Main Article Content

Vincenzo De Sanctis
Salvatore Di Maio


Transfusion-dependent β-thalassemia, menarche, menstrual cycles, secondary amenorrhea, iron overload, nutritional status



Summary. Background: Menarche is an important milestone in the reproductive life of a woman, and regular menstrual cycles reflect normal functioning of the hypothalamic-pituitary-ovarian axis, a vital sign of women’s general health. Aim of the study:We explored the age at menarche and the following menstrual cycles characteristics among 85 unmarried Transfusion-Dependent β-Thalassemia (TDT) women,borned between 1965 and 1995, in relation to iron chelation therapy (ICT) with desferrioxamine (DFO) and nutritional status, assessed by body mass index (BMI). Results: 53 adolescents who had begun ICT before the age of 10 years experienced menarche at 13,7 ± 1,6 years (mean ± DS), whereas 32 who begun treatment after 10 years experienced menarche at the significantly later age (15.5 ± 1.9 yrs; p: 0.001). At the age of menarche: BMI-Z score (n= 67, - 0,09 ±1) was inversely correlated with both age at starting ICT (r = - 0,39; p = 0001) and age at menarche ( - 0,45, p = 0,0001). Serum ferritin levels (SF) were significantly correlated with the age at starting chelation therapy (n = 79; r = 0,34; p = 0,022). In 56 TDT adolescents who developed secondary amenorrhea (SA), the SF levels were significantly higher (4,098 ± 1,907 ng/mL) compared to 23 TDT adolescents with regular menstrual cycles (2,913±782 ng/mL; p = 0,005). A nutritional status of "thinness" at menarche was associated to a lower prevalence of subsequent regular menstrual cycles and to a higher prevalence of early SA. Conclusion: An early ICT in TDT patients was associated to a normal "tempo" of pubertal onset and to a higher frequency of subsequent regular menstrual cycles. In TDT patients, who developed SA, a diagnosis of acquired central hypogonadism was made, mainly due to the chronic exposure to iron overload, however other potential causes linked to nutritional status, deficient levels of circulating nutrientsand the chronic disease itself cannot be excluded.



Download data is not yet available.

Abstract 903
PDF Downloads 293
HTML Downloads 100


1. Weatherall DJ. Thalassemia as a global health problem: recent progress toward its control in the developing countries. Ann N Y Acad Sci. 2010;1202:17-23.
2. Viprakasit V, Ekwattanakit S. Clinical Classification, Screening and Diagnosis for Thalassemia. HematolOncolClin North Am. 2018;32:193-211.
3. Thalassaemia International Federation. Guidelines for the management of transfusion dependent thalassaemia (TDT). 3rd ed. 2014 Available from www. thalassaemia.org.cy. Accessed 15 June 2018.
4. Kanbour I, Chandra P, Soliman A, De Sanctis V, Nashwan A, Abusamaan S, Moustafa A, Yassin MA. Severe Liver Iron Concentrations (LIC) in 24 Patients with β-Thalassemia Major: Correlations with Serum Ferritin, Liver Enzymes and Endocrine Complications. Mediterr J Hematol Infect Dis. 2018;10(1):e2018062. doi: 10.4084/MJHID.2018.062.
5. Hankins JS, McCarville MB, Loeffler RB, Smeltzer MP, Onciu M, Hoffer FA, Li CS, Wang WC, Ware RE, Hillenbrand CM. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood. 2009;113:4853-4855.
6. St Pierre TG, El-Beshlawy A, Elalfy M, Al Jefri A, Al Zir K, Daar S, Habr D, Kriemler-Krahn U, Taher A. Multicenter validation of spin-density projection-assisted R2-MRI for the non invasive measurement of liver iron concentration. MagnReson Med. 2014;71:2215-2223.
7. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassaemia. Blood. 1997;89:739-761.
8. Berdoukas V, Farmaki K, Carson S, Wood J, Coates T. Treating thalassemia major-
related iron overload: the role of deferiprone. J Blood Med. 2012;3:119-129.

9. Wang YX, Arvizu M, Rich-Edwards JW, Stuart JJ, Manson JE, Missmer SA, Pan A, Chavarro JE. Menstrual cycle regularity and length across the reproductive lifespan and risk of premature mortality: prospective cohort study. BMJ. 2020;371: m3464. doi: 10.1136/bmj.m3464.

10. Bronspiegel-Weintrob N, Olivieri NF, Tyler B, Andrews DF, Freedman MH, Holland FJ. Effect of age at the start of iron chelation therapy on gonadal function in β-thalassemia major. N Engl J Med. 1990;323:713-719.

11. De Sanctis V, Bernasconi S, Bianchin L, Bona G, Bozzola M, Buzi F, De Sanctis C, Rigon F, Tatò L, Tonini G, Perissinotto E. Onset of menstrual cycle and menses features among secondary school girls in Italy: a questionnaire study on 3,783 students. Indian J EndocrinolMetab. 2014; 18 (suppl 1): S84-S92.

12. Papadimitriou A, Fytanidis G, Douros K, Bakoula C, Nicolaidou P, Fretzayas A. Age at menarche in contemporary Greek girls: evidence for levelling-off of the secular trend. ActaPaediatr 2008; 97:812-815.
13. Rosenfield RL, Cooke DW, Radovick S. Puberty and its disorders in the female. In: Sperling MA. Pediatric Endocrinology, fourth edition. ELSEVIER Saunders, Philadelphia 2014; pp. 694-696.
14. De Sanctis V, Soliman AT, Elsedfy H, Skordis N, Kattamis C, Angastiniatis M, Karimi M, Yassin MA, El Awwa A, Stoeva I, Raiola G, Galati MC, Bedair EM, Fiscina B, El Kholy M. Growth and endocrine disorders in thalassemia: the International network on endocrine complications in thalassemia (I-CET) position statement and guidelines. Indian J EndocrinolMetab. 2013; 17:8-18.
15. Cole TJ, Nicholls D, Jackson AA. Body Mass Index cut offs to define thinness in children and adolescents: international survey. BMJ. 2007;335(7612):194. doi:10.1136/bmj.39238.399444.55.
16. Casale M, Meloni A, Filosa A, Cuccia L, Caruso V, Palazzi G, Gamberini MR, Pitrolo L, Putti MC, D’Ascola DG, Casini T, Quarta A, Maggio A, Neri MG, Positano V, Salvatori C, Toia P, Valeri G, Midiri M, Pepe A. Multiparametric Cardiac Magnetic Resonance Survey in Children With Thalassemia Major: A Multicenter Study. CircCardiovasc Imaging. 2015 ; 8(8):e003230. doi:10.1161/ CIRCIMAGING. 115.003230.
17. Wang Z, Dang S, Xing Y, Li Q, Yan H. Correlation of body mass index levels with menarche in adolescent girls in Shaanxi, China: a cross sectional study. BMC WomensHealth. 2016;16:61. doi: 10.1186/s12905-016-0340-4.
18. Palel L. Growth and Chronic Disease. Ann Nestlé [Engl]. 2007;65:129–136.
19. Bronspiegel-Weintrob N, Olivieri NF, Tyler B, David F, Andrews DF, Melvin H, Freedman MH, Holland FJ. Effect of age at the start of iron chelation therapy on gonadal function in β-thalassemia major. N Engl J Med. 1990;323:713-719.
20. Wood JC. Guidelines for quantifying iron overload. Hematology (Am SocHematolEduc Program). 2014;2014:210–215.
21. Hekmatnia A, Radmard AR, Rahmani AA, Adibi A, Khademi H. Magnetic resonance imaging signal reduction may precede volume loss in the pituitary gland of transfusion-dependent beta-thalassemic patients. ActaRadiol. 2010;51:71–77.
22. Pippard M, Johnson D, Callender S, Finch C. Ferrioxamineexcretion in iron loaded man. Blood. 1982;60:288-294. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142532/ - B1
23. Ruder EH, Hartman TJ, Goldman MB. Impact of oxidative stress on female fertility. CurrOpinObstet Gynecol. 2009;21:219–222.
24. Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, McCord JM, Harman D. Oxygen radicals and humandisease. Ann Intern Med. 1987;107:526–545.
25. Chatterjee R, Katz M, Cox TF, Porter JB. Prospective study of hypothalamic-pituitary-axis in thalassemic patients who developed secondary amenorrhea. ClinEndocrinol (Oxf) 1993;39: 287-296.
pubertal timing derangement. J PediatrEndocrinolMetab. 2002; 16:877-881.
26.Tienboon P, Sanguansermsri T, Fuchs GJ. Malnutrition and growth abnormalities in children with beta thalassemia major. Southeast Asian J Trop Med Public Health. 1996; 27: 356-361.
27. Kiess W, Reich A, Meyer K, Glasgow A, Deutscher J, Klammt J, Yang Y, Müller G, Kratzsch J. A role for leptin in sexual maturation and puberty? Horm Res. 1999; 51 (S3): 55-63.

28. Goldberg EK, Neogi S, Lal A, Higa A, Fung E. Nutritional Deficiencies Are Common in Patients with Transfusion-Dependent Thalassemia and Associated with Iron Overload. J Food Nutr Res (Newark). 2018;6: 674-681.
29.Ott ES, Shay NF. Zinc deficiency reduces leptin gene expression and leptin secretion in rat adipocytes. ExpBiol Med (Maywood). 2001;226:841-846.
30. Perrone L, Perrotta S, Raimondo P, Mucerino J, De Rosa C, Siciliani MC, Santoro N, Miraglia del Giudice E. Inappropriate leptin secretion in thalassemia: a potential cofactor of pubertal timing derangement. J PediatrEndocrinolMetab. 2002; 16:877-881.