Blocking of β-Adrenergic Receptors During the Subfertile Period Inhibits Spontaneous Ovarian Cyst Formation in Rats

Abstract

As aging proceeds, fertility problems arise, and the success rate of in vitro fertilization declines. During reproductive aging, rat ovaries present spontaneous formation of cysts, followed by a concomitant increase in sympathetic nerve activity, causing infertility and cessation of ovarian function. β₂-Adrenergic receptors, which are activated by noradrenaline (NA), modify follicular development and steroid secretions; thus, increased nerve activity has been associated with the development and maintenance of cystic structures. The purpose of this work was to block the effect of this sympathetic activity through in vivo administration of propranolol (a β-adrenergic receptor antagonist) to determine whether it delays cyst formation and cessation of the ovarian function in rats that had reached the subfertile period. Propranolol was administrated daily to 8- and 10-month-old rats for 2 months. Estrous cycling activity was monitored by vaginal smear, serum concentration of the steroidal hormones was determined by enzyme-immune assay and morphological analysis of the ovaries was performed using 6 μm tissue slices stained with hematoxylin-eosin. Propranolol increased the number of healthy follicles, the ovulation rate, and levels of serum sexual steroids (androstenedione, testosterone, and estradiol) and recovered estrous cycling activity. It also decreased the number of follicular cysts. These results suggest that the blockade of β-adrenergic receptors recovered ovarian function during reproductive aging. It is suggested that propranolol induces a time-dependent extension of the subfertile window, and it could be used to increase the success rate of fertility programs in aging woman.

Key words

fertility - ovary - norepinephrine - steroid hormones

• References

• 1 Broekmans FJ, Knauff EA, te Velde ER, Macklon NS, Fauser BC. Female reproductive ageing: Current knowledge and future trends. Trends Endocrinol Metab 2007; 18: 58-65
• 2 Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: Implications for forecasting menopause. Hum Reprod 1992; 7: 1342-1346
• 3 Wu JM, Zelinski MB, Ingram DK, Ottinger MA. Ovarian aging and menopause: Current theories, hypotheses, and research models. Exp Biol Med (Maywood) 2005; 230: 818-828
• 4 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: 1124-1132
• 5 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: 1592-1602
• 6 Burden HW, Lawrence Jr IE, Louis TM. The adrenergic innervation of the guinea pig ovary during prenatal and postnatal periods. Acta Anat (Basel). 1985. 122. 193-196
• 7 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: 2170-2178
• 8 Paredes AH, Salvetti NR, Diaz AE, Dallard BE, Ortega HH, Lara HE. Sympathetic nerve activity in normal and cystic follicles from isolated bovine ovary: Local effect of beta-adrenergic stimulation on steroid secretion. Reprod Biol Endocrinol 2011; 9: 66
• 9 Birdsall MA, Farquhar CM. Polycystic ovaries in pre and post-menopausal women. Clin Endocrinol (Oxf) 1996; 44: 269-276
• 10 Margolin E, Zhornitzki T, Kopernik G, Kogan S, Schattner A, Knobler H. Polycystic ovary syndrome in post-menopausal women – marker of the metabolic syndrome. Maturitas 2005; 50: 331-336
• 11 Semenova II. adrenergic innervation of ovaries in stein-leventhal syndrome. Vestn Akad Med Nauk SSSR 1969; 24: 58-62
• 12 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: 1141-1147
• 13 Lara HE, Ferruz JL, Luza S, Bustamante DA, Borges Y, Ojeda SR. Activation of ovarian sympathetic nerves in polycystic ovary syndrome. Endocrinology 1993; 133: 2690-2695
• 14 Acuna E, Fornes R, Fernandois D, Garrido MP, Greiner M, Lara HE, Paredes AH. Increases in norepinephrine release and ovarian cyst formation during ageing in the rat. Reprod Biol Endocrinol 2009; 7: 64
• 15 Lara HE, Dissen GA, Leyton V, Paredes A, Fuenzalida H, Fiedler JL, Ojeda SR. 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: 1059-1072
• 16 Brawer J, Richard M, Farookhi R. Pattern of human chorionic gonadotropin binding in the polycystic ovary. Am J Obstet Gynecol 1989; 161: 474-480
• 17 Convery M, McCarthy GF, Brawer JR. Remission of the polycystic ovarian condition (pco) in the rat following hemiovariectomy. Anat Rec 1990; 226: 328-336
• 18 Paredes A, Galvez A, Leyton V, Aravena G, Fiedler JL, Bustamante D, Lara HE. Stress promotes development of ovarian cysts in rats: The possible role of sympathetic nerve activation. Endocrine 1998; 8: 309-315
• 19 te Velde ER. Ovarian ageing and postponement of childbearing. Maturitas 1998; 30: 103-104
• 20 Bevan P, Bradshaw CM, Szabadi E. The pharmacology of adrenergic neuronal responses in the cerebral cortex: Evidence for excitatory alpha- and inhibitory beta-receptors. Br J Pharmacol 1977; 59: 635-641
• 21 Chakraborty M, Asdaq SM. Interaction of semecarpus anacardium l. With propranolol against isoproterenol induced myocardial damage in rats. Indian J Exp Biol 2011; 49: 200-206
• 22 te Velde ER, Scheffer GJ, Dorland M, Broekmans FJ, Fauser BC. Developmental and endocrine aspects of normal ovarian aging. Mol Cell Endocrinol 1998; 145: 67-73
• 23 Broekmans FJ, Scheffer GJ, Bancsi LF, Dorland M, Blankenstein MA, te Velde ER. Ovarian reserve tests in infertility practice and normal fertile women. Maturitas 1998; 30: 205-214
• 24 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: 4289-4297
• 25 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: 954-960
• 26 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: 2038-2043
• 27 Bao B, Kumar N, Karp RM, Garverick HA, Sundaram K. Estrogen receptor-beta expression in relation to the expression of luteinizing hormone receptor and cytochrome p450 enzymes in rat ovarian follicles. Biol Reprod 2000; 63: 1747-1755
• 28 Kotwica J, Bogacki M, Rekawiecki R. Neural regulation of the bovine corpus luteum. Domest Anim Endocrinol 2002; 23: 299-308
• 29 Dart AM, Lewis MJ, Groom GV, Meek EM, Henderson AH. The effect of chronic propranolol treatment on overnight plasma levels of anterior pituitary and related hormones. Br J Clin Pharmacol 1981; 12: 849-853
• 30 Neal-Perry G, Nejat E, Dicken C. The neuroendocrine physiology of female reproductive aging: An update. Maturitas 2010; 67: 34-38