Journal of Molecular Histology

, Volume 49, Issue 6, pp 631–637 | Cite as

First ovarian response to gonadotrophin stimulation in rats exposed to neonatal androgen excess

  • Rebeca Chávez-GenaroEmail author
  • Gabriel Anesetti
Original Paper


This study analyzes the effects of neonatal androgenization on follicular growth and first ovulation in response to gonadotrophins, using a model of exogenous stimulation or the use of subcutaneous ovary grafts in castrated animals to replace the hypothalamus–pituitary signal. Neonatal rats (days 1–5) were treated with testosterone, dihydrotestosterone or vehicle. At juvenile period, rats were stimulated with PMSG, hCG (alone or combined) or used as ovarian donors to be grafted on castrated adult female rats. Ovulation and ovarian histology were analyzed in both groups. Animals treated with vehicle or dihydrotestosterone stimulated with gonadotrophins (pharmacological or by using an ovary graft) ovulated, showing a normal histological morphology whereas rats exposed to testosterone and injected with the same doses of gonadotrophins did not it. In this group, ovulation was reached using a higher dose of hCG. Ovaries in the testosterone group were characterized by the presence of follicles with atretic appearance and a larger size than those observed in control or dihydrotestosterone groups. A similar appearance was observed in testosterone ovary grafts although luteinization and some corpora lutea were also identified. Our findings suggest that neonatal exposure to aromatizable androgens induces a more drastic signalling on the ovarian tissue that those driven by non-aromatizable androgens in response to gonadotrophins.


Testosterone Dihydrotestosterone Follicle Ovulation Graft hCG 



We gratefully acknowledge to Karina Hernandez for histotechnical assistance and Mariela Santos for animal care support.


This work was partially supported by the PEDECIBA, Universidad de la República, Montevideo, Uruguay.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Abbott DH, Dumesic DA, Eisner JR et al (1998) Insights into the development of polycystic ovary syndrome (PCOS) from studies of prenatally androgenized female rhesus monkeys. Trends Endocrinol Metab 9:62–67CrossRefGoogle Scholar
  2. Abbott DH, Dumesic DA, Franks S (2002) Developmental origin of polycystic ovary syndrome—a hypothesis. J Endocrinol 174:1–5CrossRefGoogle Scholar
  3. Abbott DH, Dumesic DA, Levine JE et al (2006) Animal models and fetal programming of the polycystic ovary syndrome. In: Azziz R, Nestler JE, Dewailly D (eds) Androgen excess disorders in women. Humana Press, Totowa, pp 259–272Google Scholar
  4. Anesetti G, Chávez-Genaro R (2015) Neonatal testosterone exposure induces early development of follicular cysts followed by sympathetic ovarian hyperinnervation. Reprod Fertil Dev 28:1753–1761CrossRefGoogle Scholar
  5. Anesetti G, Chávez-Genaro R (2016) Ovarian follicular dynamics after aromatizable or non aromatizable neonatal androgenization. J Mol Histol 47:491–501CrossRefGoogle Scholar
  6. Arai Y, Yamanouchi K, Mizukami S et al (1981) Induction of anovulatory sterility by neonatal treatment with 5 beta-dihydrotestosterone in female rats. Acta Endocrinol 96:439–443CrossRefGoogle Scholar
  7. Bellver J, Rodríguez-Tabernero L, Robles A et al (2018) Polycystic ovary syndrome throughout a woman’s life. J Assist Reprod Genet 35:25–39CrossRefGoogle Scholar
  8. Chakraborty P, Roy SK (2017) Stimulation of primordial follicle assembly by estradiol-17β requires the action of bone morphogenetic protein-2 (BMP2). Sci Rep 7:15581CrossRefGoogle Scholar
  9. Cohen DP, Stein EM, Li Z et al (1999) Molecular analysis of the gonadotrophin-releasing hormone receptor in patients with polycystic ovary syndrome. Fertil Steril 72:360–363CrossRefGoogle Scholar
  10. Comim FV, Teerds K, Hardy K, Franks S (2013) Increased protein expression of LHCG receptor and 17α-hydroxylase/17-20-lyase in human polycystic ovaries. Hum Reprod 28:3086–3092CrossRefGoogle Scholar
  11. Dumesic DA, Abbott DH, Eisner JR, Goy RW (1997) Prenatal exposure of female rhesus monkeys to testosterone propionate increases serum luteinizing hormone levels in adulthood. Fertil Steril 67:155–163CrossRefGoogle Scholar
  12. Dutta S, Mark-Kappeler CJ, Hoyer PB, Pepling ME (2014) The steroid hormone environment during primordial follicle formation in perinatal mouse ovaries. Biol Reprod 91(68):1–12Google Scholar
  13. Filippou P, Homburg R (2017) Is foetal hyperexposure to androgens a cause of PCOS? Hum Reprod Update 23:421–432CrossRefGoogle Scholar
  14. Forsdike RA, Hardy K, Bull L et al (2007) Disordered follicle development in ovaries of prenatally androgenized ewes. J Endocrinol 192:421–428CrossRefGoogle Scholar
  15. Franks S, Hardy K (2018) Androgen Action in the Ovary. Front Endocrinol 9:452. CrossRefGoogle Scholar
  16. Gavish Z, Peer G, Roness H et al (2014) Follicle activation and “burn-out” contribute to post-transplantation follicle loss in ovarian tissue grafts: the effect of graft thickness. Hum Reprod 29:989–996CrossRefGoogle Scholar
  17. Gavish Z, Spector I, Peer G et al (2018) Follicle activation is a significant and immediate cause of follicle loss after ovarian tissue transplantation. J Assist Reprod Genet 35:61–69CrossRefGoogle Scholar
  18. Hillier SG, Tetsuka M, Fraser HM (1997) Location and developmental regulation of androgen receptor in primate ovary. Hum Reprod 12:107–111CrossRefGoogle Scholar
  19. Hogg K, McNeilly AS, Duncan WC (2011) Prenatal androgen exposure leads to alterations in gene and protein expression in the ovine fetal ovary. Endocrinology 152:2048–2059CrossRefGoogle Scholar
  20. Idris AI (2012) Ovariectomy/orchidectomy in rodents. Methods Mol Biol 816:545–551CrossRefGoogle Scholar
  21. Israely T, Dafni H, Granot D et al (2003) Vascular remodeling and angiogenesis in ectopic ovarian transplants: a crucial role of pericytes and vascular smooth muscle cells in maintenance of ovarian grafts. Biol Reprod 68:2055–2064CrossRefGoogle Scholar
  22. James KC, Nicholls PJ, Roberts M (1969) Biological half-lives of [4-14C]testosterone and some of its esters after injection into the rat. J Pharm Pharmacol 21:24–27CrossRefGoogle Scholar
  23. Jones MR, Brower MA, Xu N et al (2015) Systems genetics reveals the functional context of PCOS loci and identifies genetic and molecular mechanisms of disease heterogeneity. PLoS Genet 11:e1005455CrossRefGoogle Scholar
  24. Juengel JL, Heath DA, Quirke LD, McNatty KP (2006) Oestrogen receptor alpha and beta, androgen receptor and progesterone receptor mRNA and protein localisation within the developing ovary and in small growing follicles of sheep. Reproduction 131:81–92CrossRefGoogle Scholar
  25. Karavan JR, Pepling ME (2012) Effects of estrogenic compounds on neonatal oocyte development. Reprod Toxicol 34:51–56CrossRefGoogle Scholar
  26. Lebbe M, Woodruff TK (2013) Involvement of androgens in ovarian health and disease. Mol Hum Reprod 19:828–837CrossRefGoogle Scholar
  27. McCartney CR, Eagleson CA, Marshall JC (2002) Regulation of gonadotrophin secretion: implications for polycystic ovary syndrome. Semin Reprod Med 20:317–326CrossRefGoogle Scholar
  28. Moore AM, Campbell RE (2017) Polycystic ovary syndrome: understanding the role of the brain. Front Neuroendocrinol 46:1–14CrossRefGoogle Scholar
  29. Prizant H, Gleicher N, Sen A (2014) Androgen actions in the ovary: balance is key. J Endocrinol 222:R141–R151CrossRefGoogle Scholar
  30. Richards JS, Ren YA, Candelaria N et al (2018) Ovarian follicular theca cell recruitment, differentiation, and impact on fertility: 2017 update. Endocr Rev 39:1–20CrossRefGoogle Scholar
  31. Silva MSB, Prescott M, Campbell RE (2018) Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS. JCI Insight. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Siristatidis CS, Maheshwari A, Bhattacharya S (2009) In vitro maturation in sub fertile women with polycystic ovarian syndrome undergoing assisted reproduction. Cochrane Database Syst Rev. CrossRefPubMedGoogle Scholar
  33. Sir-Petermann T, Maliqueo M, Angel B et al (2002) Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod 17:2573–2579CrossRefGoogle Scholar
  34. Sotomayor-Zárate R, Tiszavari M, Cruz G, Lara HE (2011) Neonatal exposure to single doses of estradiol or testosterone programs ovarian follicular development-modified hypothalamic neurotransmitters and causes polycystic ovary during adulthood in the rat. Fertil Steril 96:1490–1496CrossRefGoogle Scholar
  35. Steckler T, Manikkam M, Keith Inskeep E, Padmanabhan V (2007) Developmental programming: follicular persistence in prenatal testosterone-treated sheep is not programmed by androgenic actions of testosterone. Endocrinology 148:3532–3540CrossRefGoogle Scholar
  36. Steckler TL, Herkimer C, Dumesic DA, Padmanabhan V (2009) Developmental programming: excess weight gain amplifies the effects of prenatal testosterone excess on reproductive cyclicity–implication for polycystic ovary syndrome. Endocrinology 150:1456–1465CrossRefGoogle Scholar
  37. Sullivan SD, Moenter SM (2004) Prenatal androgens alter GABAergic drive to gonadotrophin-releasing hormone neurons: implications for a common fertility disorder. Proc Natl Acad Sci U S A 101:7129–7134CrossRefGoogle Scholar
  38. Tyndall V, Broyde M, Sharpe R et al (2012) Effect of androgen treatment during foetal and/or neonatal life on ovarian function in prepubertal and adult rats. Reproduction 143:21–33CrossRefGoogle Scholar
  39. Vendola KA, Zhou J, Adesanya OO et al (1998) Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest 101:2622–2629CrossRefGoogle Scholar
  40. Xita N, Tsatsoulis A (2006) Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies. J Clin Endocrinol Metab 91:1660–1666CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Histology and Embryology Department, School of MedicineUdelaRMontevideoUruguay

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