Skip to main content
SpringerLink
Log in

Developmental Programming: Postnatal Estradiol Amplifies Ovarian Follicular Defects Induced by Fetal Exposure to Excess Testosterone and Dihydrotestosterone in Sheep

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Excess of prenatal testosterone (T) induces reproductive defects including follicular persistence. Comparative studies with T and dihydrotestosterone (DHT) have suggested that follicular persistence is programmed via estrogenic actions of T. This study addresses the androgenic and estrogenic contributions in programming follicular persistence. Because humans are exposed to estrogenic environmental steroids from various sources throughout their life span and postnatal insults may also induce organizational and/or activational changes, we tested whether continuous postnatal exposure to estradiol (E) will amplify effects of prenatal steroids on ovarian function. Pregnant sheep were treated with T, DHT, E, or ED (E and DHT) from days 30 to 90 of gestation. Postnatally, a subset of the vehicle (C), T, and DHT females received an E implant. Transrectal ultrasonography was performed in the first breeding season during a synchronized cycle to monitor ovarian follicular dynamics. As expected, number of ≥8 mm follicles was higher in the T versus C group. Postnatal E reduced the number of 4 to 8 mm follicles in the DHT group. Percentage of females bearing luteinized follicles and the number of luteinized follicles differed among prenatal groups. Postnatal E increased the incidence of subluteal cycles in the prenatal T-treated females. Findings from this study confirm previous findings of divergences in programming effects of prenatal androgens and estrogens. They also indicate that some aspects of follicular dynamics are subject to postnatal modulation as well as support the existence of an extended organizational period or the need for a second insult to uncover the previously programmed event.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sawyer HR, Smith P, Heath DA, Juengel JL, Wakefield SJ, McNatty KP. Formation of ovarian follicles during fetal development in sheep. Biol Reprod. 2002;66(4):1134–1150.

    Article  CAS  PubMed  Google Scholar 

  2. Kerr JB, Brogan L, Myers M, et al. The primordial follicle reserve is not renewed after chemical or gamma-irradiation mediated depletion. Reproduction. 2012;143(4):469–476.

    Article  CAS  PubMed  Google Scholar 

  3. Rodriguez HA, Santambrosio N, Santamaría CG, Munoz-de-Toro M, Luque EH. Neonatal exposure to bisphenol A reduces the pool of primordial follicles in the rat ovary. Reprod Toxicol. 2010; 30(4):550–557.

    Article  CAS  PubMed  Google Scholar 

  4. Padmanabhan V, Veiga-Lopez A. Developmental origin of reproductive and metabolic dysfunctions: androgenic versus estrogenic reprogramming. Semin Reprod Med. 2011;29(3):173–186.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Smith P, Steckler TL, Veiga-Lopez A, Padmanabhan V. Developmental programming: differential effects of prenatal testosterone and dihydrotestosterone on follicular recruitment, depletion of follicular reserve, and ovarian morphology in sheep. Biol Reprod. 2009;80(4):726–736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Padmanabhan V, Smith P, Veiga-Lopez A. Developmental programming: impact of prenatal testosterone treatment and postnatal obesity on ovarian follicular dynamics. J Dev Health Dis. 2012;3(4):276–286.

    Article  CAS  Google Scholar 

  7. Manikkam M, Steckler TL, Welch KB, Inskeep EK, Padmanabhan V. Fetal programming: prenatal testosterone treatment leads to follicular persistence/luteal defects; partial restoration of ovarian function by cyclic progesterone treatment. Endocrinology. 2006; 147(4): 1997–2007.

    Article  CAS  PubMed  Google Scholar 

  8. West C, Foster DL, Evans NP, Robinson J, Padmanabhan V. Intrafollicular activin availability is altered in prenatally-androgenized lambs. Mol Cell Endocrinol. 2001;185(1–2):51–59.

    Article  CAS  PubMed  Google Scholar 

  9. Steckler T, Manikkam M, Inskeep EK, Padmanabhan V. Developmental programming: follicular persistence in prenatal testosterone-treated sheep is not programmed by androgenic actions of testosterone. Endocrinology. 2007;148(7):3532–3540.

    Article  CAS  PubMed  Google Scholar 

  10. Dickerson SM, Gore AC. Estrogenic environmental endocrine-disrupting chemical effects on reproductive neuroendocrine function and dysfunction across the life cycle. Rev Endocr Metab Disord. 2007;8(2):143–159.

    Article  CAS  PubMed  Google Scholar 

  11. Latini G, Knipp G, Mantovani A, Loredana M, Chiarelli F, Söder O. Endocrine disruptors and human health. Mini Rev Med Chem. 2010;10(9):846–855.

    Article  CAS  PubMed  Google Scholar 

  12. Bayer TA, Falkai P, Maier W. Genetic and non-genetic vulnerability factors in schizophrenia: the basis of the “two hit hypothesis”. J Psychiatr Res. 1999;33(6):543–548.

    Article  CAS  PubMed  Google Scholar 

  13. Steckler TL, Herkimer C, Dumesic DA, Padmanabhan V. Developmental programming: excess weight gain amplifies the effects of prenatal testosterone excess on reproductive cyclicity—implication for polycystic ovary syndrome. Endocrinology. 2009; 150(3):1456–1465.

    Article  PubMed  CAS  Google Scholar 

  14. Veiga-Lopez A, Ye W, Phillips DJ, Herkimer C, Knight PG, Padmanabhan V. Developmental programming: deficits in reproductive hormone dynamics and ovulatory outcomes in prenatal, testosterone-treated sheep. Biol Reprod. 2008;78(4):636–647.

    Article  CAS  PubMed  Google Scholar 

  15. Adams NR. Detection of the effects of phytoestrogens on sheep and cattle. J Anim Sci. 1995;73(5):1509–1515.

    Article  CAS  PubMed  Google Scholar 

  16. Manikkam M, Crespi EJ, Doop DD, et al. Fetal programming: prenatal testosterone excess leads to fetal growth retardation and postnatal catch-up growth in sheep. Endocrinology. 2004;145(2): 790–798.

    Article  CAS  PubMed  Google Scholar 

  17. Masek KS, Wood RI, Foster DL. Prenatal dihydrotestosterone differentially masculinizes tonic and surge modes of luteinizing hormone secretion in sheep. Endocrinology. 1999;140(8):3459–3466.

    Article  CAS  PubMed  Google Scholar 

  18. Foster DL. Preovulatory gonadotropin surge system of prepubertal female sheep is exquisitely sensitive to the stimulatory feedback action of estradiol. Endocrinology. 1984;115(3): 1186–1189.

    Article  CAS  PubMed  Google Scholar 

  19. Goodman RL, Legan SJ, Ryan KD, Foster DL, Karsch FJ. Two effects of estradiol that normally contribute to the control of tonic LH secretion in the ewe. Biol Reprod. 1980;23(2):415–422.

    Article  CAS  PubMed  Google Scholar 

  20. Padmanabhan V, Evans NP, Dahl GE, McFadden KL, Mauger DT, Karsch FJ. Evidence for short or ultrashort loop negative feedback of gonadotropin-releasing hormone secretion. Neuroendocrinology. 1995;62(3):248–258.

    Article  CAS  PubMed  Google Scholar 

  21. Campbell BK, Scaramuzzi RJ, Webb R. Control of antral follicle development and selection in sheep and cattle. J Reprod Fert Supplement. 1995;49:335–350.

    CAS  Google Scholar 

  22. Driancourt MA. Regulation of ovarian follicular dynamics in farm animals. Implications for manipulation of reproduction. Theriogenology. 2001;55(6):1211–1239.

    Article  CAS  PubMed  Google Scholar 

  23. Hunter MG, Robinson RS, Mann GE, Webb R. Endocrine and paracrine control of follicular development and ovulation rate in farm species. Anim Reprod Sci. 2004;82–83:461–477.

    Article  PubMed  CAS  Google Scholar 

  24. Flynn JD, Duffy P, Boland MP, Evans AC. Progestagen synchronisation in the absence of a corpus luteum results in the ovulation of a persistent follicle in cyclic ewe lambs. Anim Reprod Sci. 2000;62(4):285–296.

    Article  CAS  PubMed  Google Scholar 

  25. Ginther OJ, Kot K, Wiltbank MC. Associations between emergence of follicular waves and fluctuations in FSH concentrations during the estrous cycle in ewes. Theriogenology. 1995;43(3): 689–703.

    Article  CAS  PubMed  Google Scholar 

  26. Wright C, Evans AC, Evans NP, et al. Effect of maternal exposure to the environmental estrogen, octylphenol, during fetal and/or postnatal life on onset of puberty, endocrine status, and ovarian follicular dynamics in ewe lambs. Biol Reprod. 2002;67(6):1734–1740.

    Article  CAS  PubMed  Google Scholar 

  27. Killick S, Elstein M. Pharmacologic production of luteinized unruptured follicles by prostaglandin synthetase inhibitors. Fertil Steril. 1987;47(5):773–777.

    Article  CAS  PubMed  Google Scholar 

  28. Coetsier T, Dhont M. Complete and partial luteinized unruptured follicle syndrome after ovarian stimulation with clomiphene citrate/human menopausal gonadotrophin/human chorionic gonadotrophin. Hum Reprod. 1996;11(3):583–587.

    Article  CAS  PubMed  Google Scholar 

  29. D’Hooghe TM, Bambra CS, Raeymaekers BM, Koninckx PR. Increased incidence and recurrence of recent corpus luteum without ovulation stigma (luteinized unruptured follicle syndrome?) in baboons with endometriosis. J Soc Gynecol Investig. 1996;3(3): 140–144.

    Article  PubMed  Google Scholar 

  30. Cuervo-Arango J, Newcombe JR. Ultrasound characteristics of experimentally induced luteinized unruptured follicles (LUF) and naturally occurring hemorrhagic anovulatory follicles (HAF) in the mare. Theriogenology. 2012;77(3):514–524.

    Article  CAS  PubMed  Google Scholar 

  31. Murdoch WJ, Dunn TG. Luteal function after ovulation blockade by intrafollicular injection of indomethacin in the ewe. J Reprod Fertil. 1983;69(2):671–675.

    Article  CAS  PubMed  Google Scholar 

  32. Ginther OJ, Gastal MO, Gastal EL, Jacob JC, Beg MA. Induction of haemorrhagic anovulatory follicles in mares. Reprod Fertil Dev. 2008;20(8):947–954.

    Article  CAS  PubMed  Google Scholar 

  33. Cuervo-Arango J, Newcombe JR. The effect of hormone treatments (hCG and cloprostenol) and season on the incidence of hemorrhagic anovulatory follicles in the mare: a field study. Theriogenology. 2009;72(9):1262–1267.

    Article  CAS  PubMed  Google Scholar 

  34. Sirois J, Dore M. The late induction of prostaglandin G/H synthase-2 in equine preovulatory follicles supports its role as a determinant of the ovulatory process. Endocrinology. 1997; 138(10):4427–4434.

    Article  CAS  PubMed  Google Scholar 

  35. Sarma HN, Manikkam M, Herkimer C, et al. Fetal programming: excess prenatal testosterone reduces postnatal luteinizing hormone, but not follicle-stimulating hormone responsiveness, to estradiol negative feedback in the female. Endocrinology. 2005; 146(10):4281–4291.

    Article  CAS  PubMed  Google Scholar 

  36. Manikkam M, Thompson RC, Herkimer C, et al. Developmental programming: impact of prenatal testosterone excess on pre- and postnatal gonadotropin regulation in sheep. Biol Reprod. 2008; 78(4):648–660.

    Article  CAS  PubMed  Google Scholar 

  37. Ortega HH, Salvetti NR, Padmanabhan V. Developmental programming: prenatal androgen excess disrupts ovarian steroid receptor balance. Reproduction. 2009;137(5):865–877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ortega HH, Rey F, Velazquez MM, Padmanabhan V. Developmental programming: effect of prenatal steroid excess on intraovarian components of insulin signaling pathway and related proteins in sheep. Biol Reprod. 2010;82(6):1065–1075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Salvetti NR, Ortega HH, Veiga-Lopez A, Padmanabhan V. Developmental programming: impact of prenatal testosterone excess on ovarian cell proliferation and apoptotic factors in sheep. Biol Reprod. 2012;87(1):22, 21–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Pangas SA, Li X, Robertson EJ, Matzuk MM. Premature luteinization and cumulus cell defects in ovarian-specific Smad4 knockout mice. Mol Endocrinol. 2006;20(6):1406–1422.

    Article  CAS  PubMed  Google Scholar 

  41. Luense LJ, Veiga-Lopez A, Padmanabhan V, Christenson LK. Developmental programming: gestational testosterone treatment alters fetal ovarian gene expression. Endocrinology. 2011;152(12):4974–4983.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. van den Hurk R, Zhao J. Formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles. Theriogenology. 2005;63(6):1717–1751.

    Article  PubMed  CAS  Google Scholar 

  43. George FW, Wilson JD. Sex determination and differentiation. In: Knobil E, Neill JD, eds. The Physiology of Reproduction. New York, NY: Raven Press; 1994:3–28.

    Google Scholar 

  44. Veiga-Lopez A, Astapova OI, Aizenberg EF, Lee JS, Padmanabhan V. Developmental programming: contribution of prenatal androgen and estrogen to estradiol feedback systems and periovulatory hormonal dynamics in sheep. Biol Reprod. 2009;80(4):718–725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hillier SG, Tetsuka M, Fraser HM. Location and developmental regulation of androgen receptor in primate ovary. Hum Reprod. 1997;12(1):107–111.

    Article  CAS  PubMed  Google Scholar 

  46. Billig H, Furuta I, Hsueh AJ. Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis. Endocrinology. 1993; 133(5):2204–2212.

    Article  CAS  PubMed  Google Scholar 

  47. Hillier SG, Ross GT. Effects of exogenous testosterone on ovarian weight, follicular morphology and intraovarian progesterone concentration in estrogen-primed hypophysectomized immature female rats. Biol Reprod. 1979;20(2):261–268.

    Article  CAS  PubMed  Google Scholar 

  48. Rivera OE, Varayoud J, Rodriguez HA, Munoz-de-Toro M, Luque EH. Neonatal exposure to bisphenol A or diethylstilbestrol alters the ovarian follicular dynamics in the lamb. Reprod Toxicol. 2011;32(3):304–312.

    Article  CAS  PubMed  Google Scholar 

  49. Jackson LM, Timmer KM, Foster DL. Organizational actions of postnatal estradiol in female sheep treated prenatally with testosterone: programming of prepubertal neuroendocrine function and the onset of puberty. Endocrinology. 2009;150(5): 2317–2324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Murphy BD. Models of luteinization. Biol Reprod. 2000;63(1):2–11.

    Article  CAS  PubMed  Google Scholar 

  51. Richards JS, Russell DL, Robker RL, Dajee M, Alliston TN. Molecular mechanisms of ovulation and luteinization. Mol Cell Endocrinol. 1998;145(1–2):47–54.

    Article  CAS  PubMed  Google Scholar 

  52. Sharma TP, Herkimer C, West C, et al. Fetal programming: prenatal androgen disrupts positive feedback actions of estradiol but does not affect timing of puberty in female sheep. Biol Reprod. 2002;66(4):924–933.

    Article  CAS  PubMed  Google Scholar 

  53. Schug TT, Janesick A, Blumberg B, Heindel JJ. Endocrine disrupting chemicals and disease susceptibility. J Steroid Biochem Mol Biol. 2011;127(3–5):204–215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Michigan, 300 N. Ingalls Bldg, Rm 1137, 48109-0404, Ann Arbor, MI, USA

    A. Veiga-Lopez DVM, PhD, T. L. Steckler PhD & V. Padmanabhan MS, PhD

  2. Division of Animal and Veterinary Sciences, West Virginia University, Morgantown, WV, USA

    A. K. Wurst PhD

  3. Department of Life and Physical Sciences, Lincoln University, Jefferson City, MO, USA

    A. K. Wurst PhD

  4. Extension and Outreach, University of Illinois, Urbana-Champaign, IL, USA

    T. L. Steckler PhD

  5. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    W. Ye PhD

  6. Reproductive Sciences Program, University of Michigan, Ann Arbor, MI, USA

    V. Padmanabhan MS, PhD

Authors
  1. A. Veiga-Lopez DVM, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. K. Wurst PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. L. Steckler PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Ye PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V. Padmanabhan MS, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. Padmanabhan MS, PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Veiga-Lopez, A., Wurst, A.K., Steckler, T.L. et al. Developmental Programming: Postnatal Estradiol Amplifies Ovarian Follicular Defects Induced by Fetal Exposure to Excess Testosterone and Dihydrotestosterone in Sheep. Reprod. Sci. 21, 444–455 (2014). https://doi.org/10.1177/1933719113503412

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719113503412

Keywords

Search

Navigation