Evaluation of the interaction effect of low-dose estrogen on morphine-induced ovarian polycystic in rats

Document Type : Research Paper


Department of Biology, Faculty of Basic Sciences, Shahed University, Tehran, Iran


Background and Objective: Polycystic ovary syndrome (PCOS) is a relatively common problem among women of reproductive age. Morphine can disrupt the reproductive axis and cause ovarian cysts. Estrogen can reduce the incidence of benign cysts and ovarian cancer. We investigated the interfering effect of low-dose estrogen on morphine-induced PCOS in rats.
Materials and Methods: Female Wistar rats (weighing 200 to 250 g) were purchased from Pasteur Institute of Iran and adapted to standard conditions in an animal care center. In the diestrous phase, they were randomly divided into four groups: single morphine (5 mg/kg), alone estrogen (0.03, 0. 06 and 0.09 mg/kg), estrogen + morphine, and control (saline, 1 mL/kg). Seventy-two h after injection (i.p.), blood samples were taken from animals under anesthesia to analyze serum factors. After surgery, the uteri and ovaries were examined biometrically, then collected in formalin and examined. Statistical analysis was performed by analysis of variance (ANOVA).
Results: The ovaries of morphine-treated rats showed polycystic feature, however, the number of cysts was significantly reduced in the presence of estrogen (especially at a very low dose of 0.03 mg/kg). Morphine also reduced LH level, which was improved by co-injection of low-dose estrogen (0.03 mg/kg).
Conclusion: Administration of estrogen in low doses may have a protective effect on morphine-induced PCOS in rat.


  1. Direkvand-Moghadam A, Sayehmiri K, Delpisheh A, Direkvand-Moghadam A. The global trend of infertility: an original review and meta-analysis. International Journal of Epidemiologic Research 2014; 1(1): 35-43.
  2. Singh, Krishna B. Rat models of polycystic ovary syndrome. Sourcebook of models for biomedical research. Humana Press Inc., Totowa, NJ 2008: 405-410.
  3. Sharifi N, Fath Nejad Kazemi A, Ghafari-Novin M. Infertility, Ovulation induction, and cancers risk in women: Review Article. Journal of Fasa University of Medical Sciences 2016; 6 (3): 283-295.
  4. Piroozpanah S, Taliban FA, Atri M, Abadi A, Mehdipour P. Relationship between plasma folate, cobalamin and total plasma homocysteine levels with estrogen receptor-alpha gene hypermethylation in breast cancer patients. Iranian Journal of Nutrition Sciences and Food Technology 2009; 3(4): 39-48.
  5. Clarke BL, Khosla S. Female reproductive system and bone. Archives of Biochemistry and Biophysics 2010; 503(1): 118-128.
  6. Vause TDR, Cheung AP, Sierra S, Claman P, Graham Jo-A. Ovulation induction in polycystic ovary syndrome. International Journal of Gynecology and Obstetrics 2010; 111(242): 95-100.
  7. Tannys DRV, Cheung AP, Sierra S, Claman P, Graham J,  Guillemin JA, et al. Ovulation induction in polycystic ovary syndrome. International Journal of Gynecology and Obstetrics 2010: 111(1); 95-100.
  8. Kantivan GP, Khale A, Ogale S. Natural remedies for polycystic ovarian syndrome (PCOS): a review. International Journal of Pharmaceutical and Phytopharmacological Research 2017; 1(6): 396-402.
  9. Ratka A, Simpkins JW. Effects of estradiol and progesterone on the sensitivity to pain and on morphine-induced antinociception in female rats. Hormones and Behavior 1991; 25(2): 217-228.
  10. Dehghan M, Jafarpour M, Mahmoudian A. The effect of morphine administration on structure and ultrastructure of uterus in pregnant mice. International Journal of Reproductive BioMedicine 2010; 8(3): 111-118.
  11. Vuong CVU, O'Dell SHM, Lutfy LE. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocrine Reviews 2010; 31(1): 98-132.
  12. Mohammadi M, Karami M, Afraz S. Survey on the interaction effect of dopamine D2 receptor antagonist on morphine-induced polycystic ovary syndrome in rat. Daneshvar Medicine 2020; 28(3): 16-27.
  13. Russell WF. The female rat reproductive cycle: a practical histological guide to staging. Toxicologic Pathology 2008; 36 (3): 375-384.
  14. Treinen KA, Rehm S,  Wier PJ. An evaluation of the novel selective estrogen receptor modulator, idoxifene, for effects on reproduction in rats and rabbits. Toxicological Sciences 1998; 41(2): 199-207. doi: 10.1006/toxs.1997.2404.
  15. Hilbish KG,  Breslin WJ,  Johnson JT,  Sloter ED. Fertility and developmental toxicity assessment in rats and rabbits with LY500307, a selective estrogen receptor beta (ERβ) agonist. Birth Defects Research Part B: Developmental and Reproductive Toxicology 2013; 98(5): 400-15. doi: 10.1002/bdrb.21083.
  16. Karami M, Darban Fooladi M, Jalali Nadoushan MR, Lakzaei F. Ovarian polycystic induction with morphine in Wistar rat. Journal of Basic and Clinical Pathophysiology 2015; 3(1): 1-6.
  17. Manocha A, Kankra M, Singla P, Sharma A, Ahirwar AK, Bhargava S. Clinical significance of reproductive hormones. Current Medicine Research and Practice 2018; 8(3): 100-108.
  18. Salehpour S, Tamimi M. Polycyctic ovary. The Iranian Journal of Obstetrics, Gynecology and Infertility 2011; 4(Issue 6): 42-46.
  19. Ben-Jonathan N, Hnasko R. Dopamine as a Prolactin (PRL) Inhibitor. Endocrine Reviews 2001; 22(Issue 6): 724-763.