Retrospective study on long-term effects of hormone replacement therapy (HRT) and iron chelation therapy on glucose homeostasis and insulin secretion in female ß- thalassemia major (β-TM) patients with acquired hypogonadotropic- hypogonadism (AHH)
Treatment of hypogonadal female thalassemic patients and OGTT
Keywords:
ß- thalassemia major, acquired hypogonadotropic- hypogonadism in females, hormone replacement therapy, oral glucose tolerance test, glucose homeostasis, iron overload.Abstract
Background and aim: Hypogonadism and abnormalities of glucose homeostasis, resulting from iron-induced pituitary and pancreatic β-cell dysfunction respectively, are the most frequently reported endocrine abnormalities in patients with ß-thalassemia major (β-TM), also identified as transfusion-dependent thalassemia (TDT).
Study design and Patients: The aim of the present retrospective study was to evaluate the long-term effects of hormone replacement therapy (HRT) on glucose metabolism and insulin secretion/sensitivity during 3-h oral glucose tolerance test (OGTT) in adolescent and young β-TM women with acquired hypogonadototropic -hypogonadism (AHH).Twelve hypogonadal β-TM females with AHH on HRT were followed for 8.26 ± 1.49 years.
Results: At baseline, 10 patients (83.3%) had normal OGTT, 1 patient presented with impaired glucose tolerance (IGT) and 1 patient had an isolated PG level of 165 mg/dL at 1-h during OGTT (H-NGT). At last evaluation, 7 patients (58.4 %) had normal OGTT, while 5 patients (41.6%) had abnormal OGTT. Reduced insulin sensitivity and impaired first-phase insulin secretion were also documented. Three of 4 β-TM patients on treatment with estradiol hemihydrate MX 50 patches plus oral medroxyprogesterone acetate (MPA), associated with a very effective iron chelation therapy, maintained normal glucose tolerance from baseline to last evaluation. Significant adverse events due to HRT or additional endocrine complications were not documented in any cases during the follow-up.
Conclusion: Deterioration of glycemia (dysglycemia) occurred in 45.4% (5/11) of thalassemic females on long-term HRT. Additional studies are needed to elucidate the validity of our preliminary observations.
References
Soliman AT, Elalaily R, Soliman N. Prevalence of Short Stature and Endocrinopathy in β-thalassemia Major Patients on Conventional Therapy in the Mediterranean and the Middle East countries. 60th Annual Meeting of the ESPE. Horm Res Paediatr 2022;95 (suppl 2):1–616.doi:10.1159/000525606.
Young J, Xu C, Papadakis GE, et al. Clinical Management of Congenital Hypogonadotropic Hypogonadism. Endocrine Rev. 2019; 40(2):669–710. doi:10.1210/er.2018-00116.
Srisukh S, Ongphiphadhanakul B, Bunnag P. Hypogonadism in thalassemia major patients. J Clin Transl Endocrinol. 2016;5: 42–5. doi: 10.1016/j.jcte.2016.08.001.
Tzoulis P. Review of Endocrine Complications in Adult Patients with β-thalassaemia Major. Thalass Rep. 2014;4(3):4871. doi.org/10.4081/thal.2014.4871.
De Sanctis V, Elsedfy H, Soliman AT, et al. Clinical and Biochemical Data of Adult Thalassemia Major patients (TM) with Multiple Endocrine Complications (MEC) versus TM Patients with Normal Endocrine Functions: A long-term Retrospective Study (40 years) in a Tertiary Care Center in Italy. Mediterr J Hematol Infect Dis.2016;8(1): e2016022. doi: 10.4084/MJHID.2016.022.
De Sanctis V, Soliman AT, Daar S, et al. The experience of a tertiary unit on the clinical phenotype and management of hypogonadism in female adolescents and young adults with transfusion dependent thalassemia. Acta Biomed. 2019;90(1):158-67. doi:10. 23750/ abm. v90i1.8143.
De Sanctis V, Soliman AT, Elsedfy H, Di Maio S. Current practice in treating adult female thalassemia major patients with hypogonadism: An International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine survey from Italy. Indian J Endocr Metab.2016;20:880-1. doi:10. 4103/2230-8210.192905.
Taher A, Isma'eel H, Mehio G, et al. Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran. Thromb Haemost. 2006; 96(4):488-91.doi 10.1160/TH06-05-0267.
Haghpanah S, Karimi M. Cerebral thrombosis in patients with β-thalassemia: a systematic review. Blood Coagul Fibrinolysis. 2012;23:212–7. doi:10.1097/MBC.013e3283502975.
Iolascon A, Giordano P, Storelli S, et al. Thrombophilia in thalassemia major patients: analysis of genetic predisposing factors. Haematologica. 2001; 86:1112-3.PIMD:11602424.
De Sanctis V, Soliman AT, Elsedfy H, et al. Review and Recommendations on Management of Adult Female Thalassemia Patients with Hypogonadism based on Literature Review and Experience of ICET-A Network Specialists Mediterr J Hematol Infect Dis. 2017; 9(1): e2017001. doi:10.4084/ MJHID.2017.001.
Cacciari E, Milani S, Balsamo A, et al. Italian cross-sectional growth charts for height, weight and BMI (6 – 20 y). Eur J Clin Nutr. 2002; 56(2):171- 80. doi:10.1038/ sj.ejcn 1601314.
De Sanctis V, Soliman AT, Elsedfy H, et al. Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines. Indian J Endocrinol Metab. 2013;17(1):8-18.doi.org/10.4103/ 2230-8210.107808.
WHO. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser.1995;854:1-452.
American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes - 2020. Diabetes Care. 2020; 43(Suppl.1): S14-S31.doi.org/ 10.2337/dc20-S002.
De Sanctis V, Soliman A, Tzoulis P, et al. The clinical characteristics, biochemical parameters and insulin response to oral glucose tolerance test (OGTT) in 25 transfusion dependent β-thalassemia (TDT) patients recently diagnosed with diabetes mellitus (DM): Diabetes mellitus in β-thalassemia. Acta Biomed. 2022;92 (6):e2021488. doi.org/10.2 3750/abm.v92i6.12366.
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care.1999;22(9):1462-70. doi:10.2337/ diacare. 22.9.1462.
Sluiter WJ, Erkelens DW, Reitsma WD, Doorenbos H. Glucose tolerance and insulin release, a mathematical approach I. Assay of the β-cell response after oral glucose loading. Diabetes. 1976; 25:241–4.doi: 10.2337/diab.25.4.245.
Gutch M, Kumar S, Razi SM, Gupta KK, Gupta A. Assessment of insulin sensitivity/ resistance. Indian J Endocr Metab. 2015;19:160-4. doi: 10.4103/2230-8210.146874.
Park SY, Gautier JF, Suk Chon S. Assessment of Insulin Secretion and Insulin Resistance in Human. Diabetes Metab J 2021;45:641-54. doi.org/10.4093/ dmj. 2021.0220.
Hayashi T, Boyko EJ, Sato KK, et al. Patterns of insulin concentration during the OGTT predict the risk of type 2 diabetes in Japanese Americans. Diabetes Care. 2013;36(5):1229-35. doi:10.2337/dc12-0246.
Utzschneider KM, Prigeon RL, Faulenbach MV, et al. Oral disposition index predicts the development of future diabetes above and beyond fasting and 2-h glucose levels. Diabetes Care. 2009;32(2):335-41.doi: 10.2337/dc08-1478.
Taher AT, Porter J, Viprakasit V, et al. Deferasirox reduces iron overload significantly in non transfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood. 2012;120(5):970-7.doi.org/10.1182/blood-2012-02-412692
Brittenham GM, Farrell DE, Harris JW, et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med.1982;307(27):1671-5. doi.org/10.1056/ NEJM 198212303072703.
Pepe A, Meloni A, Rossi G, et al. Prediction of cardiac complications for thalassemia major in the widespread cardiac magnetic resonance era: a prospective multicentre study by a multi-parametric approach. Eur Heart J Cardiovasc Imaging. 2018;19(3):299-309.doi.org/ 10.1093/ehjci/jex012.
Alder R, Roesser EB. Introduction to probability and statistics. WH Freeman and Company Eds. Sixth Edition. San Francisco (USA), 1975.PMID:1674139.
Viswanathan V, Erica A. Eugster EA. Etiology and Treatment of Hypogonadism in Adolescents. Pediatr Clin North Am. 2011; 58(5):1181–x. doi:10.1016/j.pcl.2011.07.009.
Farmakis D, Porter J, Taher A, Cappellini MD, Angastiniotis M, Eleftheriou A. 2021 Thalassaemia International Federation Guidelines for the Management of Transfusion-dependent Thalassemia. Hemasphere. 2022;6(8):e732. doi: 10.1097/HS9. 0000000 000 000732.
De Sanctis V, Daar S, Soliman AT, et al. Screening for glucose dysregulation in β-thalassemia major (β-TM): An update of current evidences and personal experience. Acta Biomed. 2022;93(1): e2022158. doi: 10.23750/abm.v93i1.12802.
De Sanctis V, Soliman AT, Daar S, Tzoulis P, Fiscina B, Kattamis C, International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A). Retrospective observational studies: Lights and shadows for medical writers. Acta Biomed. 2022;93(5):e2022319. doi.org /10.23750/abm.v93i5.13179.
Faculty of Sexual & Reproductive Healthcare. UK Medical Eligibility Criteria for Contraceptive Use. UKMEC; 2016. [Last Accessed date: January 5, 2020]. (Amended September 2019) Available from: https://www.fsrh.org/standards-and-guidance /documents/ ukmec-2016.
World Health Organization. Selected practice recommendations for contraceptive use. Third Edition. Geneva, Switzerland: 2016.
Curtis KM, Jatlaoui TC, Tepper NK, et al. U.S. Selected Practice Recommendations for Contraceptive Use, 2016. MMWR Recomm Rep. 2016;65:1–66. doi:10.15585/ mmwr. rr6504a1.
Katz M, De Sanctis V, Vullo C, Wonke B, McGarrigle HH, Bagni B. Pharmacokinetics of sex steroids in patients with beta thalassaemia major. J Clin Pathol. 1993;46(7): 660–4. doi: 10.1136/ jcp.46.7.660.
De Sanctis V, Eleftheriou A, Malaventura C. Thalassaemia International Federation Study Group on Growth and Endocrine Complications in Thalassaemia. Prevalence of endocrine complications and short stature in patients with thalassaemia major: a multicenter study by the Thalassaemia International Federation (TIF) Pediatr Endocrinol Rev. 2004;(2 Suppl. 2):249–55.PIMD:16462705.
Chon S, Gautier JF. An update on the effect of incretin-based therapies on β-cell function and mass. Diabetes Metab J. 2016; 40(2):99-114.doi:10.4093/dmj.2016.40.2.99.
Luzi L, DeFronzo RA. Effect of loss of first-phase insulin secre¬tion on hepatic glucose production and tissue glucose disposal in humans. Am J Physiol. 1989;257(2 Pt 1):E241-6.doi:10.1152/ ajpendo.1989. 257. 2.E241.
Hollingdal M, Sturis J, Gall MA, et al. Repaglinide treatment amplifies first-phase insulin secretion and high-frequency pulsatile insulin release in Type 2 diabetes Diabetic Med.2005;22(10):1408-13. doi.org/10.1111/j.1464-5491.2005.01652.x.
Haverinen A, Kangasniemi MH, Luiro K, Piltonen T, Heikinheimo O, Tapanainen JS. Ethinyl estradiol vs estradiol valerate in combined oral contraceptives—effect on glucose tolerance: a randomized, controlled clinical trial. Contraception 2021;103(1):53–9.doi:10.1016/ j.contraception. 2020.10.014.
Godsland IF. Oestrogens and insulin secretion. Diabetologia. 2005;48: 2213–20. doi:10.1007/ s00125-005-1930-0.
Kenigsberg L, Balachandar S, Prasad K, Shah B. Exogenous pubertal induction by oral versus transdermal estrogen therapy. J Pediatr Adolesc Gynecol. 2013;26(2):71–9. PIMD: 22112543.
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Copyright (c) 2023 Vincenzo De Sanctis, shahina daar, Ashraf Soliman, Ploutarchos Tzoulis, Salvatore Di Maio, Christos Kattamis
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