-IR, ISI, and QUICKI) were extracted. Using Comprehensive Meta-Analysis software, the pooled standard difference in the means (SDM) and 95%CIs were calculated. RESULTS 11 publications (12 studies) were selected. There was not a benefit of adding Metformin to a hypocaloric diet with respect to FPG (SDM= -0.17; 95%CI: -0.48-0.14, p = .28) and FPI (SDM = 0.16; 95%CI: -0.24-0.55, p = .45). None of the IR indices also demonstrated any benefit of using Metformin when a diet intervention was implemented (HOMA1-IR: SDM = 0.28; 95%CI: -0.27-0.84, p = .315; ISI: SDM = 0.344; 95%CI: -0.17-0.85, p = .186; QUICKI: SDM= -0.01; 95%CI: -0.42-0.41, p = .968). CONCLUSION Here, we determined that adding Metformin to hypocaloric diets did not improve serum glucose or insulin concentrations as well as IR in PCOS women.
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Affiliation(s)
| | - Leonardo M Porchia
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - Blanca T Pacheco-Soto
- Departamento de Genética, Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
| | - Esther López-Bayghen
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - M Elba Gonzalez-Mejia
- Departamento de Genética, Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico
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21
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Kumariya S, Ubba V, Jha RK, Gayen JR. Autophagy in ovary and polycystic ovary syndrome: role, dispute and future perspective. Autophagy 2021; 17:2706-2733. [PMID: 34161185 PMCID: PMC8526011 DOI: 10.1080/15548627.2021.1938914] [Citation(s) in RCA: 155] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 05/30/2021] [Accepted: 06/02/2021] [Indexed: 02/05/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is a unification of endocrine and metabolic disorders and has become immensely prevalent among women of fertile age. The prime organ affected in PCOS is the ovary and its distressed functioning elicits disturbed reproductive outcomes. In the ovary, macroautophagy/autophagy performs a pivotal role in directing the chain of events starting from oocytes origin until its fertilization. Recent discoveries demonstrate a significant role of autophagy in the pathogenesis of PCOS. Defective autophagy in the follicular cells during different stages of follicles is observed in the PCOS ovary. Exploring different autophagy pathways provides a platform for predicting the possible cause of altered ovarian physiology in PCOS. In this review, we have emphasized autophagy's role in governing follicular development under normal circumstances and in PCOS, including significant abnormalities associated with PCOS such as anovulation, hyperandrogenemia, metabolic disturbances, and related abnormality. So far, few studies have linked autophagy and PCOS and propose its essential role in PCOS progression. However, detailed knowledge in this area is lacking. Here we have summarized the latest knowledge related to autophagy associated with PCOS. This review's main objective is to provide a background of autophagy in the ovary, its possible connection with PCOS and suggested a novel proposal for future studies to aid a better understanding of PCOS pathogenesis.Abbreviations: AE: androgen excess; AF: antral follicle; AKT/PKB: AKT serine/threonine kinase; AMH: anti-Mullerian hormone; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BMP: bone morphogenetic protein; CASP3: caspase 3; CL: corpus luteum; CYP17A1/P450C17: cytochrome P450 family 17 subfamily A member 1; CYP19A1: cytochrome P450 family 19 subfamily A member 1; DHEA: dehydroepiandrosterone; EH: endometrial hyperplasia; FF: follicular fluid; FOXO: forkhead box O; FSH: follicle stimulating hormone; GC: granulosa cell; GDF: growth differentiation factor; HA: hyperandrogenemia; HMGB1: high mobility group box 1; IGF1: insulin like growth factor 1; INS: insulin; IR: insulin resistance; LHCGR/LHR: luteinizing hormone/choriogonadotropin receptor; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase; MAPK8/JNK: mitogen-activated protein kinase 8; MTOR: mechanistic target of rapamycin kinase; MTORC: mechanistic target of rapamycin complex; NAFLD: nonalcoholic fatty liver disease; NFKB: nuclear factor kappa B; OLR1/LOX-1: oxidized low density lipoprotein receptor 1; oxLDL: oxidized low-density lipoproteins; PA: palmitic acid; PCOS: polycystic ovary syndrome; PF: primary follicle; PGC: primordial germ cell; PI3K: phosphoinositide 3-kinase; PMF: primordial follicle; ROS: reactive oxygen species; RP: resting pool; SIRT1: sirtuin 1; SQSTM1/p62: sequestosome 1; T2DM: type 2 diabetes mellitus; TC: theca cell; TUG1: taurine up-regulated 1.
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Affiliation(s)
- Sanjana Kumariya
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute CSIR-Central Drug Research Institute, Lucknow, India
| | - Vaibhave Ubba
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Rajesh K. Jha
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, Ghaziabad, India
| | - Jiaur R. Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, Ghaziabad, India
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India
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22
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Dube R. Does endothelial dysfunction correlate with endocrinal abnormalities in patients with polycystic ovary syndrome? Avicenna J Med 2021; 6:91-102. [PMID: 27843797 PMCID: PMC5054651 DOI: 10.4103/2231-0770.191445] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
To study and critically analyze the published evidence on correlation of hormonal abnormalities and endothelial dysfunction (ED) in polycystic ovary syndrome (PCOS) through a systematic review. The databases including MEDLINE, PubMed, Up-To-Date, and Science Direct were searched using Medical subject handling terms and free text term keywords such as endocrine abnormalities in PCOS, ED assessment in PCOS, ED in combination with insulin resistance (IR), hyperandrogenism (HA), increased free testosterone, free androgen index (FAI), gonadotrophin levels, luteinizing hormone (LH), prolactin, estrogen, adipocytokines to search trials, and observational studies published from January 1987 to September 2015. Authors of original studies were contacted for additional data when necessary. PCOS increases the risk of cardiovascular disease in women. ED, which is a reliable indicator of cardiovascular risk in general population, is seen in most (but not all) women with PCOS. IR, seen in 70% patients with PCOS, is associated with ED in these women, but patients can have normal endothelial function even in the presence of IR. Free testosterone and FAI are consistently associated with ED, but endothelial function can be normal despite HA. Estradiol (not estrone) appears to be protective against ED though estrone is the predominant estrogen produced in PCOS. Increased levels of adipocytokines (visfatin) are promising in predicting ED and cardiovascular risk. However, more studies are required focusing on direct correlation of levels of prolactin, LH, estrone, and visfatin with ED in PCOS.
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Affiliation(s)
- Rajani Dube
- Department of Obstetrics and Gynaecology, Ras al-Khaimah Medical and Health Sciences University, Al Qusaidat, Ras al-Khaimah, United Arab Emirates
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23
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Phylactou M, Clarke SA, Patel B, Baggaley C, Jayasena CN, Kelsey TW, Comninos AN, Dhillo WS, Abbara A. Clinical and biochemical discriminants between functional hypothalamic amenorrhoea (FHA) and polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2021; 95:239-252. [PMID: 33354766 PMCID: PMC11497304 DOI: 10.1111/cen.14402] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND Secondary oligo/amenorrhoea occurs in 3%-5% of women of reproductive age. The two most common causes are polycystic ovary syndrome (PCOS) (2%-13%) and functional hypothalamic amenorrhoea (FHA) (1%-2%). Whilst both conditions have distinct pathophysiology and their diagnosis is supported by guidelines, in practice, differentiating these two common causes of menstrual disturbance is challenging. Moreover, both diagnoses are qualified by the need to first exclude other causes of menstrual disturbance. AIM To review clinical, biochemical and radiological parameters that could aid the clinician in distinguishing PCOS and FHA as a cause of menstrual disturbance. RESULTS FHA is uncommon in women with BMI > 24 kg/m2 , whereas both PCOS and FHA can occur in women with lower BMIs. AMH levels are markedly elevated in PCOS; however, milder increases may also be observed in FHA. Likewise, polycystic ovarian morphology (PCOM) is more frequently observed in FHA than in healthy women. Features that are differentially altered between PCOS and FHA include LH, androgen, insulin, AMH and SHBG levels, endometrial thickness and cortisol response to CRH. Other promising diagnostic tests with the potential to distinguish these two conditions pending further study include assessment of 5-alpha-reductase activity, leptin, INSL3, kisspeptin and inhibin B levels. CONCLUSION Further data directly comparing the discriminatory potential of these markers to differentiate PCOS and FHA in women with secondary amenorrhoea would be of value in defining an objective probability for PCOS or FHA diagnosis.
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Affiliation(s)
- Maria Phylactou
- Section of Endocrinology and Investigative MedicineHammersmith HospitalImperial College LondonLondonUK
| | - Sophie A. Clarke
- Section of Endocrinology and Investigative MedicineHammersmith HospitalImperial College LondonLondonUK
| | - Bijal Patel
- Section of Endocrinology and Investigative MedicineHammersmith HospitalImperial College LondonLondonUK
| | - Caitlin Baggaley
- Section of Endocrinology and Investigative MedicineHammersmith HospitalImperial College LondonLondonUK
| | - Channa N. Jayasena
- Section of Endocrinology and Investigative MedicineHammersmith HospitalImperial College LondonLondonUK
- Department of EndocrinologyImperial College Healthcare NHS TrustLondonUK
| | - Tom W. Kelsey
- School of Computer ScienceUniversity of St AndrewsSt AndrewsUK
| | - Alexander N. Comninos
- Section of Endocrinology and Investigative MedicineHammersmith HospitalImperial College LondonLondonUK
- Department of EndocrinologyImperial College Healthcare NHS TrustLondonUK
| | - Waljit S. Dhillo
- Section of Endocrinology and Investigative MedicineHammersmith HospitalImperial College LondonLondonUK
- Department of EndocrinologyImperial College Healthcare NHS TrustLondonUK
| | - Ali Abbara
- Section of Endocrinology and Investigative MedicineHammersmith HospitalImperial College LondonLondonUK
- Department of EndocrinologyImperial College Healthcare NHS TrustLondonUK
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24
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Abstract
Current diagnostic criteria for polycystic ovary syndrome (PCOS) are based on expert opinion. This article reviews the rationale for and the limitations of these criteria as well as which criteria to use and when. The insights provided into PCOS pathogenesis by modern genetic analyses and the promise of objective data mining approaches for biologically relevant disease classification are discussed.
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Affiliation(s)
- Sydney Chang
- Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Zucker School of Medicine at Hofstra/Northwell, 210A E 64th St. 1st Floor, New York, NY 10065, USA
| | - Andrea Dunaif
- Department of Medicine, Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, Atran Building, 1428 Madison Avenue, 4th Floor, Room 4-36, New York, NY 10029, USA.
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25
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Jayaraj A, Schwanz HA, Spencer DJ, Bhasin S, Hamilton JA, Jayaram B, Goldman AL, Krishna M, Krishnan M, Shah A, Jin Z, Krenzel E, Nair SN, Ramesh S, Guo W, Wagner G, Arthanari H, Peng L, Lawney B, Jasuja R. Allosterically Coupled Multisite Binding of Testosterone to Human Serum Albumin. Endocrinology 2021; 162:5944062. [PMID: 33125473 PMCID: PMC7774055 DOI: 10.1210/endocr/bqaa199] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Indexed: 12/25/2022]
Abstract
Human serum albumin (HSA) acts as a carrier for testosterone, other sex hormones, fatty acids, and drugs. However, the dynamics of testosterone's binding to HSA and the structure of its binding sites remain incompletely understood. Here, we characterize the dynamics of testosterone's binding to HSA and the stoichiometry and structural location of the binding sites using 2-dimensional nuclear magnetic resonance (2D NMR), fluorescence spectroscopy, 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid dipotassium salt partitioning, and equilibrium dialysis, complemented by molecular modeling. 2D NMR studies showed that testosterone competitively displaced 18-[13C]-oleic acid from at least 3 known fatty acid binding sites on HSA that also bind many drugs. Binding isotherms of testosterone's binding to HSA generated using fluorescence spectroscopy and equilibrium dialysis were nonlinear and the apparent dissociation constant varied with different concentrations of testosterone and HSA. The binding isotherms neither conformed to a linear binding model with 1:1 stoichiometry nor to 2 independent binding sites; the binding isotherms were most consistent with 2 or more allosterically coupled binding sites. Molecular dynamics studies revealed that testosterone's binding to fatty acid binding site 3 on HSA was associated with conformational changes at site 6, indicating that residues in in these 2 distinct binding sites are allosterically coupled. There are multiple, allosterically coupled binding sites for testosterone on HSA. Testosterone shares these binding sites on HSA with free fatty acids, which could displace testosterone from HSA under various physiological states or disease conditions, affecting its bioavailability.
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Affiliation(s)
- Abhilash Jayaraj
- Department of Chemistry, Bioinformatics and Computational Biology, Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi, India
| | - Heidi A Schwanz
- Department of Biophysics, Boston University School of Medicine, Boston, MA, USA
| | - Daniel J Spencer
- Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Shalender Bhasin
- Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - James A Hamilton
- Department of Biophysics, Boston University School of Medicine, Boston, MA, USA
| | - B Jayaram
- Department of Chemistry, Bioinformatics and Computational Biology, Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi, India
| | - Anna L Goldman
- Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Meenakshi Krishna
- Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Maya Krishnan
- Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Aashay Shah
- Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA
| | - Zhendong Jin
- Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA
| | - Eileen Krenzel
- Department of Biophysics, Boston University School of Medicine, Boston, MA, USA
| | - Sashi N Nair
- Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Sid Ramesh
- Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Wen Guo
- Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Gerhard Wagner
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Haribabu Arthanari
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Liming Peng
- Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Brian Lawney
- Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA
| | - Ravi Jasuja
- Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Correspondence: Ravi Jasuja, Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115. E-mail:
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26
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Abstract
Probiotics and synbiotics are known to have beneficial effects on human health and disease. Hirsutism, a disorder that is characterised by the presence of coarse terminal hairs in a male-like pattern, is usually caused by elevated androgen levels in blood plasma. This disorder is usually observed in PCOS women and it is linked to insulin resistance (IR). Although idiopathic hirsutism (IH) is not shown to have excess androgen production from the ovarian and adrenal glands, increased 5α-reductase in peripheral tissues and insulin resistance are common observations. The effect of probiotics and synbiotics have been recently studied on PCOS women; androgens were also included in the hormonal groups that were investigated. Only a few studies focus on hirsutism and the potential effect of the beneficial microbes mentioned, whereas the increasing interest on insulin resistance and synbiotics indicate a potential beneficial effect on hirsutism through the management of insulin resistance.
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Affiliation(s)
- Vasiliki Lolou
- Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK
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27
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Li H, Zhang G, Guo Y, Deng J, Fischer H, Craig LB, Kem DC, Yu X. Autoimmune activation of the GnRH receptor induces insulin resistance independent of obesity in a female rat model. Physiol Rep 2021; 8:e14672. [PMID: 33356018 PMCID: PMC7757370 DOI: 10.14814/phy2.14672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 11/24/2022] Open
Abstract
Polycystic ovary syndrome (PCOS), a metabolic and reproductive disease, is frequently associated with type 2 diabetes. We have demonstrated activating autoantibodies (AAb) directed toward the second extracellular loop (ECL2) of the gonadotropin-releasing hormone receptor (GnRHR) are present in a significant subgroup of PCOS patients. It is unclear whether GnRHR-AAb can induce peripheral tissue insulin resistance (IR) in animal models. Sixteen rats were divided equally into a GnRHR ECL2 peptide-immunized group (IMM group) and a control group (CON group). Sera GnRHR-AAb titer, luteinizing hormone (LH), and testosterone (T) were higher in IMM rats compared with CON rats. No significant difference in fasting blood glucose was observed between the two groups. However, the plasma glucose level at other time points of the IMM group was higher than that of the CON group during an intraperitoneal glucose tolerance test (IPGTT) and an insulin tolerance test (ITT) (p < 0.01). These data support the likelihood of the GnRHR-AAb induction of glucose intolerance and IR. Compared with the CON group, the IMM group showed a significant increase in insulin-stimulated phosphorylation of IRS-1 (p-IRS-1 S636/639) and a decrease in insulin-stimulated phosphorylation of Akt (p-AKT S473). Expression of the glucose transport genes including GLUT-2 in liver and GLUT-4 in white adipose tissue and skeletal muscle was significantly decreased in IMM rats compared with the CON rats. Serum levels of proinflammatory cytokines (TNF-α, IL-1α, and IL-18) were increased, while anti-inflammatory cytokines (IL-4 and IL-10) were decreased in the IMM group. Taken together, elevated GnRHR-AAb enhanced LH, hyperandrogenism, and inflammation. These changes are likely related to the observed peripheral tissue IR through the downregulation of the insulin-stimulated IRS/PI3K/Akt/Glut signaling pathway.
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Affiliation(s)
- Hongliang Li
- Section of Endocrinology and DiabetesDepartment of MedicineUniversity of Oklahoma Health Sciences CenterOklahomaOKUSA
| | - Gege Zhang
- Section of Endocrinology and DiabetesDepartment of MedicineUniversity of Oklahoma Health Sciences CenterOklahomaOKUSA
- Cardiac Pacing and Electrophysiology DepartmentThe First Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
- Xinjiang Key Laboratory of Cardiac Electrophysiology and RemodelingThe First Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
| | - Yankai Guo
- Section of Endocrinology and DiabetesDepartment of MedicineUniversity of Oklahoma Health Sciences CenterOklahomaOKUSA
- Cardiac Pacing and Electrophysiology DepartmentThe First Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
- Xinjiang Key Laboratory of Cardiac Electrophysiology and RemodelingThe First Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
| | - Jielin Deng
- Section of Endocrinology and DiabetesDepartment of MedicineUniversity of Oklahoma Health Sciences CenterOklahomaOKUSA
- Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanHubeiChina
| | - Hayley Fischer
- Section of Endocrinology and DiabetesDepartment of MedicineUniversity of Oklahoma Health Sciences CenterOklahomaOKUSA
| | - LaTasha B. Craig
- Section of Reproductive Endocrinology & InfertilityDepartment of Obstetrics & GynecologyUniversity of Oklahoma Health Sciences CenterOklahomaOKUSA
| | - David C. Kem
- Section of Endocrinology and DiabetesDepartment of MedicineUniversity of Oklahoma Health Sciences CenterOklahomaOKUSA
| | - Xichun Yu
- Section of Endocrinology and DiabetesDepartment of MedicineUniversity of Oklahoma Health Sciences CenterOklahomaOKUSA
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28
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Abstract
(1) Background: Myoinositol (MI) and D-chiro-inositol (DCI) are involved in a number of biochemical pathways within oocytes having a role in oocyte maturation, fertilization, implantation, and post-implantation development. Both inositols have a role in insulin signaling and hormonal synthesis in the ovaries. (2) Methods: Literature search (with key words: inositols, myo-inositol, d-chiro-inositol, PCOS) was done in PubMed until Sept. 2020 and 197 articles were identified, of which 47 were of clinical trials (35 randomized controlled trials). (3) Results: Many studies have demonstrated that in patients with polycystic ovarian syndrome (PCOS) MI treatment improved ovarian function and fertility, decreased the severity of hyperandrogenism including acne and hirsutism, positively affected metabolic aspects, and modulated various hormonal parameters deeply involved in the reproductive axis function and ovulation. Thus treating with MI has become a novel method to ameliorate PCOS symptoms, improve spontaneous ovulation, or induce ovulation. The current review is focused on the effects of MI and DCI alone or in combination with other agents on the pathological features of PCOS with focus on insulin resistance and adverse metabolic outcomes. (4) Conclusions: The available clinical data suggest that MI, DCI, and their combination in physiological ratio 40:1 with or without other compound could be beneficial for improving metabolic, hormonal, and reproductive aspects of PCOS.
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Affiliation(s)
- Zdravko Kamenov
- Department of Internal Medicine, Clinic of Endocrinology University Hospital Alexandrovska, Medical University—Sofia, 1431 Sofia, Bulgaria;
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29
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30
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Kurnaz E, Çetinkaya S, Özalkak Ş, Bayramoğlu E, Demirci G, Öztürk HS, Erdeve ŞS, Aycan Z. Serum Fetuin-A and Insulin Levels in Classic Congenital Adrenal Hyperplasia. Horm Metab Res 2020; 52:654-659. [PMID: 32108931 DOI: 10.1055/a-1116-2173] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Androgens play a pivotal role in non-reproductive organs such as the kidney, heart, liver, and pancreas. As androgen receptors are expressed in pancreatic and liver cells, excess testosterone can result in hypersecretion of insulin and fetuin-A, a protein produced in the liver. The expression of fetuin-A, a natural inhibitor of tyrosine kinase activity in muscle and liver, leads to insulin resistance. In addition, insulin and fetuin-A levels are thought to be affected by drugs such as glucocorticoids (GCs) and fludrocortisone. However, whether fetuin-A and insulin levels are affected by androgens and GCs in patients with classic congenital adrenal hyperplasia (CAH) is unknown. This cross-sectional study included 56 CAH patients and 70 controls. Analyses were stratified by sex and prepubertal/pubertal status to control for potential changes in serum metabolic/inflammatory markers associated with the production of sex steroids. Fasting blood glucose, insulin, triglyceride, total cholesterol, high density lipoprotein-cholesterol, aspartate aminotransferase, alanine aminotransferase, fetuin-A, and high-sensitivity C-reactive protein (hs-CRP) levels were measured in blood samples. In addition, 17α-hydroxyprogesterone, androstenedione, total testosterone, free testosterone, and dehydroepiandrosterone sulfate levels were measured before medication was administered. Insulin and fetuin-A levels were significantly higher in CAH patients than in controls. The unfavourably high levels of these substances exhibited a positive correlation with total and free testosterone. Regression analysis revealed that fetuin-A and free testosterone were the only independent predictors of the insulin level, while insulin and free testosterone levels significantly predicted the fetuin-A level (R2=42.7% and 59.8%). Differences were also observed in triglyceride and hs-CRP levels between the pubertal and prepubertal groups. We conclude that serum fetuin-A and insulin levels may be associated with androgens in CAH patients.
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Affiliation(s)
- Erdal Kurnaz
- Pediatric Endocrinology Clinic, Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, Ankara, Turkey
| | - Semra Çetinkaya
- Pediatric Endocrinology Clinic, Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, Ankara, Turkey
| | - Şervan Özalkak
- Pediatric Endocrinology Clinic, Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, Ankara, Turkey
| | - Elvan Bayramoğlu
- Pediatric Endocrinology Clinic, Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, Ankara, Turkey
| | - Gülşah Demirci
- Department of Medical Biochemistry, Ankara University Medical Faculty, Ankara, Turkey
| | - Hasan Serdar Öztürk
- Department of Medical Biochemistry, Ankara University Medical Faculty, Ankara, Turkey
| | - Şenay Savaş Erdeve
- Pediatric Endocrinology Clinic, Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, Ankara, Turkey
| | - Zehra Aycan
- Pediatric Endocrinology Clinic, Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, Ankara, Turkey
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31
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Mandal S, Pradhan RR, Mols Kowalczewski B. Atypical Presentation of Myocardial Infarction in a Young Patient With Polycystic Ovarian Syndrome. Cureus 2020; 12:e9494. [PMID: 32879818 PMCID: PMC7458705 DOI: 10.7759/cureus.9494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Polycystic ovarian syndrome (PCOS) is one of the common endocrinopathy noted in women of childbearing age groups. Patients with PCOS have increased cardiovascular risk factors compared with age-matched control; hence, these patients are believed to be at an increased risk for cardiovascular events. Here, we report a case of a young female with PCOS, who presented with atypical back pain in the thoracic region. Initially, her electrocardiogram (EKG) and troponin were normal; hence, it was thought to be a muscle spasm but the back pain continued; repeat EKG and troponin came abnormal suggestive of myocardial infarction (MI). The patient underwent primary percutaneous coronary intervention and was discharged on dual antiplatelet therapy. MI is common in patients with PCOS. MI is the most important differential diagnosis in any patients of PCOS presenting with chest pain or back pain. Early diagnosis and prompt treatment of MI in patients with PCOS prevent adverse outcomes.
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Affiliation(s)
- Shobha Mandal
- Internal Medicine, Guthrie Robert Packer Hospital, Sayre, USA
| | - Ravi R Pradhan
- Internal Medicine, Tribhuvan University Institute of Medicine, Kathmandu, NPL
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32
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Álvarez-Villalobos NA, Rodríguez-Gutiérrez R, González-Saldivar G, Sánchez-García A, Gómez-Flores M, Quintanilla-Sánchez C, Treviño-Álvarez AM, Mancillas-Adame LG, González-González JG. Acanthosis nigricans in middle-age adults: A highly prevalent and specific clinical sign of insulin resistance. Int J Clin Pract 2020; 74:e13453. [PMID: 31769902 DOI: 10.1111/ijcp.13453] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 10/12/2019] [Accepted: 11/20/2019] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) precedes the diagnosis of many metabolic and non-metabolic illnesses, including type 2 diabetes mellitus (T2DM). Acanthosis nigricans (AN) is a clinical sign associated with IR. However, AN prevalence and diagnostic accuracy in middle-age adults before or at the time of prediabetes/diabetes diagnosis remain uncertain. METHODS With the aim to define AN prevalence and diagnostic accuracy, adults between 40 and 60 years of age were consecutively invited to participate in the study. Participants were categorised into one of two main groups: individuals with normoglycaemia (group 1) and hyperglycaemia (group 2 [ie, prediabetes/diabetes]). Demographic, clinical, anthropometric characteristics, homeostasis model assessment of IR, homeostatic model assessment of β-cell function, as well as the presence of AN on the neck, axillae, elbows and knuckles were assessed. RESULTS A total of 320 consecutive participants with a mean age of 49.3 years (59.4% women) were included. Overall, AN prevalence was 46.3%, while AN in group 1 and group 2 was 36.3% and 49.6%, respectively (P = .04). The most common affected sites in group 1 (n = 80) were the knuckles (21.2%) and the neck (17.5%), while in group 2 (n = 240), the neck (29.6%) followed by the knuckles (26.7%). The specificity and positive predictive value of AN for IR were 0.85 and 0.86 in group 1 and 0.90 and 0.96 in group 2, respectively. CONCLUSIONS In middle-age adults, within the entire spectrum of carbohydrate tolerance, AN is highly prevalent and specific. This finding supports its assessment as a reliable and convenient clinical sign of IR. The understanding of AN behaviour through different carbohydrate tolerance strata, and its different locations, could lead to early detection of individuals at high metabolic risk or help direct a more pathophysiological treatment approach in patients with T2DM.
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Affiliation(s)
- Neri Alejandro Álvarez-Villalobos
- Research Unit, Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
- Knowledge and Evaluation Research Unit in Endocrinology, Mayo Clinic, Rochester, MN, USA
- Plataforma INVEST Medicina UANL-KER Unit Mayo Clinic (KER Unit México), Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
| | - René Rodríguez-Gutiérrez
- Knowledge and Evaluation Research Unit in Endocrinology, Mayo Clinic, Rochester, MN, USA
- Plataforma INVEST Medicina UANL-KER Unit Mayo Clinic (KER Unit México), Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
- Endocrinology Division, Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
| | - Gloria González-Saldivar
- Dermatology Division, Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
| | - Adriana Sánchez-García
- Endocrinology Division, Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
| | - Minerva Gómez-Flores
- Dermatology Division, Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
| | - Carolina Quintanilla-Sánchez
- Research Unit, Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
| | - Andrés Marcelo Treviño-Álvarez
- Research Unit, Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
| | - Leonardo Guadalupe Mancillas-Adame
- Endocrinology Division, Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
| | - José Gerardo González-González
- Research Unit, Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
- Plataforma INVEST Medicina UANL-KER Unit Mayo Clinic (KER Unit México), Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
- Endocrinology Division, Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez", Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico
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Mezza T, Cinti F, Cefalo CMA, Pontecorvi A, Kulkarni RN, Giaccari A. β-Cell Fate in Human Insulin Resistance and Type 2 Diabetes: A Perspective on Islet Plasticity. Diabetes 2019; 68:1121-1129. [PMID: 31109941 PMCID: PMC6905483 DOI: 10.2337/db18-0856] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 03/17/2019] [Indexed: 12/23/2022]
Abstract
Although it is well established that type 2 diabetes (T2D) is generally due to the progressive loss of β-cell insulin secretion against a background of insulin resistance, the actual correlation of reduced β-cell mass to its defective function continues to be debated. There is evidence that a compensatory increase in β-cell mass, and the consequent insulin secretion, can effectively cope with states of insulin resistance, until hyperglycemia supervenes. Recent data strongly indicate that the mechanisms by which islets are able to compensate in response to insulin resistance in peripheral tissues is secondary to hyperplasia, as well as the activation of multiple cellular machineries with diverse functions. Importantly, islet cells exhibit plasticity in altering their endocrine commitment; for example, by switching from secretion of glucagon to secretion of insulin and back (transdifferentiation) or from an active secretory state to a nonsecretory quiescent state (dedifferentiation) and back. Lineage tracing (a method used to track each cell though its differentiation process) has demonstrated these potentials in murine models. A limitation to drawing conclusions from human islet research is that most studies are derived from human autopsy and/or organ donor samples, which lack in vivo functional and metabolic profiling. In this review, we specifically focus on evidence of islet plasticity in humans-from the normal state, progressing to insulin resistance to overt T2D-to explain the seemingly contradictory results from different cross-sectional studies in the literature. We hope the discussion on this intriguing scenario will provide a forum for the scientific community to better understand the disease and in the long term pave the way for personalized therapies.
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Affiliation(s)
- Teresa Mezza
- U.O.C. Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italia
- Istituto di Patologia Speciale Medica e Semeiotica Clinica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Francesca Cinti
- U.O.C. Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italia
- Istituto di Patologia Speciale Medica e Semeiotica Clinica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Chiara Maria Assunta Cefalo
- U.O.C. Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italia
- Istituto di Patologia Speciale Medica e Semeiotica Clinica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Alfredo Pontecorvi
- U.O.C. Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italia
- Istituto di Patologia Speciale Medica e Semeiotica Clinica, Università Cattolica del Sacro Cuore, Roma, Italia
| | - Rohit N Kulkarni
- Islet Cell & Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Andrea Giaccari
- U.O.C. Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italia
- Istituto di Patologia Speciale Medica e Semeiotica Clinica, Università Cattolica del Sacro Cuore, Roma, Italia
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Jacewicz-Święcka M, Kowalska I. Polycystic ovary syndrome and the risk of cardiometabolic complications in longitudinal studies. Diabetes Metab Res Rev 2018; 34:e3054. [PMID: 30089337 DOI: 10.1002/dmrr.3054] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Revised: 06/18/2018] [Accepted: 07/29/2018] [Indexed: 12/11/2022]
Abstract
The purpose of this study was to perform a review of the longitudinal studies to determine whether polycystic ovary syndrome is associated with higher prevalence of metabolic complications and cardiovascular morbidity and mortality. The primary outcomes included body mass index, metabolic syndrome and its components (waist circumference, lipid profile, arterial hypertension, abnormal glucose metabolism (impaired fasting glucose, impaired glucose tolerance, type 2 diabetes), insulin resistance, and cardiovascular diseases like stroke, angina, and coronary heart disease. Complications in pregnant women were beyond the scope of this review. PubMed database (1992-2018) was searched to identify proper publications. Finally, data from 47 articles were analysed. Studies differed in the design (prospective, retrospective, cohort, observational), research methods, polycystic ovary syndrome diagnostic criteria, studied populations, race, and ethnicity of the participants. Based on the data collected, it appears that women with polycystic ovary syndrome have higher prevalence of obesity, abdominal fat distribution, dyslipidaemia and deterioration of glucose metabolism, but increased prevalence of cardiovascular diseases is not proven.
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Affiliation(s)
- Małgorzata Jacewicz-Święcka
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Irina Kowalska
- Department of Internal Medicine and Metabolic Diseases, Medical University of Bialystok, Bialystok, Poland
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Ibáñez L, Oberfield SE, Witchel S, Auchus RJ, Chang RJ, Codner E, Dabadghao P, Darendeliler F, Elbarbary NS, Gambineri A, Garcia Rudaz C, Hoeger KM, López-Bermejo A, Ong K, Peña AS, Reinehr T, Santoro N, Tena-Sempere M, Tao R, Yildiz BO, Alkhayyat H, Deeb A, Joel D, Horikawa R, de Zegher F, Lee PA. An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence. Horm Res Paediatr 2018; 88:371-395. [PMID: 29156452 DOI: 10.1159/000479371] [Citation(s) in RCA: 230] [Impact Index Per Article: 32.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 07/10/2017] [Indexed: 12/11/2022] Open
Abstract
This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.
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Affiliation(s)
- Lourdes Ibáñez
- Endocrinology, Hospital Sant Joan de Deu, Esplugues, Barcelona, Spain.,CIBERDEM, ISCIII, Madrid, Spain
| | - Sharon E Oberfield
- Division of Pediatric Endocrinology, CUMC, New York-Presbyterian Morgan Stanley Children's Hospital, New York, New York, USA
| | - Selma Witchel
- Division of Pediatric Endocrinology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA
| | | | - R Jeffrey Chang
- Department of Reproductive Medicine, UCSD School of Medicine, La Jolla, California, USA
| | - Ethel Codner
- Institute of Maternal and Child Research, University of Chile, School of Medicine, Santiago, Chile
| | - Preeti Dabadghao
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | | | | | - Alessandra Gambineri
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Cecilia Garcia Rudaz
- Division of Women, Youth and Children, Australian National University, Canberra, Australian Capital Territory, Australia
| | - Kathleen M Hoeger
- Department of OBGYN, University of Rochester Medical Center, Rochester, New York, USA
| | - Abel López-Bermejo
- Pediatric Endocrinology, Hospital de Girona Dr. Josep Trueta, Girona, Spain
| | - Ken Ong
- MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Alexia S Peña
- The University of Adelaide and Robinson Research Institute, Adelaide, South Australia, Australia
| | - Thomas Reinehr
- University of Witten/Herdecke, Vestische Kinder- und Jugendklinik, Pediatric Endocrinology, Diabetes, and Nutrition Medicine, Datteln, Germany
| | - Nicola Santoro
- Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA
| | | | - Rachel Tao
- Division of Pediatric Endocrinology, CUMC, New York-Presbyterian Morgan Stanley Children's Hospital, New York, New York, USA
| | - Bulent O Yildiz
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Hacettepe University School of Medicine, Ankara, Turkey
| | - Haya Alkhayyat
- Medical University of Bahrain, BDF Hospital, Riffa, Bahrein
| | - Asma Deeb
- Mafraq Hospital, Abu Dhabi, United Arab Emirates
| | - Dipesalema Joel
- Department of Paediatrics and Adolescent Health, University of Botswana Teaching Hospital, Gaborone, Botswana
| | - Reiko Horikawa
- Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan
| | - Francis de Zegher
- Department Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium
| | - Peter A Lee
- Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania, USA
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Liu S, Sun Q. Sex differences, endogenous sex-hormone hormones, sex-hormone binding globulin, and exogenous disruptors in diabetes and related metabolic outcomes. J Diabetes 2018; 10:428-441. [PMID: 27990781 DOI: 10.1111/1753-0407.12517] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 12/13/2016] [Indexed: 12/26/2022] Open
Abstract
In assessing clinical and pathophysiological development of type 2 diabetes (T2D), the critical role of the sex steroids axis is underappreciated, particularly concerning the sex-specific relationships with many relevant cardiometabolic outcomes. In this issue of the Journal of Diabetes, we provide a comprehensive overview of these significant associations of germline variants in the genes governing the sex steroid pathways, plasma levels of steroid hormones, and sex hormone-binding globulin (SHBG) with T2D risk that have been observed in many clinical and high-quality large prospective cohorts of men and women across ethnic populations. Together, this body of evidence indicates that sex steroids and SHBG should be routinely incorporated into clinical characterization of T2D patients, particularly in screening prediabetic patients, such as those with metabolic syndrome, using plasma levels of SHBG. Given that several germline mutations in the SHBG gene have also been directly related to both plasma concentrations of SHBG and clinical manifestation of T2D, targeting signals in the sex steroid axis, particularly SHBG, may have significant utility in the prediction and treatment of T2D. Further, many of the environmental endocrine disrupting chemicals may exert their potential adverse effects on cardiometabolic outcomes via either estrogenic or androgenic signaling pathways, highlighting the importance of using the sex steroids and SHBG as important biochemical markers in both clinical and population studies in studying sex-specific mechanisms in the pathogenesis of T2D and its complications, as well as the need to equitably allocate resources in studying both men and women.
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Affiliation(s)
- Simin Liu
- Department of Endocrinology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, China
- Departments of Epidemiology, Brown University, Providence, Rhode Island, USA
- Departments of Medicine, Brown University, Providence, Rhode Island, USA
- Center for Global Cardiometabolic Health, Brown University, Providence, Rhode Island, USA
- Departments of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Qi Sun
- Departments of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Condorelli RA, Calogero AE, Di Mauro M, Mongioi' LM, Cannarella R, Rosta G, La Vignera S. Androgen excess and metabolic disorders in women with PCOS: beyond the body mass index. J Endocrinol Invest 2018; 41:383-388. [PMID: 28942551 DOI: 10.1007/s40618-017-0762-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 09/13/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Insulin resistance is a common feature among women with polycystic ovary syndrome (PCOS), especially in those patients with hyperandrogenism and chronic anovulation. PCOS women are at risk for developing metabolic syndrome, impaired glucose tolerance and type II diabetes mellitus (DM II). OBJECTIVE The aim of this review is to explore the existing knowledge of the interplay between androgen excess, pancreatic β-cell function, non-alcoholic fatty liver disease (NAFLD), intra-abdominal and subcutaneous (SC) abdominal adipocytes in PCOS, providing a better comprehension of the molecular mechanisms of diabetologic interest. METHODS A comprehensive MEDLINE® search was performed using relevant key terms for PCOS and DM II. RESULTS Insulin-induced hyperandrogenism could impair pancreatic β-cell function, the SC abdominal adipocytes' lipid storage capacity, leading to intra-abdominal adipocyte hypertrophy and lipotoxicity, which in turn promotes insulin resistance, and could enhance NAFLD. Fetal hyperandrogenism exposure prompts to metabolic disorders. Treatment with flutamide showed to partially reverse insulin resistance. CONCLUSIONS Metabolic impairment seems not to be dependent only on the total fat mass content and body weight in women with PCOS and might be ascribed to the androgen excess.
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Affiliation(s)
- R A Condorelli
- Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Via S. Sofia 78, 95123, Catania, Italy
| | - A E Calogero
- Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Via S. Sofia 78, 95123, Catania, Italy
| | - M Di Mauro
- Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Via S. Sofia 78, 95123, Catania, Italy
| | - L M Mongioi'
- Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Via S. Sofia 78, 95123, Catania, Italy
| | - R Cannarella
- Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Via S. Sofia 78, 95123, Catania, Italy
| | - G Rosta
- Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Via S. Sofia 78, 95123, Catania, Italy
| | - S La Vignera
- Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Via S. Sofia 78, 95123, Catania, Italy.
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Abstract
Androgen production by the ovary is an essential requirement for normal cyclical secretion of estradiol but its physiological role extends to important actions on both preantral and antral follicle development, including promotion of granulosa cell proliferation. It is likely only in mature antral follicles that androgens encourage apoptosis and consequent follicle atresia, and this may be an important mechanism to ensure mono-follicular ovulation in primates, including humans. Recent studies have provided new insight into the mechanism of androgen signaling in the ovary which involves both genomic and non-genomic effects that are complementary in effecting a cellular response. In polycystic ovary syndrome, a condition characterized by intra-ovarian androgen excess, aberrant development of both preantral and antral follicles is a salient feature. We present evidence that local action of androgens plays a part in such abnormalities. Finally, we review the role of androgens in follicle atresia and conclude that the effects are part of the normal physiology of follicle maturation.
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Abstract
PURPOSE OF REVIEW Polycystic ovary syndrome (PCOS) is diagnosed by its characteristic reproductive features. However, PCOS is also associated with metabolic abnormalities, including insulin resistance and β-cell dysfunction. The severity of these abnormalities varies according to the reproductive phenotype, with the so-called NIH or classic phenotype conferring the greatest metabolic risk. The increased risk for type 2 diabetes (T2D) is well established among affected women with the NIH phenotype, but whether PCOS also confers an increased risk for cardiovascular events remains unknown. RECENT FINDINGS Recent studies in daughters of affected women have found evidence for pancreatic β-cell dysfunction prior to menarche. Further, genetic analyses have provided evidence that metabolic abnormalities such as obesity and insulin resistance contribute to the pathogenesis of PCOS. PCOS increases the risk for T2D. However, the risk for cardiovascular disease has not been quantified, and prospective, longitudinal studies are still critically needed.
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Affiliation(s)
- Laura C Torchen
- Division of Endocrinology, Ann & Robert H Lurie Children's Hospital of Chicago, 225 E Chicago Ave, Box 54, Chicago, IL, 60611, USA.
- Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
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Unfer V, Facchinetti F, Orrù B, Giordani B, Nestler J. Myo-inositol effects in women with PCOS: a meta-analysis of randomized controlled trials. Endocr Connect 2017; 6:647-658. [PMID: 29042448 PMCID: PMC5655679 DOI: 10.1530/ec-17-0243] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 09/20/2017] [Indexed: 12/17/2022]
Abstract
Myo-inositol (MI) supplementation in women with polycystic ovary syndrome (PCOS) has been evaluated over the last years. Many hormonal and reproductive impairments associated with this disorder seem relieved by the supplement. The objective of the meta-analysis was to assess the effects of MI alone or combined with d-chiro-inositol (DCI) on the endocrine and metabolic abnormalities of women with PCOS. Literature was retrieved from selected databases, MEDLINE, EMBASE, PubMed and Research Gate (up to November 2016). Only randomized controlled trials (RCTs) investigating the effects of MI alone or combined with DCI were reviewed. Nine RCTs involving 247 cases and 249 controls were included. Significant decreases in fasting insulin (SMD = -1.021 µU/mL, 95% CI: -1.791 to -0.251, P = 0.009) and homeostasis model assessment (HOMA) index (SMD = -0.585, 95% CI: -1.145 to -0.025, P = 0.041) were identified after MI supplementation. The trial sequential analysis of insulin meta-analysis illustrates that the cumulative z-curve crossed the monitoring boundary, providing firm evidence of the intervention effect. A slight trend toward a reduction of testosterone concentration by MI with respect to controls was found (SMD = -0.49, 95% CI: -1.072 to 0.092, P = 0.099), whereas androstenedione levels remained unaffected. Throughout a subgroup's meta-analysis, a significant increase in serum SHBG was observed only in those studies where MI was administered for at least 24 weeks (SMD = 0.425 nmol/L, 95% CI: 0.050-0.801, P = 0.026). These results highlight the beneficial effect of MI in improving the metabolic profile of women with PCOS, concomitantly reducing their hyperandrogenism.
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Affiliation(s)
- Vittorio Unfer
- Health DepartmentUniPoliSi - Institut des Etudes Universitaires, Disentis, Switzerland
| | - Fabio Facchinetti
- Mother-Infant DepartmentUniversity of Modena and Reggio Emilia, Modena, Italy
| | - Beatrice Orrù
- Medical Affairs DepartmentLo.Li. Pharma, Rome, Italy
| | | | - John Nestler
- Departments of Medicine and Obstetrics and GynecologyVirginia Commonwealth University, Richmond, Virginia, USA
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Metformin Therapy for the Management of Infertility in Women with Polycystic Ovary Syndrome. BJOG 2017; 124:e306-e313. [DOI: 10.1111/1471-0528.14764] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Davidson MA, Mattison DR, Azoulay L, Krewski D. Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future. Crit Rev Toxicol 2017; 48:52-108. [PMID: 28816105 DOI: 10.1080/10408444.2017.1351420] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Thiazolidinedione (TZD) drugs used in the treatment of type 2 diabetes mellitus (T2DM) have proven effective in improving insulin sensitivity, hyperglycemia, and lipid metabolism. Though well tolerated by some patients, their mechanism of action as ligands of peroxisome proliferator-activated receptors (PPARs) results in the activation of several pathways in addition to those responsible for glycemic control and lipid homeostasis. These pathways, which include those related to inflammation, bone formation, and cell proliferation, may lead to adverse health outcomes. As treatment with TZDs has been associated with adverse hepatic, cardiovascular, osteological, and carcinogenic events in some studies, the role of TZDs in the treatment of T2DM continues to be debated. At the same time, new therapeutic roles for TZDs are being investigated, with new forms and isoforms currently in the pre-clinical phase for use in the prevention and treatment of some cancers, inflammatory diseases, and other conditions. The aims of this review are to provide an overview of the mechanism(s) of action of TZDs, a review of their safety for use in the treatment of T2DM, and a perspective on their current and future therapeutic roles.
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Affiliation(s)
- Melissa A Davidson
- a Faculty of Health Sciences , University of Ottawa , Ottawa , Canada.,b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada
| | - Donald R Mattison
- b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada.,c Risk Sciences International , Ottawa , Canada
| | - Laurent Azoulay
- d Center for Clinical Epidemiology , Lady Davis Research Institute, Jewish General Hospital , Montreal , Canada.,e Department of Oncology , McGill University , Montreal , Canada
| | - Daniel Krewski
- a Faculty of Health Sciences , University of Ottawa , Ottawa , Canada.,b McLaughlin Centre for Population Health Risk Assessment , Ottawa , Canada.,c Risk Sciences International , Ottawa , Canada.,f Faculty of Medicine , University of Ottawa , Ottawa , Canada
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Cree-Green M, Rahat H, Newcomer BR, Bergman BC, Brown MS, Coe GV, Newnes L, Garcia-Reyes Y, Bacon S, Thurston JE, Pyle L, Scherzinger A, Nadeau KJ. Insulin Resistance, Hyperinsulinemia, and Mitochondria Dysfunction in Nonobese Girls With Polycystic Ovarian Syndrome. J Endocr Soc 2017; 1:931-944. [PMID: 29264544 PMCID: PMC5686696 DOI: 10.1210/js.2017-00192] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 05/26/2017] [Indexed: 01/28/2023] Open
Abstract
Objective: Obese girls with polycystic ovarian syndrome (PCOS) have decreased insulin sensitivity (IS), muscle mitochondrial dysfunction and increased liver fat, which may contribute to their increased risk for type 2 diabetes. Less is known regarding normal-weight girls with PCOS. Methods: Normal-weight girls with PCOS [n =18, age 15.9 ± 1.8 years, body mass index (BMI) percentile 68 ± 18] and normal-weight controls (NWC; n = 20; age 15.0 ± 2.1 years, BMI percentile 60 ± 21) were studied. Tissue-specific IS was assessed with a four-phase hyperinsulinemic-euglycemic clamp with isotope tracers and a 2-hour oral glucose tolerance test (OGTT). Hepatic fat was determined using magnetic resonance imaging. Postexercise muscle mitochondrial function was assessed with 31P MR spectroscopy. Results: Both groups had similar demographics, anthropomorphics, physical attributes, habitual physical activity levels and fasting laboratory values, except for increased total testosterone and DHEAS in PCOS. Clamp-assessed peripheral IS was lower in PCOS (10.4 ± 2.4 mg/kg/min vs 12.7 ± 2.1; P = 0.024). The 120-minute OGTT insulin and glucose concentrations were higher in PCOS (114 IU/mL ± 26 vs 41 ± 25, P = <0.001 and 119 ± 22 mg/dL vs 85 ± 23, P = 0.01, respectively). Muscle mitochondrial ADP and phosphocreatine time constants were slower in PCOS. Despite a higher percentage liver fat in PCOS, hepatic IS was similar between groups, as was adipose IS. Conclusions: Normal-weight girls with PCOS have decreased peripheral IS and muscle mitochondrial dysfunction, abnormal glucose disposal, relative postprandial hyperinsulinemia, and increased hepatic fat compared to NWC. Despite a normal BMI, multiple aspects of metabolism appear altered in normal-weight girls with PCOS.
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Affiliation(s)
- Melanie Cree-Green
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.,Center for Women's Health Research, Aurora, Colorado 80045
| | - Haseeb Rahat
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045
| | - Bradley R Newcomer
- Deptartment of Physics, James Madison University, Harrisburg, Virginia 22807
| | - Bryan C Bergman
- Division of Endocrinology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045
| | - Mark S Brown
- Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045
| | - Gregory V Coe
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045
| | - Lindsey Newnes
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045
| | - Yesenia Garcia-Reyes
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045
| | - Samantha Bacon
- Division of Endocrinology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045
| | - Jessica E Thurston
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado 80045
| | - Laura Pyle
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado 80045.,Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045
| | - Ann Scherzinger
- Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045
| | - Kristen J Nadeau
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.,Center for Women's Health Research, Aurora, Colorado 80045
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Li S, Chu Q, Ma J, Sun Y, Tao T, Huang R, Liao Y, Yue J, Zheng J, Wang L, Xue X, Zhu M, Kang X, Yin H, Liu W. Discovery of Novel Lipid Profiles in PCOS: Do Insulin and Androgen Oppositely Regulate Bioactive Lipid Production? J Clin Endocrinol Metab 2017; 102:810-821. [PMID: 27886515 PMCID: PMC5477809 DOI: 10.1210/jc.2016-2692] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 11/23/2016] [Indexed: 11/20/2022]
Abstract
CONTEXT Polycystic ovary syndrome (PCOS) is a complex syndrome showing clinical features of an endocrine/metabolic disorder, including hyperinsulinemia and hyperandrogenism. Polyunsaturated fatty acids (PUFAs) and their derivatives, both tightly linked to PCOS and obesity, play important roles in inflammation and reproduction. OBJECTIVE This study aimed to investigate serum lipid profiles in newly diagnosed patients with PCOS using lipidomics and correlate these features with the hyperinsulinemia and hyperandrogenism associated with PCOS and obesity. DESIGN AND SETTING Thirty-two newly diagnosed women with PCOS and 34 controls were divided into obese and lean subgroups. A PCOS rat model was used to validate results of the human studies. MAIN OUTCOME MEASURES Serum lipid profiles, including phospholipids, free fatty acids (FFAs), and bioactive lipids, were analyzed using gas chromatography-mass spectrometry (MS) and liquid chromatography-MS. RESULTS Elevation in phosphatidylcholine and a concomitant decrease in lysophospholipid were found in obese patients with PCOS vs lean controls. Obese patients with PCOS had decreased PUFA levels and increased levels of long-chain saturated fatty acids vs lean controls. Serum bioactive lipids downstream of arachidonic acid were increased in obese controls, but reduced in both obese and lean patients with PCOS vs their respective controls. CONCLUSIONS Patients with PCOS showed abnormal levels of phosphatidylcholine, FFAs, and PUFA metabolites. Circulating insulin and androgens may have opposing effects on lipid profiles in patients with PCOS, particularly on the bioactive lipid metabolites derived from PUFAs. These clinical observations warrant further studies of the molecular mechanisms and clinical implications of PCOS and obesity.
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Affiliation(s)
| | | | - Jing Ma
- Department of Endocrinology and
| | - Yun Sun
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Center for Reproductive Medicine and
| | - Tao Tao
- Department of Endocrinology and
| | | | - Yu Liao
- Department of Endocrinology and
| | | | | | | | - Xinli Xue
- Key Laboratory of Food Safety Research and
- University of the Chinese Academy of Sciences, Shanghai 200031, China; and
| | | | - Xiaonan Kang
- Department of Biobank, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Huiyong Yin
- Key Laboratory of Food Safety Research and
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
| | - Wei Liu
- Department of Endocrinology and
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Stassek J, Erdmann J, Ohnolz F, Berg FD, Kiechle M, Seifert-Klauss V. C-Peptide, Baseline and Postprandial Insulin Resistance after a Carbohydrate-Rich Test Meal - Evidence for an Increased Insulin Clearance in PCOS Patients? Geburtshilfe Frauenheilkd 2017; 77:59-65. [PMID: 28190890 DOI: 10.1055/s-0042-119199] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Introduction Known characteristics of patients with PCOS include infertility, menstrual disorders, hirsutism and also often insulin resistance. These symptoms increase with increasing body weight. In the LIPCOS study (Lifestyle Intervention for Patients with Polycystic Ovary Syndrome [PCOS]) long-term changes of the PCOS in dependence on pregnancy and parenthood were systematically assessed. In the framework of the LIPCOS study, PCOS patients were given a standardised carbohydrate-rich test meal in order to examine glucose homeostasis and insulin secretion. The results were compared with those of a eumenorrhoeic control group who all had corresponding BMI values and corresponding ages. Methods and Patients 41 PCOS patients (without diabetes) and 68 controls received a standardised carbohydrate-rich test meal (260 kcal, 62 % carbohydrates, 32 % fat, 6 % proteins) in order to generate a submaximal insulin and glucose stimulation. The values were determined at baseline and postprandial after 60, 120 and 180 minutes. In addition, the corresponding C-peptide levels were recorded. Results In the PCOS patients (n = 41), the insulin secretion test after a standardised test meal showed almost identical baseline and postprandial insulin levels when compared with those of the age- and BMI-matched eumenorrhoeic controls (n = 68). In the PCOS patients, the baseline and postprandial glucose levels were significantly elevated (92.88 ± 10.28 [PCOS] vs. 85.07 ± 9.42 mg/dL [controls]; p < 0.001) so was C-peptide (p < 0.025). Conclusions In the present study we have shown for the first time that, after consumption of a standardised test meal, PCOS patients formally exhibit a higher fasting insulin resistance than controls. In spite of the higher stimulated C-peptide levels, the insulin levels did not increase more strongly with increasing glucose levels than in controls which may be indicative of a higher insulin clearance in PCOS patients.
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Affiliation(s)
- J Stassek
- Frauenklinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - J Erdmann
- Hochschule Weihenstephan-Triesdorf, Weidenbach, Germany
| | - F Ohnolz
- Frauenklinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - F D Berg
- Gemeinschaftspraxis Prof. Berg und Dr. Lesoine, München, Germany
| | - M Kiechle
- Frauenklinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - V Seifert-Klauss
- Frauenklinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany
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Rostami Dovom M, Ramezani Tehrani F, Djalalinia S, Cheraghi L, Behboudi Gandavani S, Azizi F. Menstrual Cycle Irregularity and Metabolic Disorders: A Population-Based Prospective Study. PLoS One 2016; 11:e0168402. [PMID: 27992506 PMCID: PMC5161370 DOI: 10.1371/journal.pone.0168402] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 11/29/2016] [Indexed: 01/16/2023] Open
Abstract
The regularity of menstrual cycles is considered an indicator of women's reproductive health. Previous studies with a cross-sectional design have documented the relationship between menstrual cycle irregularities, insulin-resistance and the future risks for metabolic disorders. Limited data documented by prospective studies can lead to premature conclusions regarding the relationship between menstrual cycle irregularities and other conditions influencing women's health. The present study therefore, using a prospective design aimed to assess the risk of metabolic disorders in women with a history of irregular menstrual cycles, was based on the data gathered from the Tehran Lipid and Glucose study (TLGS) an ongoing prospective cohort study initiated in 1999. Participants of the current study were 2128 women, aged between 18-49 years, followed for 15 years. Based on their menstrual cycles, the women were divided into two groups: (i) women with regular menstrual cycles (n = 1749), and (ii) those with irregular menstrual cycles (n = 379). The proportional COX regression model was used to compare hazard ratios (HRs) between the groups for the proposed events, including diabetes mellitus (DM), pre-diabetes (pre-DM), hypertension (HTN), pre-hypertension (pre-HTN) and dyslipidemia. It was found that during a 15-year follow up, there were 123 cases of DM, 456 cases of pre-DM, 290 cases of HTN, 481 cases of pre-HTN, and 402 cases of dyslipidemia. Compared to those with regular cycles, women with irregular menstrual cycles were found to have an increased risk for DM2 (age adjusted Hazard Ratios (HRs), 2.01; 95% confidence intervals (CI:1.59-3.50), the increased risk for DM, associated with irregular cycles remained significant after the adjustment for Body Mass Index (BMI), fasting blood sugar (FBS), family history of diabetes, and parity (HRS, 1.73; 95% CI: 1.14-2.64). There was no significant difference in the increased risk for pre-DM between the groups (age adjusted HRs, 1.33, 95% CI: 1.05-1.69). However, after the adjustment of BMI, FBS and family history of pre-DM, compared to those with regular menstrual cycles, irregular menstrual cycles showed an increased risk for pre-DM (HRs, 1.33; 95% CI: 1.05-1.69). No statistically significant difference was found in the increasing risk for other proposed events between the groups demonstrating that menstrual cycle irregularities could be considered a marker of metabolic disorders and a predisposing factor of the increased risk for diabetes mellitus and pre-diabetes in women with irregular menstrual cycles.
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Affiliation(s)
- Marzieh Rostami Dovom
- Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fahimeh Ramezani Tehrani
- Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Djalalinia
- Non_communicable Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran, Development of Research Technology Center, Deputy of Research and Technology, Ministry of Health and Medical Education, Tehran, Iran
| | - Leila Cheraghi
- Department of Biostatistics and Epidemiology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samira Behboudi Gandavani
- Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Cree-Green M, Bergman BC, Coe GV, Newnes L, Baumgartner AD, Bacon S, Sherzinger A, Pyle L, Nadeau KJ. Hepatic Steatosis is Common in Adolescents with Obesity and PCOS and Relates to De Novo Lipogenesis but not Insulin Resistance. Obesity (Silver Spring) 2016; 24:2399-2406. [PMID: 27804265 PMCID: PMC5117819 DOI: 10.1002/oby.21651] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 07/18/2016] [Accepted: 07/20/2016] [Indexed: 01/13/2023]
Abstract
OBJECTIVE Increased liver fat and type 2 diabetes are prevalent in women with polycystic ovarian syndrome (PCOS) and cause excess mortality, yet little is known about their development during adolescence. The objective of this study was to measure hepatic steatosis and related metabolic contributors in girls with obesity, with and without PCOS. METHODS Nondiabetic adolescents with obesity, 41 with PCOS (PCOS; age 15.0 [13.0-16.0] years, BMI 35.2 ± 0.61 kg/m2 ) and 30 without PCOS (OB; age 14.5 [13.0-17.0], BMI 33.2 ± 1.8), were studied. Visceral and liver fat were assessed with MRI. Serum measures included androgens and 16:1 and 18:1 N7 fatty acids specific to de novo lipogenesis. Adipose, hepatic, and peripheral insulin sensitivity (IS) were assessed with a four-phase hyperinsulinemic-euglycemic clamp with isotope tracers. RESULTS Forty-nine percent of the PCOS group had hepatic steatosis versus fourteen percent of the OB group (P = 0.02), and the PCOS group had higher N7 (43 ± 4 vs. 29 ± 5 nmol/g; P = 0.02). Peripheral IS was lower in PCOS (9.4 [7.2-12.3] vs. 14.5 [13.1-18.05 mg/lean kg/min]; P < 0.001) as was hepatic (P = 0.006) and adipose IS (P = 0.005). Percent liver fat correlated with N7 (R = 0.46, P = 0.02) and visceral fat (R = 0.42, P < 0.001), not androgens or peripheral IS. CONCLUSIONS Nearly 50% of nondiabetic girls with PCOS and obesity have hepatic steatosis, which relates to visceral fat and lipogenesis, but not to IS or androgens.
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Affiliation(s)
- Melanie Cree-Green
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
- Department of Pediatric Endocrinology, Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
| | - Bryan C Bergman
- Department of Medicine, Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Gregory V Coe
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Lindsey Newnes
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Amy D Baumgartner
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Samantha Bacon
- Department of Medicine, Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Ann Sherzinger
- Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Laura Pyle
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA
| | - Kristen J Nadeau
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Pediatric Endocrinology, Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Akpinar F, Dilbaz B, Cırık DA, Yilmaz S, Kiykac S, Karahanoglu E, Mollamahmutoglu L. The significance of anthropometric and endocrine parameters in ovulation induction with clomiphene citrate in women with polycystic ovary syndrome. Saudi Med J 2016; 37:1272-1275. [PMID: 27761570 PMCID: PMC5303809 DOI: 10.15537/smj.2016.11.15006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Objectives: To investigate factors associated with the response to ovarian stimulation in patients with polycystic ovary syndrome. Methods: The records of patients with polycystic ovary syndrome and infertility who underwent ovulation induction with clomiphene citrate were reviwed between January 2011 and December 2014 in Etlik Zübeyde Hanim Women’s Health Training and Research Hospital Ankara, Turkey. The anthropometric and endocrine factors of patients who were resistant to treatment at a dose of 150 mg/day (n=84) were compared with those who responded with growth of at least one graaffian follicle at a dose of 50 mg/day (n=342). Results: Of the parameters examined, body mass index, luteinizing hormone level, and luteinizing hormone/follicle stimulating hormone ratio were significantly higher in the clomiphene citrate-resistant group compared with the responsive group. Conclusion: Reproductive treatment in patients with polycystic ovary syndrome show different outcomes. Significantly higher body mass index, luteinizing hormone level, and luteinizing hormone/follicle stimulating hormone ratio observed in clomiphene citrate resistant group can be a possible explanation for this impedance.
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Affiliation(s)
- Funda Akpinar
- Department of Obstetrics and Gynecology, Etlik Zübeyde Hanım Women's Health Training and Research Hospital, Ankara, Turkey. E-mail.
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Jovanovska-Mishevska S, Atanasova-Boshku A, Bitoska I, Ahmeti I, Todorova B, Pemovska G, Milenkovic T, Krstevska B. Indexes of Insulin Resistance in Hyperinsulinemic Polycystic Ovary Syndrome in a Macedonian Cohort of Women of Reproductive Age: A Cross-Sectional Study. Open Access Maced J Med Sci 2016; 4:607-612. [PMID: 28028399 PMCID: PMC5175507 DOI: 10.3889/oamjms.2016.107] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 09/20/2016] [Accepted: 09/22/2016] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND: Polycystic ovary syndrome (PCOS) is complex hormonal, metabolic and reproductive disorder and is a leading cause of female infertility. Hyperinsulinemia secondary to insulin resistance plays important role in the pathogenesis of PCOS. AIM: To assess the sensitivity of different indices of insulin resistance and their relevance in a clinical setting. MATERIAL AND METHODS: A cross-sectional study of 43 patients with PCOS and 29 noromo ovulatory women as a control group was conducted. Standard clinical, anthropometrical and hormonal testing for hyperandrogenism was conducted, as well as oral glucose tolerance test with determination of basal and stimulated glucose and insulin values. RESULTS: The dynamic I/G index showed the highest sensitivity and specificity, but the static indexes HOMA-IR and QUICKI, although based on only basal glycemic and insulinemic values, showed good sensitivity, 90.38% and 94.01% respectively. HOMA-IR showed significant positive correlation with the stimulated insulin values. CONCLUSIONS: Our results support the use of static indexes in the evaluation of insulin resistance in women with PCOS in a clinical setting, offering a simple assessment of insulin resistance in PCOS, which holds great prognostic and treatment implications.
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Affiliation(s)
- Sasha Jovanovska-Mishevska
- University Clinic of Endocrinology, Diabetes and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Aleksandra Atanasova-Boshku
- University Clinic of Gynecology and Obstetrics, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Iskra Bitoska
- University Clinic of Endocrinology, Diabetes and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Irfan Ahmeti
- University Clinic of Endocrinology, Diabetes and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Biljana Todorova
- University Clinic of Endocrinology, Diabetes and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Gordana Pemovska
- University Clinic of Endocrinology, Diabetes and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Tatjana Milenkovic
- University Clinic of Endocrinology, Diabetes and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
| | - Brankica Krstevska
- University Clinic of Endocrinology, Diabetes and Metabolic Disorders, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia
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50
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McManus RM, Gottschalk R, Alanen K, Shum DT, Grundy P. Microscopic Acanthosis Nigricans in Type 2 Diabetes. J Cutan Med Surg 2016. [DOI: 10.1177/120347540100500503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: Acanthosis nigricans (AN) has been associated with insulin resistance. Individuals with type 2 diabetes are insulin-resistant and, therefore, could be expected to manifest AN. However, the prevalence and predictors of AN are unknown in this population. Objective: An outpatient population with Type 2 diabetes (DM) was compared with matched controls (C) for microscopic and clinical AN along with measurement of body habitus, insulin, glucose, and androgen levels. Methods: Twenty-four individuals with DM (12M, 12F) from a tertiary care center were compared with 24 C (12M, 12F). Fasting glucose, insulin, sex hormone binding globulin, androstenedione, dihydroepiandrosterone sulfate, and testosterone were measured. Height, weight, waist/hip measures, and a clinical survey for acanthosis were recorded. A 2-mm skin biopsy from midaxilla of the nondominant arm was taken for pathological review. Results: C and DM were matched for age and body mass index (BMI). Prevalence of microscopic AN in C was 12% (3/24) and in DM was 21% (5/24; NS). In C, AN was predicted by waist, waist/hip ratio, and fasting insulin measures, while none of the variables examined was predicative of AN in DM. Conclusions: Microscopic acanthosis nigricans was found in similar numbers of people with DM when compared with C. Fasting insulin levels most strongly predicted the presence of AN in C, while no significant predictors of AN were found in the population with DM.
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Affiliation(s)
- R. M. McManus
- Division of Endocrinology and Metabolism, Department of Medicine, The University of Western Ontario, London, Ontario, Canada
| | - R. Gottschalk
- Division of Dermatology, The University of Western Ontario, London, Ontario, Canada
| | - K. Alanen
- Department of Pathology, The University of Western Ontario, London, Ontario, Canada
| | - D. T. Shum
- Department of Pathology, The University of Western Ontario, London, Ontario, Canada
| | - P. Grundy
- Division of Endocrinology and Metabolism, Department of Medicine, The University of Western Ontario, London, Ontario, Canada
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