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Dehydroepiandrosterone supplementation attenuates ovarian ageing in a galactose-induced primary ovarian insufficiency rat model

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Almost every female classic galactosemia patient develops primary ovarian insufficiency (POI). The unique pathophysiology of classic galactosemia, with a severely reduced follicle pool at an early age, requires a new therapeutic approach. This study evaluated the effect of dehydroepiandrosterone (DHEA) on ovarian tissue in a galactose-induced POI rat model.

Methods

Pregnant rats were fed with either a normal or a 35% galactose-containing diet from day 3 of conception continuing through weaning of the litters. Galactose-exposed female offspring were further divided into 5 groups on PND21. The first group received no application. Treatment groups were fed orally by gavage once daily with sesame oil (group 2), or DHEA at doses of 0.1 mg/kg (group 3), 1 mg/kg (group 4) or 10 mg/kg (group 5) until PND70. Fertility rates of mothers with galactosemia, body weights (BWs), and ovarian weights of the litters from PND21 to PND70 were recorded. Ovarian follicle count, immunohistochemistry for proliferation and apoptosis marker expressions and TUNEL for cell death assessment were performed in offspring ovaries.

Results

Decreased fertility, ovarian/body weights were observed under galactosemic conditions, together with decreased follicle number and increased atresia. Improved postnatal development, primordial follicle recruitment and follicular growth were observed after DHEA treatment. After DHEA treatment, the expression of Ki67 protein was found to be increased; elevated expression of cleaved-caspase-3 under galactosemia was found to be reduced.

Conclusions

Our data suggests that DHEA treatment may be a potentially useful clinical therapy to improve ovarian ageing in women with POI-induced by galactosemia.

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References

  1. Shelling AN. Premature ovarian failure. Reproduction. 2010;140(5):633–41.

    Article  CAS  PubMed  Google Scholar 

  2. Qin Y, Jiao X, Simpson JL, Chen ZJ. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015;21(6):787–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fridovich-Keil JL, Gubbels CS, Spencer JB, Sanders RD, Land JA, Rubio-Gozalbo E. Ovarian function in girls and women with GALT-deficiency galactosemia. J Inherit Metab Dis. 2011;34(2):357–66.

    Article  CAS  PubMed  Google Scholar 

  4. Silva CA, Yamakami LYS, Aikawa NE, Araujo DB, Carvalho JF, Bonfá E. Autoimmune primary ovarian insufficiency. Autoimmun Rev. 2014;13(4–5):427–30.

    Article  CAS  PubMed  Google Scholar 

  5. Rubio-Gozalbo ME, Gubbels CS, Bakker JA, Menheere PPCA, Wodzig WKWH, Land JA. Gonadal function in male and female patients with classic galactosemia. Hum Reprod Update. 2010;16(2):177–88.

    Article  CAS  PubMed  Google Scholar 

  6. Kaufman F, et al. Ovarian failure in galactosaemia. Lancet. 1979;2(8145):737–8.

    Article  CAS  PubMed  Google Scholar 

  7. Liu G, Hale GE, Hughes CL. Galactose metabolism and ovarian toxicity. Reprod Toxicol. 2000;14(5):377–84.

    Article  CAS  PubMed  Google Scholar 

  8. Chen YT, et al. Reduction in oocyte number following prenatal exposure to a diet high in galactose. Science. 1981;214(4525):1145–7.

    Article  CAS  PubMed  Google Scholar 

  9. Swartz WJ, Mattison DR. Galactose inhibition of ovulation in mice. Fertil Steril. 1988;49(3):522–6.

    Article  CAS  PubMed  Google Scholar 

  10. Bandyopadhyay S, et al. Galactose toxicity in the rat as a model for premature ovarian failure: an experimental approach readdressed. Hum Reprod. 2003;18(10):2031–8.

    Article  CAS  PubMed  Google Scholar 

  11. Burger HG. Androgen production in women. Fertil Steril. 2002;77(Suppl 4):S3–5.

    Article  PubMed  Google Scholar 

  12. Casson PR, Santoro N, Elkind-Hirsch K, Carson SA, Hornsby PJ, Abraham G, et al. Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: a six-month trial. Fertil Steril. 1998;70(1):107–10.

    Article  CAS  PubMed  Google Scholar 

  13. Mamas L, Mamas E. Premature ovarian failure and dehydroepiandrosterone. Fertil Steril. 2009;91(2):644–6.

    Article  CAS  PubMed  Google Scholar 

  14. Barad D, Gleicher N. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod. 2006;21(11):2845–9.

    Article  CAS  PubMed  Google Scholar 

  15. Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod. 2000;15(10):2129–32.

    Article  CAS  PubMed  Google Scholar 

  16. Fusi FM, Ferrario M, Bosisio C, Arnoldi M, Zanga L. DHEA supplementation positively affects spontaneous pregnancies in women with diminished ovarian function. Gynecol Endocrinol. 2013;29(10):940–3.

    Article  CAS  PubMed  Google Scholar 

  17. Labrie C, et al. High bioavailability of dehydroepiandrosterone administered percutaneously in the rat. J Endocrinol. 1996;150 Suppl:S107–18.

    CAS  PubMed  Google Scholar 

  18. Li J, Yuan H, Chen Y, Wu H, Wu H, Li L. A meta-analysis of dehydroepiandrosterone supplementation among women with diminished ovarian reserve undergoing in vitro fertilization or intracytoplasmic sperm injection. Int J Gynaecol Obstet. 2015;131(3):240–5.

    Article  CAS  PubMed  Google Scholar 

  19. Yan Z, Lee GY, Anderson E. Influence of dehydroepiandrosterone on the expression of insulin-like growth factor-1 during cystogenesis in polycystic rat ovaries and in cultured rat granulosa cells. Biol Reprod. 1997;57(6):1509–16.

    Article  CAS  PubMed  Google Scholar 

  20. van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update. 1999;5(5):483–92.

    Article  PubMed  Google Scholar 

  21. Narkwichean A, Jayaprakasan K, Maalouf WE, Hernandez-Medrano JH, Pincott-Allen C, Campbell BK. Effects of dehydroepiandrosterone on in vivo ovine follicular development. Hum Reprod. 2014;29(1):146–54.

    Article  CAS  PubMed  Google Scholar 

  22. Sato K, Iemitsu M, Aizawa K, Mesaki N, Ajisaka R, Fujita S. DHEA administration and exercise training improves insulin resistance in obese rats. Nutr Metab (Lond). 2012;9:47.

    Article  CAS  Google Scholar 

  23. Mehlmann LM, Saeki Y, Tanaka S, Brennan TJ, Evsikov AV, Pendola FL, et al. The Gs-linked receptor GPR3 maintains meiotic arrest in mammalian oocytes. Science. 2004;306(5703):1947–50.

    Article  CAS  PubMed  Google Scholar 

  24. Liu L, Rajareddy S, Reddy P, du C, Jagarlamudi K, Shen Y, et al. Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a. Development. 2007;134(1):199–209.

    Article  CAS  PubMed  Google Scholar 

  25. Wang N, Luo LL, Xu JJ, Xu MY, Zhang XM, Zhou XL, et al. Obesity accelerates ovarian follicle development and follicle loss in rats. Metabolism. 2014;63(1):94–103.

    Article  CAS  PubMed  Google Scholar 

  26. Segal S. In utero galactose intoxication in animals. Eur J Pediatr. 1995;154(7 Suppl 2):S82–6.

    Article  CAS  PubMed  Google Scholar 

  27. Cramer DW, Harlow BL, Barbieri RL, Ng WG. Galactose-1-phosphate uridyl transferase activity associated with age at menopause and reproductive history. Fertil Steril. 1989;51(4):609–15.

    Article  CAS  PubMed  Google Scholar 

  28. Adhikari D, Liu K. Molecular mechanisms underlying the activation of mammalian primordial follicles. Endocr Rev. 2009;30(5):438–64.

    Article  CAS  PubMed  Google Scholar 

  29. Castrillon DH, et al. Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science. 2003;301(5630):215–8.

    Article  CAS  PubMed  Google Scholar 

  30. Watkins WJ, et al. Mutational screening of FOXO3A and FOXO1A in women with premature ovarian failure. Fertil Steril. 2006;86(5):1518–21.

    Article  CAS  PubMed  Google Scholar 

  31. Gallardo TD, John GB, Bradshaw K, Welt C, Reijo-Pera R, Vogt PH, et al. Sequence variation at the human FOXO3 locus: a study of premature ovarian failure and primary amenorrhea. Hum Reprod. 2008;23(1):216–21.

    Article  CAS  PubMed  Google Scholar 

  32. Gleicher N, Weghofer A, Barad DH. The role of androgens in follicle maturation and ovulation induction: friend or foe of infertility treatment? Reprod Biol Endocrinol. 2011;9:116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tetsuka M, Hillier SG. Androgen receptor gene expression in rat granulosa cells: the role of follicle-stimulating hormone and steroid hormones. Endocrinology. 1996;137(10):4392–7.

    Article  CAS  PubMed  Google Scholar 

  34. Rice S, Ojha K, Whitehead S, Mason H. Stage-specific expression of androgen receptor, follicle-stimulating hormone receptor, and anti-Mullerian hormone type II receptor in single, isolated, human preantral follicles: relevance to polycystic ovaries. J Clin Endocrinol Metab. 2007;92(3):1034–40.

    Article  CAS  PubMed  Google Scholar 

  35. Sen A, Prizant H, Light A, Biswas A, Hayes E, Lee HJ, et al. Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Proc Natl Acad Sci U S A. 2014;111(8):3008–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to Asli Okan (MSc) for the technical help and Andy Cox (PhD) for helpful comments and English proofreading on this article.

Funding

This study was supported by the Akdeniz University Scientific Research Fund (2013.01.0103.008)

Author information

Author notes

  1. Berna Sozen

    Present address: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK

  2. Berna Sozen and Murat Ozekinci contributed equally to this work.

Authors and Affiliations

  1. Department of Histology and Embryology, School of Medicine, Akdeniz University, Campus, 07070, Antalya, Turkey

    Berna Sozen & Necdet Demir

  2. Department of Obstetrics and Gynecology, Akdeniz University School of Medicine, 07058, Antalya, Turkey

    Murat Ozekinci & Munire Erman

  3. IVF Andrologia and Genetics Center, Antalya Memorial Hospital, Yildirim Beyazit St. Kepez, 07025, Antalya, Turkey

    Murat Ozekinci

  4. Department of Obstetrics and Gynecology, Memorial Private Hospital, Antalya, Turkey

    Tonguc Gunduz

  5. Department of Obstetrics and Gynecology, Goteburg University, Gothenburg, Sweden

    Randa Akouri

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  1. Berna Sozen
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Contributions

B.S., M.O., M.E., and T.G. designed the study. B.S. and M.O. created the gal-exposed animal model. B.S. performed data collection and statistical analysis. B.S. wrote the article with the help of M.E. and M.O. M.E., R.A. and N.D. provided a critical discussion of the data and manuscript.

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Correspondence to Murat Ozekinci.

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Sozen, B., Ozekinci, M., Erman, M. et al. Dehydroepiandrosterone supplementation attenuates ovarian ageing in a galactose-induced primary ovarian insufficiency rat model. J Assist Reprod Genet 36, 2181–2189 (2019). https://doi.org/10.1007/s10815-019-01560-4

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  • DOI: https://doi.org/10.1007/s10815-019-01560-4

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