Yonsei Med J.  2005 Aug;46(4):471-479. 10.3349/ymj.2005.46.4.471.

Effect of Long-Term Hormone Therapy on Telomere Length in Postmenopausal Women

• Lee DC
• Im JA
• Kim JH
• Lee HR
• Shim JY

• KMID: 1716515
• DOI: http://doi.org/10.3349/ymj.2005.46.4.471

Abstract

Telomeres undergo attrition with each cell division, and telomere length is associated with age-related diseases and mortality in the elderly. Estrogen can influence the attrition of telomeres by diverse mechanisms. This is a retrospective case control study that investigated the influence of long-term hormone therapy (HT) on telomere length in postmenopausal women. We recruited 130 postmenopausal women from 55 to 69 years of age for this study, and divided them into two groups. The first group included 65 women who had been on estrogen and progesterone therapy for more than five years (HT group). The other group was composed of 65 women matched in age to the HT group who had never had HT (non- HT group). The relative ratios of telomere length of study subjects to a reference DNA from a healthy young female were measured using quantitative PCR. Plasma levels of lipid profiles, total antioxidant status (TAS), C-reactive proteins (CRP), fasting glucose levels, and estradiol levels were measured. Age at menopause, vitamin use, and exercise, alcohol, and cigarette smoking histories were also assessed in a questionnaire. Mean duration (+/- SD) of HT was 8.4 +/- 2.3 years. Prevalence of vitamin use and regular exercise were higher in the HT group than in the non-HT group (p < 0.01). Relative telomere length ratios in the HT group were significantly greater than those in the non-HT group (p < 0.01). HT was significantly correlated with the relative telomere length ratio in multivariate analysis when potential confounding variables were controlled for (p < 0.05). In conclusion, telomere lengths were longer in postmenopausal women who had a history of long-term HT than in postmenopausal women without HT. Long-term HT in postmenopausal women may alleviate telomere attrition.

Keyword

Telomere; estrogen; menopause; hormone therapy; quantitative PCR

MeSH Terms

Aged
DNA Damage
Estrogens/*administration & dosage
Female
*Hormone Replacement Therapy
Humans
Middle Aged
Postmenopause
Progesterone/*administration & dosage
Research Support, Non-U.S. Gov't
Telomere/*drug effects
Time Factors

Figure

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  Fig. 1 Agarose gel electrophoresis following telomere PCR. Each 20µl aliquot of the PCR product was loaded onto prepared 4% metaphor agarose gels in 45 mM tris borate and 1 mM EDTA with ethidium bromide. The gel was run at 50 V for one hr and visualized and photographed under UV illumination. Lanes 1 and 6, size marker; lane 2, DNA without telomere primers; lane 3, telomere primers without DNA; lanes 4 and 5, human DNA with telomere primers. The bottom of the smear in lanes 4 and 5 was estimated to contain a 78 bp telomere product.

Reference

1. Meyne J, Ratliff RL, Myozis RK. Conservation of the human telomere sequence (TTAGGG)_n among vertebrate. Proc Natl Acad Sci USA. 1989. 86:7049–7053.

2. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing human fibroblasts. Nature. 1990. 345:458–460.

3. Von Zglinicki T, Serra V, Lorenz M, Saretzki G, Lenzen-Grossimlighaus R, Gessner R, et al. Short telomeres in patients with vascular dementia: an indicator of low antioxidative capacity and a possible risk factor? Lab Invest. 2000. 80:1739–1747.

4. Harley CB, Vaziri H, Counter CM, Allsopp RC. The telomere hypothesis of cellular aging. Exp Gerontol. 1992. 27:375–382.

5. Metcalfe JA, Parkhill J, Campbell L, Stacey M, Biggs P, Byrd PJ, et al. Accelerated telomere shortening in ataxia telangiectasia. Nat Genet. 1996. 13:350–353.

6. Wyllies FS, Jones CJ, Skinner JW, Haughton MF, Wallis C, Wynford-Thomas D, et al. Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts. Nat Genet. 2000. 24:16–17.

7. Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, et al. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet. 1993. 52:661–667.

8. Benetos A, Okuda K, Lajemi M, Kimura M, Thomas F, Skurnick J, et al. Telomere length as an indicator of biological aging: the gender effect and relation with pulse pressure and pulse wave velocity. Hypertension. 2001. 37:381–385.

9. Jeanclos E, Schork NJ, Kyvik KO, Kimura M, Skurnick JH, Aviv A. Telomere length inversely correlates with pulse pressure and is highly familial. Hypertension. 2000. 36:195–200.

10. Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D, et al. Telomere shortening in T cells correlates with Alzheimer's disease status. Neurobiol Aging. 2003. 24:77–84.

11. Cawthon RM, Smith KR, O'Biren E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 2003. 361:393–395.

12. Cherif H, Tarry JL, Ozanne SE, Hales CN. Ageing and telomeres: a study into organ-and gender-specific telomere shortening. Nucleic Acids Res. 2003. 31:1576–1583.

13. Von Zglinicki T. Oxidative stress shortens telomeres. Trens Biochem Sci. 2002. 27:339–344.

14. Okuda K, Bardeguez A, Gardner JP, Rodriguez P, Ganesh V, Kimura M, et al. Telomere length in the new born. Pediatr Res. 2002. 52:377–381.

15. Aviv A. Telomeres, sex, reactive oxygen species, and human cardiovascular aging. J Mol Med. 2002. 80:689–695.

16. Vasa M, Breitschopf K, Zeiher AM, Dimmeler S. Nitric oxide activates telomerase and delays endothelial cell senescence. Circ Res. 2000. 87:540–542.

17. Friedewald WT, Levy RI, Fredrikson DS. Estimation of concentration of low-density lipoprotein cholesterol in plasma, without use of preparative ultracentrifuge. Clin Chem. 1972. 18:499–502.

18. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. Antioxidant activity applying an imporved ABTS radical cation decolorization assay. Free Radic Biol Med. 1999. 26:1231–1237.

19. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acid Res. 2002. 30:e47.

20. Von Zglinicki T, Saretzki G, Docke W, Lotze C. Mild hypoxia shortens telomeres and inhibits proliferation of fibroblast: a model for senescence? Exp Cell Res. 1995. 220:186–193.

21. Von Zglinicki T, Pilger R, Sitte N. Accumulation of single-stranded breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med. 2000. 28:64–74.

22. Petersen S, Saretzki G, von Zglinicki T. Preferential Accumulation of single stranded regions in telomeres of human fibroblasts. Exp Cell Res. 1998. 239:152–160.

23. Von Zglinicki T. Role of oxidative stress in telomere length regulation and replicative senescence. Ann NY Acad Sci. 2000. 908:99–110.

24. Serra V, von Zglinicki T, Lorenz M, Saretzki G. Extracellular superoxide dismutase is a major antioxidant in human fibroblast and slows telomere shortening. J Biol Chem. 2003. 278:6824–6830.

25. King CM, Bristow-Craig HE, Gillespie ES, Barnett YA. In vivo antioxidant status, DNA damage, mutation and DNA repair capacity in cultured lymphocytes from healthy 75- to 80-year-old humans. Mutat Res. 1997. 377:137–147.

26. Mendoza-Nunez VM, Sanchez-Rodriguez MA, Retana-Ugalde R, Vargas-Guadarrama LA, Altamirano-Lozano MA. Total antioxidant levels, gender, and age as risk factors for DNA damage in lymphocytes of the elderly. Mech Ageing Dev. 2001. 122:835–847.

27. Kyo S, Takakura M, Kanaya T, Zhuo W, Fujimoto K, Nishio Y, et al. Estrogen activates telomerase. Cancer Res. 1999. 59:5917–5921.

28. Kang SS, Kwon T, Kwon DY, Do SI. Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. J Biol Chem. 1999. 274:13085–13090.

29. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phospatidylinositol-3-OH kinase. Nature. 2000. 407:538–541.

30. Rahimian R, Chan L, Goel A, Poburko D, Van Breemen C. Estrogen modulation of endothelium-derived relaxing factors by human endothelial cells. Biochem Biophys Res Commun. 2004. 322:373–379.

31. Vasa M, Breitschopf K, Zeiher AM, Dimmeler S. Nitric oxide activates telomere and delays endothelial cell senescence. Circ Res. 2000. 87:540–542.