Effect of dehydroepiandrosterone on meiotic spindle structure and oocyte quality in mice

Document Type: Original Article


1 Physiology Research Center, Faculty of Medicine, Ahvaz Jundishapour University of Medical Science, Ahvaz, Iran

2 Physiology Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran

3 Fertility and Infertility Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

4 Department of Anatomical Science, Faculty of Medicine, Tarbiat Modarres University, Tehran, Iran

5 Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran


Objective(s): Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances in women with diminished ovarian reserve (DOR) and to reduce miscarriage rates by 50–80%. This study, therefore, assesses effects of DHEA on number of retrieved oocytes and meiotic spindles.
Materials and Methods: A randomized, prospective, controlled study was conducted on eight groups, four groups of young mice and four elderly. All young and old groups received different oral doses (35, 50, 75 mg/kg) of DHEA for 3 months. Meiotic spindle assessment was done by immunocytochemical techniques using a confocal laser microscope (Leica TCS-4D).
Results: Statistical surveys showed that in control young groups 80% (P=0.0845) and in the old control group 73.3% (P=0.000) of the meiotic spindles have a normal shape and structure; the difference was meaningful. The young with 50 mg/kg of DHEA in 85.4% and the young with 75 mg/kg of DHEA in 84.2% were normal in shape and structure. Statistical analysis showed that the difference was meaningless (P=0.845). The old group with 30 mg/kg of DHEA in 81.1%, the old with 50 mg/kg of DHEA in 83.9%, and the old with 75 mg/kg of DHEA in 79.0% showed normal shape and structure. The meiotic spindle disruption ratio in old mice showed a significant difference (P=0.000) in comparison with others in young groups. Statistical analysis showed that difference between DHEA and control groups is meaningful. But this difference was meaningless between DHEA groups.
Conclusion: Results showed that DHEA has a positive and improvement effect on the meiotic spindle in old mice.


Main Subjects

1. Yang R, Yang S, Li R, Chen X, Wang H, Ma C, et al. Biochemical pregnancy and spontaneous abortion in first IVF cycles are negative predictors for subsequent cycles: an over 10,000 cases cohort study. Arch Gynecol Obstet 2015;292:453-458.
2. Schieve LA, Tatham L, Peterson HB, Toner J, Jeng G. Spontaneous abortion among pregnancies conceived using assisted reproductive technology in the United States. Obstet Gynecol 2003;101:959-967.
3. Sadler TW, editor The embryologic origin of ventral body wall defects. Seminars in pediatric surgery; 2010: Elsevier.
4. Bettio D, Venci A, Levi Setti PE. Chromosomal abnormalities in miscarriages after different assisted reproduction procedures. Placenta 2008;29 Suppl B:126-128.
5. Barad D, Gleicher N. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod 2006;21:2845-2849.  
6. Gleicher N, McCulloh DH, Kushnir VA, Ganguly N, Barad DH, Goldman KN, et al. Is there an androgen level threshold for aneuploidy risk in infertile women? Reprod Biol Endocrinol 2015 6;13:38-44.
7. Wiser A, Gonen O, Ghetler Y, Shavit T, Berkovitz A, Shulman A. Addition of dehydroepiandrosterone (DHEA) for poor-responder patients before and during IVF treatment improves the pregnancy rate: a randomized prospective study. Hum Reprod 2010;25:2496-2500.
8. Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod 2000;15:2129-2132.
9. Burger HG. Androgen production in women. Fertil Steril 2002;77:S3–S5.
10. 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: 107–110.
11. Ahn RS, Lee YJ, Choi JY, Kwon HB, Chun SI. Salivary cortisol and DHEA levels in the Korean population: age-related differences, diurnal rhythm, and correlations with serum levels. Yonsei Med J 2007 30;48:379-388.
12. Liu Y, Hu L, Fan L, Wang F. Efficacy of dehydroepiandrosterone (DHEA) supplementation for in vitro fertilization and embryo transfer cycles: a systematic review and meta-analysis. Gynecol Endocrinol 2018;34:178-183.
13. Battaglia DE, Goodwin P, Klein NA, Soules MR. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod 1996;11:2217-2222.
14. Gleicher N, Barad DH. Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). Reprod Biol Endocrinol 2011;9:67-78.
15. Gleicher N, Weghofer A, Barad DH. Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS). Reprod Biol Endocrinol 2010;8:140-144.
16. Pickering SJ, Braude PR, Johnson MH, Cant A, Currie J. Transient cooling to room temperature can cause irreversible disruption of the meiotic spindle in the  human oocyte. Fertil Steril 1990;54:102-108.
17. Joly C, Bchini O, Boulekbache H, Testart J, Maro B. Effects of 1,2-propanediol on the cytoskeletal organization of the mouse oocyte. Hum Reprod 1992;7:374-378.
18. Serhal PF, Ranieri DM, Kinis A, Marchant S, Davies M, Khadum IM. Oocyte morphology predicts outcome of intracytoplasmic sperm injection. Hum Reprod 1997;12:1267-1270.
19. Rienzi L, Ubaldi FM, Iacobelli M, Minasi MG, Romano S, Ferrero S, et al. Significance of metaphase II human oocyte morphology on ICSI outcome. Fertil Steril 2008;90:1692-1700.
20. Xia P. Intracytoplasmic sperm injection: correlation of oocyte grade based on  polar body, perivitelline space and cytoplasmic inclusions with fertilization rate and embryo quality. Hum Reprod 1997;12:1750-1755.
21. Nakamura H, Kimura T, Koyama S, Ogita K, Tsutsui T, Shimoya K, et al. Mouse model of human infertility: transient and local inhibition of endometrial STAT-3 activation results in implantation failure. FEBS Lett 2006;580:2717-2722.
22. Keane KN, Hinchliffe PM, Namdar N, Conceicao JL, Newsholme P, Yovich JL. Novel dehydroepiandrosterone troche supplementation improves the serum androgen profile of women undergoing in vitro fertilization. Drug Des Devel Ther 2015;9:5569-5578.
23. Selesniemi K, Lee HJ, Muhlhauser A, Tilly JL. Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proc Natl Acad Sci U S A 2011 26;108:12319-12324.
24. Boiso I, Martí M, Santaló J, Ponsá M, Barri PN, Veiga A. A confocal microscopy analysis of the spindle and chromosome configurations of human oocytes cryopreserved at the germinal vesicle and metaphase II stage. Hum Reprod 2002; 17:1885-1891.
25. Choi WJ, Banerjee J, Falcone T, Bena J, Agarwal A, Sharma RK. Oxidative stress and tumor necrosis factor-alpha-induced alterations in metaphase II mouse oocyte  spindle structure. Fertil Steril 2007;88:1220-1231.
26. Mamas L, Mamas E. Premature ovarian failure and dehydroepiandrosterone. Fertil Steril 2009;91:644-646.
27. Hyman JH, Margalioth EJ, Rabinowitz R, Tsafrir A, Gal M, Alerhand S, et al. DHEA supplementation may improve IVF outcome in poor responders: a proposed mechanism. Eur J Obstet Gynecol Reprod Biol 2013;168:49-53.
28. Arlt W. Dehydroepiandrosterone and ageing. Best Pract Res Clin Endocrinol Metab 2004 ;18:363-380.
29. Gleicher N, Barad DH, Kushnir VA, Sen A, Weghofer A. Poor responders and androgen adjuvant treatment: “Still haven’t found what I’m looking for …”. Reprod Biomed Online. 2014;29:650-652.
30. Chimote NM, Nath NM, Chimote NN, Chimote BN. Follicular fluid dehydroepiandrosterone sulfate is a credible marker of oocyte maturity and pregnancy outcome in conventional in vitro fertilization cycles. J Hum Reprod Sci. 2015;8 :209-213.
31. Dorrington JH, Moon YS, Armstrong DT. Estradiol-17beta biosynthesis in cultured granulosa cells from hypophysectomized immature rats; stimulation by follicle-stimulating hormone. Endocrinology 1975;97: 1328-1331.
32. 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;70:107-110.
33. Goodarzi MO, Carmina E, Azziz R. DHEA, DHEAS and PCOS. J Steroid Biochem Mol Biol 2015;145:213-225.
34. Cinar N, Harmanci A, Aksoy DY, Aydin K, Yildiz BO. Adrenocortical steroid response to ACTH in different phenotypes of non-obese polycystic ovary syndrome.  J Ovarian Res 2012;5:42-49.
35. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril 2004;82:421-429.
36. Barad DH, Gleicher N. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril 2005;84:756-758.
37. Prough RA, Clark BJ, Klinge CM. Novel mechanisms for DHEA action. J Mol Endocrinol. 2016;56:R139-R155.
38. Harper AJ, Buster JE, Casson PR. Changes in adrenocortical function with aging and therapeutic implications. Semin Reprod Endocrinol 1999;17: 327-338.
39. Arlt W, Justl HG, Callies F, Reincke M, Hübler D, Oettel M, et al. Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression. J Clin Endocrinol Metab 1998; 83:1928-1934.
40. Huang Y, Yu Y, Gao J, Li R, Zhang C, Zhao H, et  al. Impaired oocyte quality induced by dehydroepiandrosterone is partially rescued by metformin treatment. PLoS One. 2015;10:e0122370.
41. Tamura AN, Huang TT, Marikawa Y. Impact of vitrification on the meiotic spindle and components of the microtubule-organizing center in mouse mature oocytes. Biol Reprod 2013;89:112-121.
42. Jacob MH, da R Janner D, Jahn MP, Kucharski LC, Belló-Klein A, Ribeiro MF. Age-related effects of DHEA on peripheral markers of oxidative stress. Cell Biochem Funct 2010;28:52-57.
43. Kikuchi K, Naito K, Noguchi J, Shimada A, Kaneko H, Yamashita M, et al. Maturation/M-phase promoting factor: a regulator of aging in porcine oocytes. Biol Reprod 2000;63:715-722.
44.  Xu Z, Abbott A, Kopf GS, Schultz RM, Ducibella T. Spontaneous activation of ovulated mouse eggs: time-dependent effects on M-phase exit, cortical granule exocytosis, maternal messenger ribonucleic acid recruitment, and inositol 1,4,5-trisphosphate sensitivity. Biol Reprod 1997; 57:743-750.
45. Valeri C, Pappalardo S, De Felici M, Manna C. Correlation of oocyte morphometry parameters with woman’s age. J Assist Reprod Genet 2011; 28:545-552.
46. Montag M, Schimming T, Köster M, Zhou C, Dorn C, Rösing B, et al. Oocyte zona birefringence intensity is associated with embryonic implantation potential in ICSI cycles. Reprod Biomed Online 2008;16:239-244.
47. Miao YL, Kikuchi K, Sun QY, Schatten H. Oocyte aging: cellular and molecular changes, developmental potential and reversal possibility. Hum Reprod Update 2009;15:573-585.
48. Bauer J, Biolo G, Cederholm T, Cesari M, Cruz-Jentoft AJ, Morley JE, et al. Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE Study Group. J Am Med Dir Assoc 2013;14:542-559.
49. Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Schölmerich J, et al. Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and  immunosenescence. J Clin Endocrinol Metab 1998;83:2012-2017.