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Leptin Levels in Children and Adults with Classic Galactosaemia

  • Ina Knerr
  • Karen P. Coss
  • Peter P. Doran
  • Joanne Hughes
  • Nick Wareham
  • Keith Burling
  • Eileen P. Treacy
Research Report
Part of the JIMD Reports book series (JIMD, volume 9)

Abstract

Among the long-term complications of Classic Galactosaemia (Gal) is premature ovarian insufficiency (POI) in female patients with subtle abnormalities of reproductive function also reported in male patients. Leptin is a circulating hormone which reflects body energy stores and which affects the neuroendocrine reproductive axis and pubertal development.

We measured serum leptin in 28 children (10 girls, 18 boys; mean age 7.6 years, range 0.5–17.9 years) and in 22 adults (10 females, 12 males; mean age 23.9 years, range 18–37 years) with Gal on a strict galactose-restricted diet in comparison with control data.

Leptin levels (expressed as SDS for gender and pubertal stage) were lower in Gal children than controls (mean leptin-SDS = –0.71 for girls, p < 0.05, –0.97 for boys compared with SDS = 0 for controls, p < 0.05). In an age-related analysis, leptin levels did not correlate with age in children with Gal for both sexes as it did for matched controls.

As expected, females had higher leptin levels than males in either group. In adults with Gal, leptin concentrations were within normal limits for both sexes when adjusted for gender and BMI. There was a linear relationship between log-leptin and BMI in children with Gal and in controls. For Gal women, log-leptin was also associated with BMI. However, for Gal men, and hence for the entire group of adult Gal patients, this association between log-leptin and BMI was not detectable. Our findings suggest that leptin dysregulation may play a role in fertility issues in individuals with Gal from an early age.

Abbreviations

AMH

Anti-Mullerian hormone

BMI

Body mass index

FSH

Follicle-stimulating hormone

Gal

(Classic) Galactosaemia

GALT

Galactose-1-phosphate uridyltransferase

HPO

Hypothalamic-pituitary-ovarian

HRT

Hormone replacement therapy

LH

Luteinising hormone

n.s.

Not significant

SD

Standard deviation

Notes

Acknowledgement

We would like to thank all our patients who volunteered for the study. We wish to thank our colleagues Dr. Ellen Crushell and Dr. Ahmad A. Monavari for their excellent collaboration. We gratefully acknowledge Dr. Jian’an Luan for his excellent statistical advice. Leptin assays were performed by the NIHR Cambridge Biomedical Research Centre, Core Biochemical Assay Laboratory. CHFFH, Children’s University Hospital and Shire Industries are thanked for financial assistance to perform these studies.

References

  1. Banerjee S, Chakraborty P, Saha P, Bandyopadhyay SA, Banerjee S, Kabir SN (2012) Ovotoxic effects of galactose involve attenuation of follicle-stimulating hormone bioactivity and up-regulation of granulosa cell p53 expression. PLoS One 7(2):e30709CrossRefPubMedPubMedCentralGoogle Scholar
  2. Barrenetxe J, Sainz N, Barber A, Lostao MP (2004) Involvement of PKC and PKA in the inhibitory effect of leptin on intestinal galactose absorption. Biochem Biophys Res Commun 7(317):717–721CrossRefGoogle Scholar
  3. Berry GT (2008) Galactosemia and amenorrhea in the adolescent. Ann N Y Acad Sci 1135:112–117CrossRefPubMedGoogle Scholar
  4. Benetti-Pinto CL, Castro N, Grassiotto Oda R, Garmes HM (2010) Leptin and adiponectin blood levels in women with premature ovarian failure and age- and weight-matched women with normal menstrual cycles. Menopause 17:174–177CrossRefPubMedGoogle Scholar
  5. Blum WF, Englaro P, Hanitsch S, Juul A, Hertel NT, Müller J, Skakkebaek NE, Heiman ML, Birkett M, Attanasio AM, Kiess W, Rascher W (1997) Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. J Clin Endocrinol Metab 82:2904–2910PubMedGoogle Scholar
  6. Catalano S, Marsico S, Giordano C, Mauro L, Rizza P, Panno ML, Andò S (2003) Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem 278:28668–28676CrossRefPubMedGoogle Scholar
  7. Coman DJ, Murray DW, Byrne JC, Rudd PM, Bagaglia PM, Doran PD, Treacy EP (2010) Galactosemia, a single gene disorder with epigenetic consequences. Pediatr Res 67:286–292CrossRefPubMedGoogle Scholar
  8. Coss KP, Byrne JC, Coman DJ, Adamczyk B, Abrahams JL, Saldova R, Brown AY, Walsh O, Hendroff U, Carolan C, Rudd PM, Treacy EP (2012a) IgG N-glycans as potential biomarkers for determining galactose tolerance in classical Galactosaemia. Mol Genet Metab 105:212–220CrossRefPubMedGoogle Scholar
  9. Coss KP, Doran PP, Owoeye C, Codd MB, Hamid N, Mayne PD, Crushell E, Knerr I, Monavari AA, Treacy EP (2012b) Classical Galactosaemia in Ireland: incidence, complications and outcomes of treatment. J Inherit Metab Dis. 2012 Jul 3. [Epub ahead of print]Google Scholar
  10. Denver RJ, Bonnett RM, Boorse GC (2011) Evolution of leptin structure and function. Neuroendocrinoloy 94:21–38CrossRefGoogle Scholar
  11. Donato J Jr, Cravo RM, Frazão R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C, Richardson JA, Friedman J, Chua S Jr, Coppari R, Zigman JM, Elmquist JK, Elias CF (2011) Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest 121:355–368CrossRefPubMedGoogle Scholar
  12. El-Eshmawy MM, Abdel Aal IA, El Hawary AK (2010) Association of ghrelin and leptin with reproductive hormones in constitutional delay of growth and puberty. Reprod Biol Endocrinol 8:153CrossRefPubMedPubMedCentralGoogle Scholar
  13. Falorni A, Bini V, Molinari D, Papi F, Celi F, Di Stefano G, Berioli MG, Bacosi ML, Contessa G (1997) Leptin serum levels in normal weight and obese children and adolescents: relationship with age, sex, pubertal development, body mass index and insulin. Int J Obes Relat Metab Disord 21:881–890CrossRefPubMedGoogle Scholar
  14. Fridovich-Keil JL, Gubbels CS, Spencer JB, Sanders RD, Land JA, Rubio-Gozalbo E (2011) Ovarian function in girls and women with GALT-deficiency galactosemia. J Inherit Metab Dis 34:357–366CrossRefPubMedGoogle Scholar
  15. Garcia-Mayor RV, Andrade MA, Rios M, Lage M, Dieguez C, Casanueva FF (1997) Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage. J Clin Endocrinol Metab 82:2849–2855PubMedGoogle Scholar
  16. Gómez JM, Maravall FJ, Gómez N, Navarro MA, Casamitjana R, Soler J (2003) Interactions between serum leptin, the insulin-like growth factor-I system, and sex, age, anthropometric and body composition variables in a healthy population randomly selected. Clin Endocrinol 58:213–219CrossRefGoogle Scholar
  17. Goumenou AG, Matalliotakis IM, Koumantakis GE, Panidis DK (2003) The role of leptin in fertility. Eur J Obstet Gynecol Reprod Biol 106:118–124CrossRefPubMedGoogle Scholar
  18. Gubbels CS, Thomas CM, Wodzig WK, Olthaar AJ, Jaeken J, Sweep FC, Rubio-Gozalbo ME (2011) FSH isoform pattern in classic galactosemia. J Inherit Metab Dis 34:387–390CrossRefPubMedGoogle Scholar
  19. Gubbels CS, Welt CR, Dumoulin J, Robben SG, Gordon CM, Dunselman G, Rubio-Gozalbo ME, Berry GT (2011b) The male reproductive system in classic Galactosemia: cryptorchidism and low semen volume. J Inherit Metab Dis 34 (Suppl 3). S177Google Scholar
  20. Gubbels CS, Land JA, Rubio-Gozalbo ME (2008) Fertility and impact of pregnancies on the mother and child in classic galactosemia. Obstet Gynecol Surv 63:334–343CrossRefPubMedGoogle Scholar
  21. Hamm ML, Bhat GK, Thompson WE, Mann DR (2004) Folliculogenesis is impaired and granulosa cell apoptosis is increased in leptin-deficient mice. Biol Reprod 71:66–72CrossRefPubMedGoogle Scholar
  22. Hughes J, Ryan S, Lambert D, Geoghegan O, Clark A, Rogers Y, Hendroff U, Monavari A, Twomey E, Treacy EP (2009) Outcomes of siblings with classical galactosemia. J Pediatr 154:721–726CrossRefPubMedGoogle Scholar
  23. Hussein MR (2005) Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update 11:162–177CrossRefPubMedGoogle Scholar
  24. Isidori AM, Strollo F, Morè M, Caprio M, Aversa A, Moretti C, Frajese G, Riondino G, Fabbri A (2000) Leptin and aging: correlation with endocrine changes in male and female healthy adult populations of different body weights. J Clin Endocrinol Metab 85:1954–1962CrossRefPubMedGoogle Scholar
  25. Kaufman FR, Kogut MD, Donnell GN, Goebelsmann U, March C, Koch R (1981) Hypergonadotropic hypogonadism in female patients with galactosemia. N Engl J Med 304:994–998CrossRefPubMedGoogle Scholar
  26. Kilpeläinen TO, den Hoed M, Ong KK, Grøntved A, Brage S; Early Growth Genetics Consortium, Jameson K, Cooper C, Khaw KT, Ekelund U, Wareham NJ, Loos RJ (2011) Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals. Am J Clin Nutr 93:851–860Google Scholar
  27. Knerr I, Herzog D, Rauh M, Rascher W, Horbach T (2006) Leptin and ghrelin expression in adipose tissues and serum levels in gastric banding patients. Eur J Clin Invest 36:389–394CrossRefPubMedGoogle Scholar
  28. Lostao MP, Urdaneta E, Martínez-Ansó E, Barber A, Martínez JA (1998) Presence and leptin effect on sugar absorption. FEBS Lett 423:302–306CrossRefPubMedGoogle Scholar
  29. Messinis IE, Kariotis I, Milingos S, Kollios G, Seferiadis K (2000) Treatment of normal women with oestradiol plus progesterone prevents the decrease of leptin concentrations induced by ovariectomy. Hum Reprod 15:2383–2387CrossRefPubMedGoogle Scholar
  30. Meissner U, Hänisch C, Ostreicher I, Knerr I, Hofbauer KH, Blum WF, Allabauer I, Rascher W, Dötsch J (2005) Differential regulation of leptin synthesis in rats during short-term hypoxia and short-term carbon monoxide inhalation. Endocrinology 146:215–220CrossRefPubMedGoogle Scholar
  31. Panis B, Forget PP, Nieman FH, van Kroonenburgh MJ, Rubio-Gozalbo ME (2005) Body composition in children with galactosaemia. J Inherit Metab Dis 28:931–937CrossRefPubMedGoogle Scholar
  32. Phipps WR, Wangen KE, Duncan AM, Merz-Demlow BE, Xu X, Kurzer MS (2001) Lack of effect of isoflavonic phytoestrogen intake on leptin concentrations in premenopausal and postmenopausal women. Fertil Steril 75:1059–1064CrossRefPubMedGoogle Scholar
  33. Rubio-Gozalbo ME, Gubbels CS, Bakker JA, Menheere PP, Wodzig WK, Land JA (2010) Gonadal function in male and female patients with classic galactosemia. Hum Reprod Update 16:177–188CrossRefPubMedGoogle Scholar
  34. Tena-Sempere M (2006) KiSS-1 and reproduction: focus on its role in the metabolic regulation of fertility. Neuroendocrinology 83:275–281CrossRefPubMedGoogle Scholar
  35. Trinko R, Gan G, Gao XB, Sears RM, Guarnieri DJ, DiLeone RJ (2011) Erk1/2 mediates leptin receptor signaling in the ventral tegmental area. PLoS One 6(11):e27180, Epub 2011 Nov 4CrossRefPubMedPubMedCentralGoogle Scholar
  36. Vandenplas Y, De Greef E, Devreker T, Hauser B (2011) Soy infant formula: is it that bad? Acta Paediatr 100:162–166CrossRefPubMedGoogle Scholar
  37. Xu Y, O'Brien WG 3rd, Lee CC, Myers MG Jr, Tong Q (2012) Role of GABA release from leptin receptor-expressing neurons in body weight regulation. Endocrinology 153:2223–2233CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Ina Knerr
    • 1
  • Karen P. Coss
    • 2
  • Peter P. Doran
    • 2
  • Joanne Hughes
    • 1
  • Nick Wareham
    • 3
  • Keith Burling
    • 4
  • Eileen P. Treacy
    • 1
    • 5
  1. 1.National Centre for Inherited Metabolic DisordersChildren’s University HospitalDublinIreland
  2. 2.University College Dublin, Clinical Research Centre, Mater Misericordiae University HospitalDublinIreland
  3. 3.Medical Research Council Epidemiology UnitAddenbrooke’s HospitalCambridgeUK
  4. 4.Core Biochemical Assay LaboratoryCambridge University HospitalsCambridgeUK
  5. 5.Trinity CollegeDublinIreland

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