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Henryk F Urbanski Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA
Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon, USA
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA
Department of Physiology & Pharmacology, Oregon Health & Science University, Portland, Oregon, USA

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Kevin Mueller Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon, USA

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Cynthia L Bethea Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA
Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon, USA
Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, Oregon, USA

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Like women, old female rhesus macaques undergo menopause and show many of the same age-associated changes, including perturbed activity/rest cycles and altered circulating levels of many hormones. Previous studies showed that administration of an estrogen agonist increased activity in female monkeys, that hormone therapy (HT) increased activity in postmenopausal women and that obesity decreased activity in women. The present study sought to determine if postmenopausal activity and circulating hormone levels also respond to HT when monkeys are fed a high-fat, high-sugar Western style diet (WSD). Old female rhesus macaques were ovo-hysterectomized (OvH) to induce surgical menopause and fed a WSD for 2 years. Half of the animals received estradiol-17β (E), beginning immediately after OvH, while the other half received placebo. Animals in both groups showed an increase in body weight and a decrease in overall activity levels. These changes were associated with a rise in both daytime and nocturnal serum leptin concentrations, but there was no change in serum concentrations of either cortisol or dehydroepiandrosterone sulfate (DHEAS). These data suggest that 2 years of HT has little or no effect on locomotor activity or circadian hormone patterns in menopausal macaques fed an obesogenic diet.

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Marília D’Elboux Guimarães Brescia Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Karine Candido Rodrigues Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
Endocrine Oncology Division, Institute of Cancer of the State of São Paulo (ICESP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, São Paulo, Brazil

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André Fernandes d’Alessandro Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Wellington Alves Filho Department of Surgery, Walter Cantidio University Hospital, Federal University of Ceara School of Medicine (FAMED-UFC), Fortaleza, Brazil

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Willemijn Y van der Plas Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Schelto Kruijff Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Sergio Samir Arap Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Sergio Pereira de Almeida Toledo Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil

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Fábio Luiz de Menezes Montenegro Parathyroid Unit – LIM-28, Laboratório de Cirurgia de Cabeça e Pescoço, Division of Head and Neck Surgery, Department of Surgery, Hospital das Clinicas (HCFMUSP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil

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Delmar Muniz Lourenço Jr Endocrine Genetics Unit (LIM-25), Endocrinology Division, University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), Hospital das Clinicas (HCFMUSP), São Paulo, São Paulo, Brazil
Endocrine Oncology Division, Institute of Cancer of the State of São Paulo (ICESP), University of São Paulo School of Medicine (FMUSP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, São Paulo, Brazil

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Background

Potential influences of parathyroidectomy (PTx) on the quality of life (QoL) in multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) are unknown.

Method

Short Form 36 Health Survey Questionnaire was prospectively applied to 30 HPT/MEN1 patients submitted to PTx (20, subtotal; 10, total with autograft) before, 6 and 12 months after surgery. Parameters that were analyzed included QoL, age, HPT-related symptoms, general pain, comorbidities, biochemical/hormonal response, PTx type and parathyroid volume.

Results

Asymptomatic patients were younger (30 vs 38 years; P = 0.04) and presented higher QoL scores than symptomatic ones: Physical Component Summary score (PCS) 92.5 vs 61.2, P = 0.0051; Mental Component Summary score (MCS) 82.0 vs 56.0, P = 0.04. In both groups, QoL remained stable 1 year after PTx, independently of the number of comorbidities. Preoperative general pain was negatively correlated with PCS (r = −0.60, P = 0.0004) and MCS (r = −0.57, P = 0.0009). Also, moderate/intense pain was progressively (6/12 months) more frequent in cases developing hypoparathyroidism. The PTx type and hypoparathyroidism did not affect the QoL at 12 months although remnant parathyroid tissue volume did have a positive correlation (P = 0.0490; r = 0.3625) to PCS 12 months after surgery. Patients with one to two comorbidities had as pre-PTx PCS (P = 0.0015) as 12 months and post-PTx PCS (P = 0.0031) and MCS (P = 0.0365) better than patients with three to four comorbidities.

Conclusion

A variable QoL profile was underscored in HPT/MEN1 reflecting multiple factors associated with this complex disorder as comorbidities, advanced age at PTx and presence of preoperative symptoms or of general pain perception. Our data encourage the early indication of PTx in HPT/MEN1 by providing known metabolic benefits to target organs and avoiding potential negative impact on QoL.

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Maria Stelmachowska-Banaś Department of Endocrinology, The Centre of Postgraduate Medical Education, Warsaw, Polska, Poland

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Izabella Czajka-Oraniec Department of Endocrinology, The Centre of Postgraduate Medical Education, Warsaw, Polska, Poland

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Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.

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Shuang Ye Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China

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Yuanyuan Xu Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China

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Jiehao Li Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China

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Shuhui Zheng Research Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

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Peng Sun Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

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Tinghuai Wang Department of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China

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The role of G protein-coupled estrogen receptor 1 (GPER) signaling, including promotion of Ezrin phosphorylation (which could be activated by estrogen), has not yet been clearly identified in triple-negative breast cancer (TNBC). This study aimed to evaluate the prognostic value of GPER and Ezrin in TNBC patients. Clinicopathologic features including age, menopausal status, tumor size, nuclear grade, lymph node metastasis, AJCC TNM stage, and ER, PR and HER-2 expression were evaluated from 249 TNBC cases. Immunohistochemical staining of GPER and Ezrin was performed on TNBC pathological sections. Kaplan–Meier analyses, as well as logistic regressive and Cox regression model tests were applied to evaluate the prognostic significance between different subgroups. Compared to the GPER-low group, the GPER-high group exhibited higher TNM staging (P = 0.021), more death (P < 0.001), relapse (P < 0.001) and distant events (P < 0.001). Kaplan–Meier analysis showed that GPER-high patients had a decreased OS (P < 0.001), PFS (P < 0.001), LRFS (P < 0.001) and DDFS (P < 0.001) than GPER-low patients. However, these differences in prognosis were not statistically significant in post-menopausal patients (OS, P = 0.8617; PFS, P = 0.1905; LRFS, P = 0.4378; DDFS, P = 0.2538). There was a significant positive correlation between GPER and Ezrin expression level (R = 0.508, P < 0.001) and the effect of Ezrin on survival prognosis corresponded with GPER. Moreover, a multivariable analysis confirmed that GPER and Ezrin level were both significantly associated with poor DDFS (HR: 0.346, 95% CI 0.182–0.658, P = 0.001; HR: 0.320, 95% CI 0.162–0.631, P = 0.001). Thus, overexpression of GPER and Ezrin may contribute to aggressive behavior and indicate unfavorable prognosis in TNBC; this may correspond to an individual’s estrogen levels.

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Kristin Ottarsdottir Primary Health Care, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Margareta Hellgren Primary Health Care, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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David Bock Biostatistics, School of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

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Anna G Nilsson Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden

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Bledar Daka Primary Health Care, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Purpose

We aimed to investigate the association between SHBG and the homeostatic model assessment of insulin resistance (HOMA-Ir) in men and women in a prospective observational study.

Methods

The Vara-Skövde cohort is a random population of 2816 participants living in southwestern Sweden, aged 30–74. It was recruited between 2002 and 2005, and followed up in 2012–2014. After excluding participants on insulin therapy or hormone replacement therapy, 1193 individuals (649 men, 544 women) were included in the present study. Fasting blood samples were collected at both visits and stored in biobank. All participants were physically examined by a trained nurse. SHBG was measured with immunoassay technique. Linear regressions were computed to investigate the association between SHBG and HOMA-Ir both in cross-sectional and longitudinal analyses, adjusting for confounding factors.

Results

The mean follow-up time was 9.7 ± 1.4 years. Concentrations of SHBG were significantly inversely associated with log transformed HOMA-Ir in all groups with estimated standardized slopes (95% CI): men: −0.20 (−0.3;−0.1), premenopausal women: −0.26 (−0.4;−0.2), postmenopausal women: −0.13 (−0.3;−0.0) at visit 1. At visit 2 the results were similar. When comparing the groups, a statistically significant difference was found between men and post-menopausal women (0.12 (0.0;0.2) P value = 0.04). In the fully adjusted model, SHBG at visit 1 was also associated with HOMA-Ir at visit 2, and the estimated slopes were −0.16 (−0.2;−0.1), −0.16 (−0.3;−0.1) and −0.07 (−0.2;0.0) for men, premenopausal and postmenopausal women, respectively.

Main conclusion

Levels of SHBG predicted the development of insulin resistance in both men and women, regardless of menopausal state.

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Ghazala Zaidi Departments of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Vijayalakshmi Bhatia Departments of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Saroj K Sahoo Departments of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Aditya Narayan Sarangi Departments of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Niharika Bharti Departments of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Li Zhang Department of Immunology, Barbara Davis Centre for Childhood Diabetes, Denver, USA

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Liping Yu Department of Immunology, Barbara Davis Centre for Childhood Diabetes, Denver, USA

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Daniel Eriksson Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

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Sophie Bensing Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden

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Olle Kämpe Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden

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Nisha Bharani Department of Endocrinology, Amrita Institute of Medical Sciences, Kochi, India

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Surendra Kumar Yachha Departments of Paediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Anil Bhansali Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

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Alok Sachan Department of Endocrinology, Sri Venkateshwara Institute of Medical Sciences, Tirupathi, India

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Vandana Jain Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India

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Nalini Shah Department of Endocrinology, King Edward Memorial Hospital, Seth GS Medical College, Mumbai, India

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Rakesh Aggarwal Departments of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Amita Aggarwal Departments of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Muthuswamy Srinivasan Departments of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Sarita Agarwal Departments of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Eesh Bhatia Departments of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Objective

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients.

Design

Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2–19) years.

Methods

Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied.

Results

Patients varied widely in their age of presentation [3.5 (0.1–17) years] and number of clinical manifestations [5 (2–11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3–23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians.

Conclusions

Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

Open access
Georgios Kontogeorgos Section for Geriatrics and Emergency Medicine, Department of Medicine, Sahlgrenska University Hospital/Ostra, Gothenburg, Sweden
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Zoi Mamasoula Section for Geriatrics and Emergency Medicine, Department of Medicine, Sahlgrenska University Hospital/Ostra, Gothenburg, Sweden
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Emily Krantz Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Gothenburg, Sweden

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Penelope Trimpou Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Section for Endocrinology, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden

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Kerstin Landin-Wilhelmsen Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Section for Endocrinology, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden

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Christine M Laine Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Endocrine Out-Patient Clinic, Carlanderska Hospital, Gothenburg, Sweden

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Objective

Hypoparathyroidism (HypoPT) is a rare endocrine disorder in which insufficient levels of parathyroid hormone (PTH) lead to low serum calcium (S-Ca) levels and muscular cramps. The aim was to study the health-related quality of life (HRQoL) and comorbidities in patients with HypoPT compared with the general population and to estimate the need of treatment with PTH analog.

Design

Patients with HypoPT were identified and compared with a population sample. Short Form-36 (SF-36) and EuroQol-5 Dimensions Visual Analogue Scale questionnaires were used. All patients were followed up at the Sahlgrenska University Hospital outpatient clinic.

Methods

From the medical records between 2007 and 2020, 203 patients with HypoPT were identified and compared with a population sample (n = 414) from the World Health Organization’s (WHO) MONICA project, Gothenburg, Sweden. Of the 203 patients who met the diagnostic criteria, 164 were alive and 65% answered the HRQoL questionnaires.

Results

Patients with HypoPT, 80% postsurgical, and controls had similar age (60 years) and sex distribution (80% women). Patients had lower SF-36 summary component scores for physical (40.0 (interquartile range (IQR): 21) vs 51.2 (IQR: 14.6); P < 0.001) and mental (43.1 (IQR:17.4) vs 56.1(IQR:13.3); P < 0.001) well-being, irrespective of etiology or calcium levels. Individuals with HypoPT had more medications and lower renal function but not higher mortality than controls. Low HRQoL together with low calcium was present in 23% of individuals with HypoPT.

Conclusion

HRQoL was markedly lower in patients with HypoPT than in controls and independent of S-Ca levels. Treatment with PTH analog could be considered at least among patients with both low HRQoL and low calcium levels.

Open access
Emmanuelle Noirrit Inserm U1048 (I2MC), CHU de Toulouse and Université Toulouse III, I2MC, Toulouse, France
Faculté de Chirurgie Dentaire, Université de Toulouse III, Toulouse, France

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Mélissa Buscato Inserm U1048 (I2MC), CHU de Toulouse and Université Toulouse III, I2MC, Toulouse, France

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Marion Dupuis Inserm U1048 (I2MC), CHU de Toulouse and Université Toulouse III, I2MC, Toulouse, France

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Bernard Payrastre Inserm U1048 (I2MC), CHU de Toulouse and Université Toulouse III, I2MC, Toulouse, France
CHU de Toulouse, Laboratoire d’Hématologie, Toulouse, France

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Coralie Fontaine Inserm U1048 (I2MC), CHU de Toulouse and Université Toulouse III, I2MC, Toulouse, France

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Jean-François Arnal Inserm U1048 (I2MC), CHU de Toulouse and Université Toulouse III, I2MC, Toulouse, France

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Marie-Cécile Valera Inserm U1048 (I2MC), CHU de Toulouse and Université Toulouse III, I2MC, Toulouse, France
Faculté de Chirurgie Dentaire, Université de Toulouse III, Toulouse, France

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Estrogen–progestin therapy was previously considered as the standard of care for managing bothersome symptoms associated with menopause, but it increases risks of breast cancer and of thromboembolism. The combination of conjugated estrogen (CE) with bazedoxifene (BZA) named tissue-selective estrogen complex (TSEC) was designed to minimize or even abrogate the undesirable effects on breast, while maintaining the beneficial effects such as prevention of osteoporosis and suppression of climacteric symptoms. The risk on thromboembolism associated with TSEC is unknown, although the clinical available data are reassuring. The aim of this study was to define the impact of a chronic administration of CE, BZA or CE + BZA on hemostasis and thrombosis in ovariectomized mice. As expected, CE, but not BZA neither CE + BZA, induced uterine and vagina hypertrophy. As previously demonstrated for 17β-estradiol (E2), we found that CE (i) increased tail-bleeding time, (ii) prevented occlusive thrombus formation in injured carotid artery and (iii) protected against collagen/epinephrine-induced thromboembolism. Thus, whereas BZA antagonized CE action on reproductive tissues, it had no impact on the effect of CE on hemostasis, thromboembolism and arterial thrombosis in mice. CE + BZA shared the anti-thrombotic actions of CE in these mouse models. If a similar process is at work in women, CE combined with BZA could contribute to minimize the risk of thrombosis associated with hormone replacement therapy.

Open access
Clarissa Souza Barthem Laboratório de Adaptações Metabólicas, Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Camila Lüdke Rossetti Laboratório de Adaptações Metabólicas, Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Denise P Carvalho Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Wagner Seixas da-Silva Laboratório de Adaptações Metabólicas, Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

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Estradiol has been used to prevent metabolic diseases, bone loss and menopausal symptoms, even though it might raise the risk of cancer. Metformin is usually prescribed for type 2 diabetes mellitus and lowers food intake and body mass while improving insulin resistance and the lipid profile. Ovariectomized rats show increased body mass, insulin resistance and changes in the lipid profile. Thus, the aim of this work was to evaluate whether metformin could prevent the early metabolic dysfunction that occurs early after ovariectomy. Female Wistar rats were divided into the following groups: SHAM-operated (SHAM), ovariectomized (OVX), ovariectomized + estradiol (OVX + E2) and ovariectomized + metformin (OVX + M). Treatment with metformin diminished approximately 50% of the mass gain observed in ovariectomized animals and reduced both the serum and hepatic triglyceride levels. The hepatic levels of phosphorylated AMP-activated protein kinase (pAMPK) decreased after OVX, and the expression of the inactive form of hepatic acetyl-CoA carboxylase (ACC) was also reduced. Metformin was able to increase the levels of pAMPK in the liver of OVX animals, sustaining the balance between the inactive and total forms of ACC. Estradiol effects were similar to those of metformin but with different proportions. Our results suggest that metformin ameliorates the early alterations of metabolic parameters and rescues hepatic AMPK phosphorylation and ACC inactivation observed in ovariectomized rats.

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Keina Nishio Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka 569-8686, Japan

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Akiko Tanabe Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka 569-8686, Japan

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Risa Maruoka Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka 569-8686, Japan

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Kiyoko Nakamura Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka 569-8686, Japan

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Masaaki Takai Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka 569-8686, Japan

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Tatsuharu Sekijima Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka 569-8686, Japan

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Satoshi Tunetoh Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka 569-8686, Japan

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Yoshito Terai Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka 569-8686, Japan

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Masahide Ohmichi Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka 569-8686, Japan

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Objective

Although surgical menopause may increase the risks of osteoporosis, few studies have investigated the influence of chemotherapy and radiation therapy. The aim of this study is to evaluate the effects of treatments for gynecological malignancies on bone mineral density (BMD).

Methods

This study enrolled 35 premenopausal women (15 ovarian cancers (OCs), 9 endometrial cancers (ECs), and 11 cervical cancers (CCs)) who underwent surgical treatment that included bilateral oophorectomy with or without adjuvant platinum-based chemotherapy in OC and EC patients, or concurrent chemo-radiation therapy (CCRT) in CC patients according to the established protocols at the Osaka Medical College Hospital between 2006 and 2008. The BMD of the lumbar spine (L1–L4) was measured by dual-energy X-ray absorptiometry, and urine cross-linked telopeptides of type I collagen (NTx) and bone alkaline phosphatase (BAP) were assessed for evaluation of bone resorption and bone formation respectively. These assessments were performed at baseline and 12 months after treatment.

Results

Although the serum BAP was significantly increased only in the CC group, a rapid increase in the bone resorption marker urinary NTx was observed in all groups. The BMD, 12 months after CCRT was significantly decreased in the CC group at 91.9±5.9% (P<0.05 in comparison to the baseline).

Conclusion

This research suggests that anticancer therapies for premenopausal women with gynecological malignancies increase bone resorption and may reduce BMD, particularly in CC patients who have received CCRT. Therefore, gynecologic cancer survivors should be educated about these potential risks and complications.

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