Neonatal testosterone exposure induces early development of follicular cysts followed by sympathetic ovarian hyperinnervation
Gabriel Anesetti A and Rebeca Chávez-Genaro A B
+ Author Affiliations
- Author Affiliations
A Histology and Embryology Department, School of Medicine, General Flores 2125, CP 11800, Montevideo, Uruguay.
B Corresponding author. Email: rchavez@fmed.edu.uy
Reproduction, Fertility and Development 28(11) 1753-1761 https://doi.org/10.1071/RD14460
Submitted: 21 November 2014 Accepted: 5 April 2015 Published: 20 May 2015
Abstract
This study analysed the temporal association between ovarian cyst development induced by neonatal androgenisation and sympathetic innervation. Neonatal rats (postnatal Days 1 to 5) were treated with testosterone or dihydrotestosterone and the effects were evaluated at postnatal Days 20, 40, 90 or 180. Ovulation rate, number of cystic follicles and density of sympathetic fibres were analysed. The effects of surgical denervation or gonadotrophin stimulation were also assessed. Rats exposed to testosterone showed no oestrous cycle activity and did not ovulate, maintaining a polycystic ovarian morphology at all ages studied. Also, a significant increase in ovarian density of noradrenergic fibres was detected at postnatal Days 90 and 180. Sympathectomy was unable to re-establish ovarian activity; however, human chorionic gonadotrophin stimulation was enough to induce ovulation. The impact of dihydrotestosterone on ovarian function was less noticeable, showing the coexistence of corpora lutea and cystic structures without changes in sympathetic innervation. Our findings suggest that a remodelling of ovarian sympathetic innervation occurs as a response to modifications in the pattern of follicular growth induced by testosterone. A role of sympathetic innervation in the maintenance of the polycystic condition is suggested.
Additional keywords: androgen, cysts, ovary, rat, sympathetic innervation.
References
Abbott, D. H., Dumesic, D. A., Eisner, J. R., Colman, R. J., and Kemnitz, J. W. (1998). Insights into the development of polycystic ovary syndrome (PCOS) from studies of prenatally androgenised female rhesus monkeys. Trends Endocrinol. Metab. 9, 62–67.| Insights into the development of polycystic ovary syndrome (PCOS) from studies of prenatally androgenised female rhesus monkeys.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXivVegtLo%3D&md5=eb13108fd4978568377c5525f90d1ceeCAS | 18406243PubMed |
Aguado, L. I., and Ojeda, S. R. (1984). Ovarian adrenergic nerves play a role in maintaining preovulatory steroid secretion. Endocrinology 114, 1944–1946.
| Ovarian adrenergic nerves play a role in maintaining preovulatory steroid secretion.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL2cXitVCitLs%3D&md5=cd12b5dc569188fff5404dff538ab466CAS | 6538828PubMed |
Amateau, S. K., Alt, J. J., Stamps, C. L., and McCarthy, M. M. (2004). Brain oestradiol content in newborn rats: sex differences, regional heterogeneity and possible de novo synthesis by the female telencephalon. Endocrinology 145, 2906–2917.
| Brain oestradiol content in newborn rats: sex differences, regional heterogeneity and possible de novo synthesis by the female telencephalon.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXkt12gu70%3D&md5=ab32117f869a9a7614240c18c9f4be60CAS | 14988386PubMed |
Anesetti, G., Lombide, P., and Chavez-Genaro, R. (2009). Prepubertal oestrogen exposure modifies neurotrophin receptor expression in celiac neurons and alters ovarian innervation. Auton. Neurosci. 145, 35–43.
| Prepubertal oestrogen exposure modifies neurotrophin receptor expression in celiac neurons and alters ovarian innervation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXmvVersQ%3D%3D&md5=0a8d628ba370f3cb196808c38645482bCAS | 19036644PubMed |
Arai, Y., Yamanouchi, K., Mizukami, S., Yanai, R., Shibata, K., and Nagasawa, H. (1981). Induction of anovulatory sterility by neonatal treatment with 5β-dihydrotestosterone in female rats. Acta Endocrinol. (Copenh.) 96, 439–443.
| 1:CAS:528:DyaL3MXhslWkur8%3D&md5=b7a9c26feea6c088c4c3fb693688450eCAS | 7193953PubMed |
Brawer, J. R., Munoz, M., and Farookhi, R. (1986). Development of the polycystic ovarian condition (PCO) in the oestradiol valerate-treated rat. Biol. Reprod. 35, 647–655.
| Development of the polycystic ovarian condition (PCO) in the oestradiol valerate-treated rat.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL2sXjsFak&md5=80bfea67cca41a549593bb97576741d7CAS | 3098314PubMed |
Burden, H. W., and Lawrence, I. E. (1978). Experimental studies on the acetylcholinesterase-positive nerves in the ovary of the rat. Anat. Rec. 190, 233–241.
| Experimental studies on the acetylcholinesterase-positive nerves in the ovary of the rat.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaE1c7itF2ltg%3D%3D&md5=e4f20e84042f7cf6464c23154bed0374CAS | 629404PubMed |
Chávez-Genaro, R., Lombide, P., Domínguez, R., Rosas, P., and Vázquez-Cuevas, F. (2007). Sympathetic pharmacological denervation in ageing rats: effects on ovulatory response and follicular population. Reprod. Fertil. Dev. 19, 954–960.
| Sympathetic pharmacological denervation in ageing rats: effects on ovulatory response and follicular population.Crossref | GoogleScholarGoogle Scholar | 18076827PubMed |
Cruz, G., Barra, R., Gonzalez, D., Sotomayor-Zarate, R., and Lara, H. E. (2012). Temporal window in which exposure to oestradiol permanently modifies ovarian function causing polycystic ovary morphology in rats. Fertil. Steril. 98, 1283–1290.
| Temporal window in which exposure to oestradiol permanently modifies ovarian function causing polycystic ovary morphology in rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhtFeitL%2FE&md5=bef84dcc23a9896ab6cdffdadf0fea01CAS | 22854013PubMed |
Dean, A., Smith, L. B., Macpherson, S., and Sharpe, R. M. (2012). The effect of dihydrotestosterone exposure during or prior to the masculinisation programming window on reproductive development in male and female rats. Int. J. Androl. 35, 330–339.
| The effect of dihydrotestosterone exposure during or prior to the masculinisation programming window on reproductive development in male and female rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhtFCisrbE&md5=c0ff5f8038674fcdaa8b7a37fb0efd49CAS | 22248293PubMed |
de la Torre, J. C., and Surgeon, J. W. (1976). Histochemical fluorescence of tissue and brain monoamines: results in 18 min using the sucrose–phosphate–glyoxylic acid (SPG) method. Neuroscience 1, 451–453.
| Histochemical fluorescence of tissue and brain monoamines: results in 18 min using the sucrose–phosphate–glyoxylic acid (SPG) method.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE1cXhsVymsL0%3D&md5=d30b05784b413950a2792b0dd6871b6eCAS | 11370236PubMed |
Dissen, G. A., Hirshfield, A. N., Malamed, S., and Ojeda, S. R. (1995). Expression of neurotrophins and their receptors in the mammalian ovary is developmentally regulated: changes at the time of folliculogenesis. Endocrinology 136, 4681–4692.
| 1:CAS:528:DyaK2MXot1Wlsbs%3D&md5=c81feee8e091edccab87af3473b74233CAS | 7664689PubMed |
Dissen, G. A., Romero, C., Paredes, A., and Ojeda, S. R. (2002). Neurotrophic control of ovarian development. Microsc. Res. Tech. 59, 509–515.
| Neurotrophic control of ovarian development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXjtVKntQ%3D%3D&md5=3333aa468be607db11011410aedcf97bCAS | 12467027PubMed |
Dorfman, M. D., Garcia-Rudaz, C., Alderman, Z., Kerr, B., Lomniczi, A., Dissen, G. A., Castellano, J. M., Garcia-Galiano, D., Gaytan, F., Xu, B., Tena-Sempere, M., and Ojeda, S. R. (2014). Loss of Ntrk2/Kiss1r signalling in oocytes causes premature ovarian failure. Endocrinology 155, 3098–3111.
| Loss of Ntrk2/Kiss1r signalling in oocytes causes premature ovarian failure.Crossref | GoogleScholarGoogle Scholar | 24877631PubMed |
Galas, J., Slomczynska, M., Knapczyk-Stwora, K., Durlej, M., Starowicz, A., Tabarowski, Z., Rutka, K., and Szoltys, M. (2012). Steroid levels and the spatiotemporal expression of steroidogenic enzymes and androgen receptor in developing ovaries of immature rats. Acta Histochem. 114, 207–216.
| Steroid levels and the spatiotemporal expression of steroidogenic enzymes and androgen receptor in developing ovaries of immature rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XjsVWit70%3D&md5=9646ab696208c6868c9e73e6085a127eCAS | 21620445PubMed |
George, F. W., and Ojeda, S. R. (1987). Vasoactive intestinal peptide enhances aromatase activity in the neonatal rat ovary before development of primary follicles or responsiveness to follicle-stimulating hormone. Proc. Natl. Acad. Sci. USA 84, 5803–5807.
| Vasoactive intestinal peptide enhances aromatase activity in the neonatal rat ovary before development of primary follicles or responsiveness to follicle-stimulating hormone.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL2sXlt1Ontr0%3D&md5=b21630a0ea1be80e0ff8e70faa69b4b8CAS | 3039508PubMed |
Gervásio, C. G., Bernuci, M. P., Silva-de-Sá, M. F., and Rosa, E. S. A. C. (2014). The role of androgen hormones in early follicular development. ISRN Obstet. Gynecol. 2014, 818010.
| The role of androgen hormones in early follicular development.Crossref | GoogleScholarGoogle Scholar | 25006485PubMed |
Gorski, R. A. (1963). Modification of ovulatory mechanisms by postnatal administration of estrogen to the rat. Am. J. Physiol. 205, 842–844.
| 1:CAS:528:DyaF2cXjt1Glug%3D%3D&md5=e572b152a7ffac016d131d6a2e43d998CAS | 5896305PubMed |
Heider, U., Pedal, I., and Spanel-Borowski, K. (2001). Increase in nerve fibres and loss of mast cells in polycystic and postmenopausal ovaries. Fertil. Steril. 75, 1141–1147.
| Increase in nerve fibres and loss of mast cells in polycystic and postmenopausal ovaries.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3MzhtFymsA%3D%3D&md5=e16c20c68338818cd185a9ad0799c5efCAS | 11384640PubMed |
Hirshfield, A. N. (1991). Development of follicles in the mammalian ovary. Int. Rev. Cytol. 124, 43–101.
| 1:CAS:528:DyaK3MXlsFSmsr4%3D&md5=2448df6fbcd8c9a8280058b9284ffdddCAS | 2001918PubMed |
Hotchkiss, A. K., Furr, J., Makynen, E. A., Ankley, G. T., and Gray, L. E. (2007). In utero exposure to the environmental androgen trenbolone masculinises female Sprague–Dawley rats. Toxicol. Lett. 174, 31–41.
| In utero exposure to the environmental androgen trenbolone masculinises female Sprague–Dawley rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXht1anurbP&md5=ad2a54d3f340c5ee1d71eca9eca9b66eCAS | 17931805PubMed |
James, K. C., Nicholls, P. J., and Roberts, M. (1969). Biological half-lives of [4–14C]testosterone and some of its esters after injection into the rat. J. Pharm. Pharmacol. 21, 24–27.
| Biological half-lives of [4–14C]testosterone and some of its esters after injection into the rat.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaF1MXksVGlsw%3D%3D&md5=fa6aad555610ef0521b61ed34dbe748dCAS | 4388185PubMed |
Karavan, J. R., and Pepling, M. E. (2012). Effects of oestrogenic compounds on neonatal oocyte development. Reprod. Toxicol. 34, 51–56.
| Effects of oestrogenic compounds on neonatal oocyte development.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XksFeiu7k%3D&md5=72c8359fcc780a8664d9ee97b42d3a94CAS | 22406039PubMed |
Kerr, B., Garcia-Rudaz, C., Dorfman, M., Paredes, A., and Ojeda, S. R. (2009). NTRK1 and NTRK2 receptors facilitate follicle assembly and early follicular development in the mouse ovary. Reproduction 138, 131–140.
| NTRK1 and NTRK2 receptors facilitate follicle assembly and early follicular development in the mouse ovary.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXovFemsbY%3D&md5=5b34d2f82583dfb4f9ac965b95b40690CAS | 19357131PubMed |
Konkle, A. T. M., and McCarthy, M. M. (2011). Developmental time course of oestradiol, testosterone and dihydrotestosterone levels in discrete regions of male and female rat brain. Endocrinology 152, 223–235.
| Developmental time course of oestradiol, testosterone and dihydrotestosterone levels in discrete regions of male and female rat brain.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXitVCisL4%3D&md5=f0aab55991c47974cb60ea9490fc644aCAS |
Lansdown, A., and Rees, D. A. (2012). The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target? Clin. Endocrinol. (Oxf) 77, 791–801.
| 1:CAS:528:DC%2BC38Xhs1eku7rN&md5=b97d7d969ba46ee9cc75135f9615808eCAS | 22882204PubMed |
Lara, H. E., Dissen, G. A., Leyton, V., Paredes, A., Fuenzalida, H., Fiedler, J. L., and Ojeda, S. R. (2000). 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 141, 1059–1072.
| 1:CAS:528:DC%2BD3cXisFOrsbg%3D&md5=24c3e9ad1707b1e7f0d29af770a6ec3aCAS | 10698182PubMed |
Mayerhofer, A., Dissen, G. A., Costa, M. E., and Ojeda, S. R. (1997). A role for neurotransmitters in early follicular development: induction of functional follicle-stimulating hormone receptors in newly formed follicles of the rat ovary. Endocrinology 138, 3320–3329.
| 1:CAS:528:DyaK2sXkslShurw%3D&md5=8aa17fa1def527be263f19d76a1b47acCAS | 9231784PubMed |
Miyagawa, S., Katsu, Y., Ohta, Y., Sudo, T., Lubahn, D. B., and Iguchi, T. (2010). Oestrogen receptor ESR1 is indispensable for the induction of persistent vaginal change by neonatal 5alpha-dihydrotestosterone exposure in mice. Biol. Reprod. 82, 497–503.
| Oestrogen receptor ESR1 is indispensable for the induction of persistent vaginal change by neonatal 5alpha-dihydrotestosterone exposure in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXisVekurg%3D&md5=521111d922289cbaa641f3ae1634dbd4CAS | 19864317PubMed |
Nohara, K., Waraich, R. S., Liu, S., Ferron, M., Waget, A., Meyers, M. S., Karsenty, G., Burcelin, R., and Mauvais-Jarvis, F. (2013). Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice. Am. J. Physiol. Endocrinol. Metab. 304, E1321–E1330.
| Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhtV2jurrF&md5=f823208825eee5165bb20d18e388cd7dCAS | 23612996PubMed |
Prizant, H., Gleicher, N., and Sen, A. (2014). Androgen actions in the ovary: balance is key. J. Endocrinol. 222, R141–R151.
| Androgen actions in the ovary: balance is key.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXhs1CgurjN&md5=293b38ce8178bf0db5b91a43b15c6c61CAS | 25037707PubMed |
Rosa-e-Silva, A., Guimaraes, M. A., Padmanabhan, V., and Lara, H. E. (2003). Prepubertal administration of oestradiol valerate disrupts cyclicity and leads to cystic ovarian morphology during adult life in the rat: role of sympathetic innervation. Endocrinology 144, 4289–4297.
| Prepubertal administration of oestradiol valerate disrupts cyclicity and leads to cystic ovarian morphology during adult life in the rat: role of sympathetic innervation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXns1SrtL0%3D&md5=2d4611a6d80909a525796a14d1e943f5CAS | 12960066PubMed |
Sar, M., and Welsch, F. (1999). Differential expression of oestrogen receptor-beta and oestrogen receptor-alpha in the rat ovary. Endocrinology 140, 963–971.
| 1:CAS:528:DyaK1MXntl2lsQ%3D%3D&md5=eb0a86cb5dac6e4cf888d4cee639d1deCAS | 9927330PubMed |
Shinohara, Y., Matsumoto, A., and Mori, T. (1998). Effects of prenatal exposure to diethylstilbestrol on the sympathetic nervous system in the rat ovary. Neurosci. Lett. 255, 123–126.
| Effects of prenatal exposure to diethylstilbestrol on the sympathetic nervous system in the rat ovary.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXmvFWmur8%3D&md5=ea9525e63b484fa27b867e2270699aa7CAS | 9832188PubMed |
Sir-Petermann, T., Maliqueo, M., Angel, B., Lara, H. E., Pérez-Bravo, F., and Recabarren, S. E. (2002). Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenisation. Hum. Reprod. 17, 2573–2579.
| Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenisation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38Xns1Ggt7w%3D&md5=7cba26e6887f66d13c52ed9a05397c70CAS | 12351531PubMed |
Sotomayor-Zárate, R., Dorfman, M., Paredes, A., and Lara, H. E. (2008). Neonatal exposure to oestradiol valerate programs ovarian sympathetic innervation and follicular development in the adult rat. Biol. Reprod. 78, 673–680.
| Neonatal exposure to oestradiol valerate programs ovarian sympathetic innervation and follicular development in the adult rat.Crossref | GoogleScholarGoogle Scholar | 18077802PubMed |
Sotomayor-Zárate, R., Tiszavari, M., Cruz, G., and Lara, H. E. (2011). Neonatal exposure to single doses of oestradiol or testosterone programs ovarian follicular development-modified hypothalamic neurotransmitters and causes polycystic ovary during adulthood in the rat. Fertil. Steril. 96, 1490–1496.
| Neonatal exposure to single doses of oestradiol or testosterone programs ovarian follicular development-modified hypothalamic neurotransmitters and causes polycystic ovary during adulthood in the rat.Crossref | GoogleScholarGoogle Scholar | 21982285PubMed |
Sverrisdóttir, Y. B., Mogren, T., Kataoka, J., Janson, P. O., and Stener-Victorin, E. (2008). Is polycystic ovary syndrome associated with high sympathetic nerve activity and size at birth? Am. J. Physiol. Endocrinol. Metab. 294, E576–E581.
| Is polycystic ovary syndrome associated with high sympathetic nerve activity and size at birth?Crossref | GoogleScholarGoogle Scholar | 18198350PubMed |
Teede, H., Deeks, A., and Moran, L. (2010). Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 8, 41.
| Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BC3cjgtFGntA%3D%3D&md5=6849827cd1f3bb35cdfdb782eaf83032CAS | 20591140PubMed |
Vendola, K., Zhou, J., Wang, J., Famuyiwa, O. A., Bievre, M., and Bondy, C. A. (1999). Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol. Reprod. 61, 353–357.
| Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXkslKqsbo%3D&md5=12a23eb9c96d6feccb38337f897127aaCAS | 10411511PubMed |
Walters, K. A., Middleton, L. J., Joseph, S. R., Hazra, R., Jimenez, M., Simanainen, U., Allan, C. M., and Handelsman, D. J. (2012). Targeted loss of androgen receptor signalling in murine granulosa cells of preantral and antral follicles causes female subfertility. Biol. Reprod. 87, 151.
| Targeted loss of androgen receptor signalling in murine granulosa cells of preantral and antral follicles causes female subfertility.Crossref | GoogleScholarGoogle Scholar | 23115271PubMed |
Weidner, N., Semple, J. P., Welch, W. R., and Folkman, J. (1991). Tumour angiogenesis and metastasis – correlation in invasive breast carcinoma. N. Engl. J. Med. 324, 1–8.
| Tumour angiogenesis and metastasis – correlation in invasive breast carcinoma.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK3M%2FnsVWquw%3D%3D&md5=758da841703472de1cd0a9d4a31314acCAS | 1701519PubMed |
Wu, X.-Y., Li, Z.-L., Wu, C.-Y., Liu, Y.-M., Lin, H., Wang, S.-H., and Xiao, W.-F. (2010). Endocrine traits of polycystic ovary syndrome in prenatally androgenised female Sprague–Dawley rats. Endocr. J. 57, 201–209.
| Endocrine traits of polycystic ovary syndrome in prenatally androgenised female Sprague–Dawley rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXptl2ksro%3D&md5=598f8ac53f3b1e1704d7e79b896442f2CAS | 20057162PubMed |
Xita, N., and Tsatsoulis, A. (2006). Fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical and genetic association studies. J. Clin. Endocrinol. Metab. 91, 1660–1666.
| Fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical and genetic association studies.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XkslCntrc%3D&md5=9b85d8f1face942d9c6cb7542c54a1b5CAS | 16522691PubMed |
