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Open Access 01-12-2019 | Propranolol | Research

In rats with estradiol valerate-induced polycystic ovary syndrome, the acute blockade of ovarian β-adrenoreceptors improve ovulation

Authors: Berenice Venegas, Lizzbeth Yureli De León Gordillo, Gabriela Rosas, Julieta A. Espinoza, Carolina Morán, Roberto Domínguez, Leticia Morales-Ledesma

Published in: Reproductive Biology and Endocrinology | Issue 1/2019

Abstract

Background

Polycystic ovary syndrome is characterized by hyperactivity of the ovarian sympathetic nervous system, increases in the content and release of norepinephrine, as well as decreases in the number of β-adrenoreceptors. In the present study, β-adrenoreceptors in the ovaries of rats with polycystic ovary syndrome were blocked and analyzed the resultant effects on ovulation, hormone secretion and the enzymes responsible for the synthesis of catecholamines.

Methods

At 60 days of age, vehicle or estradiol valerate-treated rats were injected with propranolol [10^− 4 M] into the ovarian bursas on oestrus day. The animals were sacrificed on the next day of oestrus, and the ovulation response, the steroid hormone levels in the serum and the immunoreactivity of tyrosine hydroxylase and dopamine β-hydroxylase in the ovaries were measured.

Results

In animals with the induction of polycystic ovary syndrome and β-adrenoreceptor blocking, ovulation was restored in more than half of the animals and resulted in decreased hyperandrogenism with respect to the levels observed in the estradiol valerate-treated group. Tyrosine hydroxylase and dopamine β-hydroxylase were present in the theca cells of the growing follicles and the interstitial gland. Injection of propranolol restored the tyrosine hydroxylase and ovarian dopamine β-hydroxylase levels in rats with polycystic ovary syndrome induction.

Conclusions

The results suggest that a single injection into the ovarian bursas of propranolol, a nonselective antagonist of β-adrenoreceptor receptors, decreases the serum testosterone concentration and the formation of ovarian cysts, improving the ovulation rate that accompanies lower levels of tyrosine hydroxylase and dopamine β-hydroxylase in the ovary.

Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr Rev. 2015;36(5):487–525. https://doi.org/10.1210/er.2015-1018.CrossRefPubMedPubMedCentral

Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106(1):6–15. https://doi.org/10.1016/j.fertnstert.2016.05.003.CrossRefPubMed

De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G, Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol. 2016;14:38. https://doi.org/10.1186/s12958-016-0173-x.CrossRefPubMedPubMedCentral

Matalliotakis I, Kourtis A, Koukoura O, Panidis D. Polycystic ovary syndrome: etiology and pathogenesis. Arch Gynecol Obstet. 2006;274(4):187–97. https://doi.org/10.1007/s00404-006-0171-x.CrossRefPubMed

Pasquali R, Stener-Victorin E, Yildiz BO, Duleba AJ, Hoeger K, Mason H, et al. PCOS Forum: Research in Polycystic Ovary Syndrome Today and Tomorrow. Clinical endocrinology. 2011;74(4):424–33. https://doi.org/10.1111/j.1365-2265.2010.03956.x.CrossRefPubMedPubMedCentral

Heider U, Pedal I, Spanel-Borowski K. Increase in nerve fibers and loss of mast cells in polycystic and postmenopausal ovaries. Fertil Steril. 2001;75(6):1141–7.CrossRef

Dissen GA, Lara HE, Leyton V, Paredes A, Hill DF, Costa ME, et al. Intraovarian excess of nerve growth factor increases androgen secretion and disrupts estrous cyclicity in the rat. Endocrinology. 2000;141(3):1073–82. https://doi.org/10.1210/endo.141.3.7396.CrossRefPubMed

Lara HE, Ferruz JL, Luza S, Bustamante DA, Borges Y, Ojeda SR. Activation of ovarian sympathetic nerves in polycystic ovary syndrome. Endocrinology. 1993;133(6):2690–5. https://doi.org/10.1210/endo.133.6.7902268.CrossRefPubMed

Aguado LI, Ojeda SR. Prepubertal rat ovary: hormonal modulation of beta-adrenergic receptors and of progesterone response to adrenergic stimulation. Biology of Reproduction. 1986;34(1):45–50. https://doi.org/10.1095/biolreprod34.1.45.CrossRefPubMed

10.

Hernandez ER, Jimenez JL, Payne DW, Adashi EY. Adrenergic regulation of ovarian androgen biosynthesis is mediated via beta 2-adrenergic theca-interstitial cell recognition sites. Endocrinology. 1988;122(4):1592–602. https://doi.org/10.1210/endo-122-4-1592.CrossRefPubMed

11.

Wasilewska-Dziubinska E, Borowiec M, Chmielowska M, Wolinska-Witort E, Baranowska B. Alfa 1 adrenergic potentiation of progesterone accumulation stimulated by vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in cultured rat granulosa cells. Neuro Endocrinol Lett. 2002;23(2):141–8.PubMed

12.

Mayerhofer A, Dissen GA, Costa ME, Ojeda SR. A role for neurotransmitters in early follicular development: induction of functional follicle-stimulating hormone receptors in newly formed follicles of the rat ovary. Endocrinology. 1997;138(8):3320–9. https://doi.org/10.1210/endo.138.8.5335.CrossRefPubMed

13.

Lara HE, McDonald JK, Ahmed CE, Ojeda SR. Guanethidine-mediated destruction of ovarian sympathetic nerves disrupts ovarian development and function in rats. Endocrinology. 1990;127(5):2199–209. https://doi.org/10.1210/endo-127-5-2199.CrossRefPubMed

14.

Burden HW. The adrenergic innervation of mammalian ovaries. In: Ben-Jonathan N, Bahr JM, Weiner RI, editors. Catecholamines as hormone regulators. New York: Raven Press; 1985;261–278.

15.

Dorfman M, Arancibia S, Fiedler JL, Lara HE. Chronic Intermittent Cold Stress Activates Ovarian Sympathetic Nerves and Modifies Ovarian Follicular Development in the Rat. Biol Reprod. 2003;68(6):2038–43. https://doi.org/10.1095/biolreprod.102.008318.CrossRefPubMed

16.

Morales-Ledesma L, Trujillo A, Apolonio J. In the pubertal rat, the regulation of ovarian function involves the synergic participation of the sensory and sympathetic innervations that arrive at the gonad. Reprod Biol Endocrinol. 2015;13:61. https://doi.org/10.1186/s12958-015-0062-8.CrossRefPubMedPubMedCentral

17.

Chavez-Genaro R, Lombide P, Dominguez R, Rosas P, Vazquez-Cuevas F. Sympathetic pharmacological denervation in ageing rats: effects on ovulatory response and follicular population. Reprod Fertil Dev. 2007;19(8):954–60.CrossRef

18.

Goldman JM, Parrish MB, Cooper RL, McElroy WK. Blockade of ovulation in the rat by systemic and ovarian intrabursal administration of the fungicide sodium dimethyldithiocarbamate. Reprod Toxicol. 1997;11(2–3):185–90. https://doi.org/10.1016/s0890-6238(97)00005-1.CrossRefPubMed

19.

Itoh MT, Ishizuka B. α1-Adrenergic receptor in rat ovary: Presence and localization. Mol Cell Endocrinol. 2005;240(1–2):58–63. https://doi.org/10.1016/j.mce.2005.05.012.CrossRefPubMed

20.

Laszlovsky I, Erdö SL. Characterization of β-adrenergic receptors in rat ovary. Eur J Pharmacol. 1983;96(1):101–4. https://doi.org/10.1016/0014-2999(83)90534-4.CrossRef

21.

Jordan AW. Changes in Ovarian β-Adrenergic Receptors During the Estrous Cycle of the Rat. Biol Reprod. 1981;24(2):245–8. https://doi.org/10.1095/biolreprod24.2.245.CrossRefPubMed

22.

Luna SL, Neuman S, Aguilera J, Brown DI, Lara HE. In vivo beta-adrenergic blockade by propranolol prevents isoproterenol-induced polycystic ovary in adult rats. Horm Metab Res. 2012;44(9):676–81. https://doi.org/10.1055/s-0031-1301304.CrossRefPubMed

23.

Fernandois D, Lara HE, Paredes AH. Blocking of beta-adrenergic receptors during the subfertile period inhibits spontaneous ovarian cyst formation in rats. Horm Metab Res. 2012;44(9):682–7. https://doi.org/10.1055/s-0032-1304607.CrossRefPubMed

24.

Dominguez R, Gaitan CM, Mendez SA, Ulloa-Aguirre A. Effects of catecholaminergic blockade by haloperidol or propranolol at different stages of the oestrous cycle on ovulation and gonadotrophin levels in the rat. J Endocrinol. 1987;113(1):37–44. https://doi.org/10.1677/joe.0.1130037.CrossRefPubMed

25.

Maliqueo M, Benrick A, Stener-Victorin E. Rodent models of polycystic ovary syndrome: phenotypic presentation, pathophysiology, and the effects of different interventions. Semin Reprod Med. 2014;32(3):183–93. https://doi.org/10.1055/s-0034-1371090.CrossRefPubMed

26.

Peecher DL, Binder AK, Gabriel KI. Rodent models of mental illness in PCOS: The potential role of HPA dysregulation and lessons for behavioral researchers. Biol Reprod. 2018;100:590–600. https://doi.org/10.1093/biolre/ioy233.CrossRef

27.

Azziz R. Animal models for PCOS — not the real thing. Nature Reviews Endocrinology. 2017;13:–382. https://doi.org/10.1038/nrendo.2017.57.CrossRef

28.

Shaaban Z, Jafarzadeh Shirazi MR, Nooranizadeh MH, Tamadon A, Rahmanifar F, Ahmadloo S, et al. Decreased Expression of Arginine-Phenylalanine-Amide-Related Peptide-3 Gene in Dorsomedial Hypothalamic Nucleus of Constant Light Exposure Model of Polycystic Ovarian Syndrome. Int J Fertil Steril. 2018;12(1):43–50. https://doi.org/10.22074/ijfs.2018.5206.CrossRefPubMedPubMedCentral

29.

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. https://doi.org/10.1016/j.fertnstert.2012.04.006.CrossRefPubMed

30.

Brawer JR, Munoz M, Farookhi R. Development of the polycystic ovarian condition (PCO) in the estradiol valerate-treated rat. Biol Reprod. 1986;35(3):647–55.CrossRef

31.

Sotomayor-Zarate R, Dorfman M, Paredes A, Lara HE. Neonatal exposure to estradiol valerate programs ovarian sympathetic innervation and follicular development in the adult rat. Biol Reprod. 2008;78(4):673–80. https://doi.org/10.1095/biolreprod.107.063974.CrossRefPubMed

32.

Barria A, Leyton V, Ojeda SR, Lara HE. Ovarian steroidal response to gonadotropins and beta-adrenergic stimulation is enhanced in polycystic ovary syndrome: role of sympathetic innervation. Endocrinology. 1993;133(6):2696–703. https://doi.org/10.1210/endo.133.6.8243293.CrossRefPubMed

33.

Stener-Victorin E, Lundeberg T, Waldenstrom U, Manni L, Aloe L, Gunnarsson S, et al. Effects of electro-acupuncture on nerve growth factor and ovarian morphology in rats with experimentally induced polycystic ovaries. Biol Reprod. 2000;63(5):1497–503.CrossRef

34.

Rosa ESA, Guimaraes MA, Padmanabhan V, Lara HE. Prepubertal administration of estradiol valerate disrupts cyclicity and leads to cystic ovarian morphology during adult life in the rat: role of sympathetic innervation. Endocrinology. 2003;144(10):4289–97. https://doi.org/10.1210/en.2003-0146.CrossRef

35.

Manni L, Holmäng A, Lundeberg T, Aloe L, Stener-Victorin E. Ovarian expression of alpha (1)- and beta (2)-adrenoceptors and p75 neurotrophin receptors in rats with steroid-induced polycystic ovaries. Autonomic Neuroscience. 2005;118(1–2):79–87. https://doi.org/10.1016/j.autneu.2005.01.004.CrossRef

36.

Morales-Ledesma L, Linares R, Rosas G, Moran C, Chavira R, Cardenas M, et al. Unilateral sectioning of the superior ovarian nerve of rats with polycystic ovarian syndrome restores ovulation in the innervated ovary. Reprod Biol Endocrinol. 2010;8:99. https://doi.org/10.1186/1477-7827-8-99.CrossRefPubMedPubMedCentral

37.

Espinoza JA, Alvarado W, Venegas B, Dominguez R, Morales-Ledesma L. Pharmacological sympathetic denervation prevents the development of polycystic ovarian syndrome in rats injected with estradiol valerate. Reprod Biol Endocrinol. 2018;16(1):86. https://doi.org/10.1186/s12958-018-0400-8.CrossRefPubMedPubMedCentral

38.

Manni L, Lundeberg T, Holmang A, Aloe L, Stener-Victorin E. Effect of electro-acupuncture on ovarian expression of alpha (1)- and beta (2)-adrenoceptors, and p75 neurotrophin receptors in rats with steroid-induced polycystic ovaries. Reprod Biol Endocrinol. 2005;3:21. https://doi.org/10.1186/1477-7827-3-21.CrossRefPubMedPubMedCentral

39.

Manni L, Cajander S, Lundeberg T, Naylor AS, Aloe L, Holmang A, et al. Effect of exercise on ovarian morphology and expression of nerve growth factor and alpha(1)- and beta(2)-adrenergic receptors in rats with steroid-induced polycystic ovaries. J Neuroendocrinol. 2005;17(12):846–58. https://doi.org/10.1111/j.1365-2826.2005.01378.x.CrossRefPubMed

40.

Venegas-Meneses B, Padilla JF, Juarez CE, Moran JL, Moran C, Rosas-Murrieta NH, et al. Effects of ovarian dopaminergic receptors on ovulation. Endocrine. 2015;50(3):783–96. https://doi.org/10.1007/s12020-015-0636-4.CrossRefPubMed

41.

Bagavandoss P, Grimshaw S. Distribution of adenylyl cyclases in the rat ovary by immunofluorescence microscopy. Anat Rec (Hoboken). 2012;295(10):1717–26. https://doi.org/10.1002/ar.22550.CrossRef

42.

Bagavandoss P, Grimshaw S. Temporal and spatial distribution of the cannabinoid receptors (CB1, CB2) and fatty acid amide hydroxylase in the rat ovary. Anat Rec (Hoboken). 2010;293(8):1425–32. https://doi.org/10.1002/ar.21181.CrossRefPubMed

43.

Stener-Victorin E. Hypothetical physiological and molecular basis for the effect of acupuncture in the treatment of polycystic ovary syndrome. Mol Cell Endocrinol. 2013;373(1–2):83–90. https://doi.org/10.1016/j.mce.2013.01.006.CrossRefPubMed

44.

Sverrisdottir YB, Mogren T, Kataoka J, Janson PO, Stener-Victorin E. Is polycystic ovary syndrome associated with high sympathetic nerve activity and size at birth? Am J Physiol Endocrinol Metab. 2008;294(3):E576–81. https://doi.org/10.1152/ajpendo.00725.2007.CrossRefPubMed

45.

Lara HE, Porcile A, Espinoza J, Romero C, Luza SM, Fuhrer J, et al. Release of norepinephrine from human ovary: coupling to steroidogenic response. Endocrine. 2001;15(2):187–92. https://doi.org/10.1385/endo:15:2:187.CrossRefPubMed

46.

Lara HE, Dissen GA, Leyton V, Paredes A, Fuenzalida H, Fiedler JL, et al. An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat. Endocrinology. 2000;141(3):1059–72. https://doi.org/10.1210/endo.141.3.7395.CrossRefPubMed

47.

Linares R, Hernandez D, Moran C, Chavira R, Cardenas M, Dominguez R, et al. Unilateral or bilateral vagotomy induces ovulation in both ovaries of rats with polycystic ovarian syndrome. Reprod Biol Endocrinol. 2013;11:68. https://doi.org/10.1186/1477-7827-11-68.CrossRefPubMedPubMedCentral

48.

Adashi EY, Hsueh AJ. Stimulation of beta 2-adrenergic responsiveness by follicle-stimulating hormone in rat granulosa cells in vitro and in vivo. Endocrinology. 1981;108(6):2170–8. https://doi.org/10.1210/endo-108-6-2170.CrossRefPubMed

49.

Aguado LI, Petrovic SL, Ojeda SR. Ovarian beta-adrenergic receptors during the onset of puberty: characterization, distribution, and coupling to steroidogenic responses. Endocrinology. 1982;110(4):1124–32. https://doi.org/10.1210/endo-110-4-1124.CrossRefPubMed

50.

Fohr KJ, Mayerhofer A, Sterzik K, Rudolf M, Rosenbusch B, Gratzl M. Concerted action of human chorionic gonadotropin and norepinephrine on intracellular-free calcium in human granulosa-lutein cells: evidence for the presence of a functional alpha-adrenergic receptor. J Clin Endocrinol Metab. 1993;76(2):367–73. https://doi.org/10.1210/jcem.76.2.8381798.CrossRefPubMed

51.

Webley GE, Luck MR, Hearn JP. Stimulation of progesterone secretion by cultured human granulosa cells with melatonin and catecholamines. J Reprod Fertil. 1988;84(2):669–77.CrossRef

52.

Ojeda SR, Lara HE. Role of the Sympathetic Nervous System in the Regulation of Ovarian Function. In: Pirke KM, Wuttke W, Schweiger U, editors. The Menstrual Cycle and Its Disorders: Influences of Nutrition, Exercise and Neurotransmitters. Berlin: Springer Berlin Heidelberg; 1989. p. 26–32.CrossRef

53.

Parra C, Fiedler JL, Luna SL, Greiner M, Padmanabhan V, Lara HE. Participation of vasoactive intestinal polypeptide in ovarian steroids production during the rat estrous cycle and in the development of estradiol valerate-induced polycystic ovary. Reproduction. 2007;133(1):147–54. https://doi.org/10.1530/rep.1.01214.CrossRefPubMed

54.

Morales-Ledesma L, Vieyra E, Ramirez DA, Trujillo A, Chavira R, Cardenas M, et al. Effects on steroid hormones secretion resulting from the acute stimulation of sectioning the superior ovarian nerve to pre-pubertal rats. Reprod Biol Endocrinol. 2012;10:88. https://doi.org/10.1186/1477-7827-10-88.CrossRefPubMedPubMedCentral

Title: In rats with estradiol valerate-induced polycystic ovary syndrome, the acute blockade of ovarian β-adrenoreceptors improve ovulation
Authors: Berenice Venegas
Lizzbeth Yureli De León Gordillo
Gabriela Rosas
Julieta A. Espinoza
Carolina Morán
Roberto Domínguez
Leticia Morales-Ledesma
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Propranolol
Polycystic Ovary Syndrome
Polycystic Ovary Syndrome
Estradiol
Testosterone
Progesterone
Published in: Reproductive Biology and Endocrinology / Issue 1/2019
Electronic ISSN: 1477-7827
DOI: https://doi.org/10.1186/s12958-019-0539-y

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In rats with estradiol valerate-induced polycystic ovary syndrome, the acute blockade of ovarian β-adrenoreceptors improve ovulation

Abstract

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