Journal of Reproduction & Infertility

Journal of Reproduction & Infertility

Ultra-low Doses of Follicle Stimulating Hormone and Progesterone Attenuate the Severity of Polycystic Ovary Syndrome Features in a Hyperandrogenized Mouse Model

Authors
Irene Tessaro 1
Silvia Modina 2
Valentina Lodde 3
Giulia Sivelli 3
Federica Franciosi 3
Laura Terzaghi 3
Patrizia Luchini 4
Cristiano Rumio 5
Alberto Luciano 2
1 Reproductive and Developmental Biology Laboratory, Department of Health, Animal Science and Food Safety, University of Milan, Milan, Italy; Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Ortopedico Galeazzi,
2 Reproductive and Developmental Biology Laboratory, Department of Health, Animal Science and Food Safety, University of Milan, Milan, Italy; Interdepartmental Centre for the Study of Biological Effects of Nano-Concentrations (CREBI
3 Reproductive and Developmental Biology Laboratory, Department of Health, Animal Science and Food Safety, University of Milan, Milan, Italy
4 Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
5 Interdepartmental Centre for the Study of Biological Effects of Nano-Concentrations (CREBION), University of Milan, Milan, Italy; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
Abstract
Background: Polycystic-ovary syndrome (PCOS) is a reproductive illness characterized by hyperandrogenism and anovulation. Using hyperandrogenized mice, it was demonstrated that the oral administration of incremental dose of follicle stimulating hormone (FSH) attenuated some of PCOS characteristics. This work aimed to study the effect of ultra-low doses of combined FSH and progesterone orally administered on PCOS murine model. Moreover, the effect of sequential kinetic activation of administered hormones was tested. Methods: Thirty-two female mice were used as animal model (four groups of eight animals each). Mice were hyperandrogenized by injection of dehyidroepiandro-sterone diluted in sesame oil. Control group received only oil. Simultaneously, each animal daily received per os an activated or a not-activated combination of FSH (0.44 pg) plus progesterone (0.44 pg) or saline solution as control. Serum testosterone, estradiol, progesterone and luteinizing hormone were analyzed as endocrine markers and a morphological study of antral follicle was conducted. Data were analyzed by one-way ANOVA, followed by multiple comparison test. The p<0.05 was considered significant. Results: Dehyidroepiandrosterone treatment increased both estradiol and progesterone serum levels, besides testosterone, while reduced luteinizing hormone (p<0.05); histological examination revealed an increase of cystic follicles (p<0.05). Irrespective of activation, the combined FSH and progesterone treatments restored estradiol level (p>0.05 vs. control group) and reduced cystic signs in the follicles (p<0.05 vs. dehyidroepiandrosterone treatment). Conclusion: This study indicate that ultra-low doses of FSH and progesterone orally administrated can reduce the sternness of PCOS in the mouse model and open a route for the study of innovative approaches for PCOS treatment.
Keywords
Follicle cyst
FSH
Mouse
Polycystic ovary syndrome
Progesterone
Sequential kinetic activation
Ultra
Low Dose
  1. Barthelmess EK, Naz RK. Polycystic ovary syndrome: current status and future perspective. Front Biosci (Elite Ed). 2014;6:104-19.
  2. Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update. 2008;14(4):367-78.
  3. Webber LJ, Stubbs S, Stark J, Trew GH, Margara R, Hardy K, et al. Formation and early development of follicles in the polycystic ovary. Lancet. 2003;362(9389):1017-21.
  4. Burt Solorzano CM, Beller JP, Abshire MY, Collins JS, McCartney CR, Marshall JC. Neuroendocrine dysfunction in polycystic ovary syndrome. Steroids. 2012;77(4):332-7.
  5. Marshall JC, Dalkin AC, Haisenleder DJ, Paul SJ, Ortolano GA, Kelch RP. Gonadotropin-releasing hormone pulses: regulators of gonadotropin synthesis and ovulatory cycles. Recent Prog Horm Res. 1991;47:155-87; discussion 188-9.
  6. Blank SK, McCartney CR, Marshall JC. The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome. Hum Reprod Update. 2006;12(4):351-61.
  7. McCartney CR, Eagleson CA, Marshall JC. Regulation of gonadotropin secretion: implications for polycystic ovary syndrome. Semin Reprod Med. 2002;20(4):317-26.
  8. Franks S, Gilling-Smith C, Watson H, Willis D. Insulin action in the normal and polycystic ovary. Endocrinol Metab Clin North Am. 1999;28(2):361-78.
  9. Qu J, Wang Y, Wu X, Gao L, Hou L, Erkkola R. Insulin resistance directly contributes to androgenic potential within ovarian theca cells. Fertil Steril. 2009;91(5 Suppl):1990-7.
  10. Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013;6:1-13.
  11. Van Der Meer M, Hompes PG, De Boer JA, Schats R, Schoemaker J. Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;83(2):423-6.
  12. Perales-Puchalt A, Legro RS. Ovulation induction in women with polycystic ovary syndrome. Steroids. 2013;78(8):767-72.
  13. Swanton A, Storey L, McVeigh E, Child T. IVF outcome in women with PCOS, PCO and normal ovarian morphology. Eur J Obstet Gynecol Reprod Biol. 2010;149(1):68-71.
  14. Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Hum Reprod Update. 1999;5(5):493-9.
  15. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril. 2008;89(3):505-22.
  16. Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Consensus on women's health aspects of polycystic ovary syndrome (PCOS). Hum Reprod. 2012;27(1):14-24.
  17. Orvieto R, Homburg R. Chronic ultra-low dose follicle-stimulating hormone regimen for patients with polycystic ovary syndrome: one click, one follicle, one pregnancy. Fertil Steril. 2009;91(4 Suppl):1533-5.
  18. Walters KA, Allan CM, Handelsman DJ. Rodent models for human polycystic ovary syndrome. Biol Reprod. 2012;86(5):149, 1-12.
  19. Shi D, Vine DF. Animal models of polycystic ovary syndrome: a focused review of rodent models in relationship to clinical phenotypes and cardiometabolic risk. Fertil Steril. 2012;98(1):185-93.
  20. McNeilly AS, Duncan WC. Rodent models of polycystic ovary syndrome. Mol Cell Endocrinol. 2013;373(1-2):2-7.
  21. Tessaro I, Modina SC, Franciosi F, Sivelli G, Terzaghi L, Lodde V, et al. Effect of oral administration of low-dose follicle stimulating hormone on hyperandrogenized mice as a model of polycystic ovary syndrome. J Ovarian Res. 2015;8:64.
  22. Avvakumov E, Chizhevskaya S, Stoyanov E, Povetkina M, Chekmarev A, Shafirov V. Influence of the nature of components in mechanically activated mixture of zirconium and silicon oxides on solid-phase synthesis of zircon. Russ J Appl Chem. 1999;72(9):1498-503.
  23. Zec S, Boskovic S. Cerium silicates formation from mechanically activated oxide mixtures. J Mater Sci. 2004;39(16):5283-6.
  24. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8(6):e1000412.
  25. Lai H, Jia X, Yu Q, Zhang C, Qiao J, Guan Y, et al. High-fat diet induces significant metabolic disorders in a mouse model of polycystic ovary syndrome. Biol Reprod. 2014;91(5):127.
  26. Gariboldi S, Palazzo M, Zanobbio L, Dusio GF, Mauro V, Solimene U, et al. Low dose oral administration of cytokines for treatment of allergic asthma. Pulm Pharmacol Ther. 2009;22(6):497-510.
  27. Barygina V, Becatti M, Lotti T, Moretti S, Taddei N, Fiorillo C. Treatment with low-dose cytokines reduces oxidative-mediated injury in perilesional keratinocytes from vitiligo skin. J Dermatol Sci. 2015;79(2):163-70.
  28. Modina SC, Tessaro I, Lodde V, Franciosi F, Corbani D, Luciano AM. Reductions in the number of mid-sized antral follicles are associated with markers of premature ovarian senescence in dairy cows. Reprod Fertil Dev. 2014;26(2):235-44.
  29. Griffin J, Emery BR, Huang I, Peterson CM, Carrell DT. Comparative analysis of follicle morphology and oocyte diameter in four mammalian species (mouse, hamster, pig, and human). J Exp Clin Assist Reprod. 2006;3:2.
  30. Pedersen T, Peters H. Proposal for a classification of oocytes and follicles in the mouse ovary. J Reprod Fertil. 1968;17(3):555-7.
  31. Wang XN, Roy SK, Greenwald GS. In vitro DNA synthesis by isolated preantral to preovulatory follicles from the cyclic mouse. Biol Reprod. 1991;44(5):857-63.
  32. Anderson E, Lee MT, Lee GY. Cystogenesis of the ovarian antral follicle of the rat: ultrastructural changes and hormonal profile following the administration of dehydroepiandrosterone. Anat Rec. 1992;234(3):359-82.
  33. Luchetti CG, Solano ME, Sander V, Arcos ML, Gonzalez C, Di Girolamo G, et al. Effects of dehydroepiandrosterone on ovarian cystogenesis and immune function. J Reprod Immunol. 2004;64(1-2):59-74.
  34. Mannerås L, Cajander S, Holmäng A, Seleskovic Z, Lystig T, Lönn M, et al. A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology. 2007;148(8):3781-91.
  35. Peluso JJ, England-Charlesworth C. Formation of ovarian cysts in aged irregularly cycling rats. Biol Reprod. 1981;24(5):1183-90.
  36. Peluso JJ, England-Charlesworth C, Bolender DL, Steger RW. Ultrastructural alterations associated with the initiation of follicular atresia. Cell Tissue Res. 1980;211(1):105-15.
  37. Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565-92.
  38. Conway G, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Franks S, Gambineri A, et al. The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol. 2014;171(4):P1-29.
  39. Azziz R, Marin C, Hoq L, Badamgarav E, Song P. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J Clin Endocrinol Metab. 2005;90(8):4650-8.
  40. Raja-Khan N, Stener-Victorin E, Wu X, Legro RS. The physiological basis of complementary and alternative medicines for polycystic ovary syndrome. Am J Physiol Endocrinol Metab. 2011;301(1):E1-E10.
  41. Passalacqua R, Caminiti C, Buti S, Porta C, Camisa R, Braglia L, et al. Adjuvant low-dose interleukin-2 (IL-2) plus interferon-α (IFN-α) in operable renal cell carcinoma (RCC): a phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC). J Immunother. 2014;37(9):440-7.
  42. Radice E, Miranda V, Bellone G. Low-doses of sequential-kinetic-activated interferon-γ enhance the ex vivo cytotoxicity of peripheral blood natural killer cells from patients with early-stage colorectal cancer. A preliminary study. Int Immunopharmacol. 2014;19(1):66-73.
  43. Roberti ML, Ricottini L, Capponi A, Sclauzero E, Vicenti P, Fiorentini E, et al. Immunomodulating treatment with low dose interleukin-4, interleukin-10 and interleukin-11 in psoriasis vulgaris. J Biol Regul Homeost Agents. 2014;28(1):133-9.
  44. van Houten EL, Visser JA. Mouse models to study polycystic ovary syndrome: a possible link between metabolism and ovarian function? Reprod Biol. 2014;14(1):32-43.
  45. Loughlin T, Cunningham S, Moore A, Culliton M, Smyth PP, McKenna TJ. Adrenal abnormalities in polycystic ovary syndrome. J Clin Endocrinol Metab. 1986;62(1):142-7.
  46. Elia E, Sander V, Luchetti CG, Solano ME, Di Girolamo G, Gonzalez C, et al. The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice. Mol Hum Reprod. 2006;12(8):475-81.
  47. Sander V, Luchetti CG, Solano ME, Elia E, Di Girolamo G, Gonzalez C, et al. Role of the N, N'-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone. Reproduction. 2006;131(3):591-602.
  48. Solano ME, Sander VA, Ho H, Motta AB, Arck PC. Systemic inflammation, cellular influx and up-regulation of ovarian VCAM-1 expression in a mouse model of polycystic ovary syndrome (PCOS). J Reprod Immunol. 2011;92(1-2):33-44.
  49. Fauser BC, Van Heusden AM. Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr Rev. 1997;18(1):71-106.
  50. Doldi N, Gessi A, Destefani A, Calzi F, Ferrari A. Polycystic ovary syndrome: anomalies in progesterone production. Hum Reprod. 1998;13(2):290-3.
  51. Montville CP, Khabbaz M, Aubuchon M, Williams DB, Thomas MA. Luteal support with intravaginal progesterone increases clinical pregnancy rates in women with polycystic ovary syndrome using letrozole for ovulation induction. Fertil Steril. 2010;94(2):678-83.
  52. Buckler HM, Phillips SE, Cameron IT, Healy DL, Burger HG. Vaginal progesterone administration before ovulation induction with exogenous gonadotropins in polycystic ovarian syndrome. J Clin Endocrinol Metab. 1988;67(2):300-6.
  53. Taylor AE, McCourt B, Martin KA, Anderson EJ, Adams JM, Schoenfeld D, et al. Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1997;82(7):2248-56.
  54. Giudice LC. Endometrium in PCOS: Implantation and predisposition to endocrine CA. Best Pract Res Clin Endocrinol Metab. 2006;20(2):235-44.
  55. Palomba S, Santagni S, La Sala GB. Progesterone administration for luteal phase deficiency in human reproduction: an old or new issue? J Ovarian Res. 2015;8:77.
  56. Apparao KB, Lovely LP, Gui Y, Lininger RA, Lessey BA. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome. Biol Reprod. 2002;66(2):297-304.
  57. Franks S, Mason H, Willis D. Follicular dynamics in the polycystic ovary syndrome. Mol Cell Endocrinol. 2000;163(1-2):49-52.
  58. Roy SK, Greenwald GS. In vitro steroidogenesis by primary to antral follicles in the hamster during the periovulatory period: effects of follicle-stimulating hormone, luteinizing hormone, and prolactin. Biol Reprod. 1987;37(1):39-46.
  59. Roy SK, Greenwald GS. In vitro effects of epidermal growth factor, insulin-like growth factor-I, fibroblast growth factor, and follicle-stimulating hormone on hamster follicular deoxyribonucleic acid synthesis and steroidogenesis. Biol Reprod. 1991;44(5):889-96.
  60. Campion CE, Trewin AL, Hutz RJ. Effects of follicle-stimulating hormone administration on oestradiol-induced cystic ovaries in guinea pigs. Zoolog Sci. 1996;13(1):137-42.
  61. Greenwald GS, Roy SK. Follicular development and its control. In: Knobil E, Neill JD, editors. Physiology of Reproduction. New York: Raven Press; 1994. p. 629-724.
  62. Lederer KJ, Luciano AM, Pappalardo A, Peluso JJ. Proliferative and steroidogenic capabilities of rat granulosa cells of different sizes. J Reprod Fertil. 1995;103(1):47-54.
  63. Mahato RI, Narang AS, Thoma L, Miller DD. Emerging trends in oral delivery of peptide and protein drugs. Crit Rev Ther Drug Carrier Syst. 2003;20(2-3):153-214.
  64. Sun L. Peptide-Based Drug Development. Mod Chem Appl. 2013;1(1):1-2.
Journal of Reproduction & Infertility
Volume 18, Issue 3
Summer 2017
Pages 288-297