Reproductive Sciences

, Volume 19, Issue 4, pp 400–406 | Cite as

Effects of Etonogestrel Treatment in the Reproductive Organs and Uterine Arteries of Nonoophorectomized Guinea Pigs

  • Graciela KrikunEmail author
  • C. J. Booth
  • L. Buchwalder
  • F. Schatz
  • G. Osol
  • Maurizio Mandala
  • C. J. Lockwood


The endometria of women treated with long-term progestin-only contraceptives (LTPOCs) display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow, oxidative stress, and unpredictable focal abnormal endometrial bleeding. Because human studies on the effects of LTPOC treatment are constrained for ethical and practical reasons, we assessed the suitability of nonoophorectomized guinea pigs (GPs) to best mimic the hormonal milieu of women. The present study demonstrates that treatment of GPs parallels the morphological changes following LTPOC treatment of the human endometrium and ovaries. Specifically, treatment resulted in larger hyperemic, uteri compared with controls. Histopathologic and immunohisto-chemical analysis demonstrated fewer endometrial glands, decreased luminal mucus, increased numbers of blood vessels, and focal hemorrhage. While increased staining for the cell mitosis marker, Ki67, was present in the zona functionalis, no such increase occurred in the basalis. Lastly, effects on vasomotor features of uterine arteries suggest changes that favor increased resistance and reduced blood flow promoting decreased ability to withstand elevations in transmural pressure.


Long-term progestin-only contraception etonogestrel abnormal uterine bleeding guinea pig 


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  1. 1.
    Hickey M, d’Arcangues C. Mechanisms underlying menstrual bleeding disturbances with progestogens. Ernst Schering Res Found Workshop. 2005;9(52):191–217.CrossRefGoogle Scholar
  2. 2.
    Collins J, Crosignani PG. Hormonal contraception without estrogens. Hum Reprod Update. 2003;9(4):373–386.CrossRefGoogle Scholar
  3. 3.
    Lockwood CJ, Schatz F, Krikun G. Angiogenic factors and the endometrium following long term progestin only contraception. Histol Histopathol. 2004;19(1):167–172.PubMedGoogle Scholar
  4. 4.
    Hague S, MacKenzie IZ, Bicknell R, Rees MC. In-vivo angiogenesis and progestogens. Hum Reprod. 2002;17(3):786–793.CrossRefGoogle Scholar
  5. 5.
    Le J, Tsourounis C. Implanon: a critical review. Ann Pharmacother. 2001;35(3):329–336.CrossRefGoogle Scholar
  6. 6.
    Bennink HJ. The pharmacokinetics and pharmacodynamics of Implanon, a single-rod etonogestrel contraceptive implant. Eur J Contracept Reprod Health Care. 2000;5(suppl 2):12–20.PubMedGoogle Scholar
  7. 7.
    Lockwood CJ, Runic R, Wan L, Krikun G, Demopolous R, Schatz F. The role of tissue factor in regulating endometrial haemostasis: implications for progestin-only contraception. Hum Reprod. 2000;15(suppl 3):144–151.CrossRefGoogle Scholar
  8. 8.
    Hickey M, Fraser IS. The structure of endometrial microvessels. Hum Reprod. 2000;15(suppl 3):57–66.CrossRefGoogle Scholar
  9. 9.
    Hickey M, Krikun G, Kodaman P, Schatz F, Carati C, Lockwood CJ. Long-term progestin-only contraceptives result in reduced endometrial blood flow and oxidative stress. J Clin Endocrinol Metab. 2006;91(9):3633–3638.CrossRefGoogle Scholar
  10. 10.
    Krikun G, Critchley H, Schatz F, et al. Abnormal uterine bleeding during progestin-only contraception may result from free radical-induced alterations in angiopoietin expression. Am J Pathol. 2002;161(3):979–986.CrossRefGoogle Scholar
  11. 11.
    Findlay JK. Future directions for research on endometrial bleeding. Hum Reprod. 1996;11(suppl 2):179–183.CrossRefGoogle Scholar
  12. 12.
    Danzo BJ, Shappell HW, Banerjee A, Hachey DL. Effects of nonylphenol, 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (p, p’-DDE), and pentachlorophenol on the adult female guinea pig reproductive tract. Reprod Toxicol. 2002;16(1):29–43.CrossRefGoogle Scholar
  13. 13.
    Cardenas I, Means RE, Aldo P, et al. Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol. 2010;185(2):1248–1257.CrossRefGoogle Scholar
  14. 14.
    Krikun G, Buhimschi IA, Hickey M, Schatz F, Buchwalder L, Lockwood CJ. Long-term progestin contraceptives (LTPOC) induce aberrant angiogenesis, oxidative stress and apoptosis in the guinea pig uterus: a model for abnormal uterine bleeding in humans. J Angiogenes Res. 2010;2(2):1–8.Google Scholar
  15. 15.
    Tremollieres F. Effect of hormonal contraception on bone mineral density. Gynecol Obstet Fertil. 2005;33(7–8):520–525.CrossRefGoogle Scholar
  16. 16.
    Durand M, del Carmen Cravioto M, Raymond EG, et al. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception. 2001;64(4):227–234.CrossRefGoogle Scholar
  17. 17.
    Affandi B. An integrated analysis of vaginal bleeding patterns in clinical trials of Implanon. Contraception. 1998;58(6 suppl):99S–107S.CrossRefGoogle Scholar
  18. 18.
    Rogers PA. Endometrial vasculature in Norplant users. Hum Reprod. 1996;11(suppl 2):45–50.CrossRefGoogle Scholar
  19. 19.
    Rodriguez-Manzaneque JC, Graubert M, Iruela-Arispe ML. Endothelial cell dysfunction following prolonged activation of progesterone receptor. Hum Reprod. 2000;15(suppl 3):39–47.CrossRefGoogle Scholar

Copyright information

© Society for Reproductive Investigation 2012

Authors and Affiliations

  • Graciela Krikun
    • 1
    Email author
  • C. J. Booth
    • 2
  • L. Buchwalder
    • 1
  • F. Schatz
    • 1
  • G. Osol
    • 3
  • Maurizio Mandala
    • 4
  • C. J. Lockwood
    • 1
  1. 1.Department of Obstetrics, Gynecology and Reproductive SciencesYale University, School of MedicineNew HavenUSA
  2. 2.Department of Comparative MedicineYale University, School of MedicineNew HavenUSA
  3. 3.Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of Vermont, School of MedicineBurlingtonUSA
  4. 4.Department of Cell BiologyUniversity of CalabriaArcavacata di Rende, CSItaly

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