Summary
Fetal exposure to cyproterone acetate (CPA), while allowing, normal sexual morphogenesis, has previously been shown to lead to functional endocrine abnormalities in adult rats of both sexes. Because of this, we examined morphologically and morphometrically the hypothalamic nuclei involved in sexual dimorphism as well as the pituitary lactotropes of rats exposed in utero from day 15 to 20 of gestation to CPA. Male and female offspring was studied at the age of 70–80 days. In both sexes the brain weight was lower (p<0.05) in CPA-treated than in control rats. Morphometrical investigations showed that the surface density (Sv) and the volume density (Vv) of the ventromedial nucleus were higher (p<0.05) in CPA-treated male than in control rats. By comparing sexes the Sv and Vv of the ventromedial nucleus were higher (p<0.01) in CPA-treated male than in corresponding female rats. Also the nuclear surface of the tyrosine hydroxylase-immunoreactive neurons of the arcuate nucleus was higher (p<0.05) in CPA-treated male than in female rats. In lactotropes of the pituitary gland the immunoreactive prolactin (PRL) was densitometrically increased (p< 0.05) in CPA-treated female compared with control rats. By electron microscopy, PRL granules and autophagocytosis appeared to be more abundant in CPA-treated rats of both sexes. These data show that fetal exposure to CPA results in long-term anatomical and physiological alterations of hypothalamic and preoptic nuclei as well as of the pituitary lactotropes. These permanent changes support the functional endocrine abnormalities observed in adult rats.
Similar content being viewed by others
References
Agnati LF, Fuxe K, Zoli M, Zini I, Härfstrand A, Toffano G, Goldstein M (1988) Morphometrical and microdensitometrical studies on phenylethanolamine-N-methyltransferase-and neuropeptide Y-immunoreactive neurons in the rostral medulla oblongata of the adult and old male rat. Neuroscience 26:461–478
Arnold AP, Gorski RA (1984) Gonadal steroid induction of structural sex differences in the central nervous system. Ann Rev Neurosci 7:413–442
Brinkmann AO, Lindh LM, Breedveld DI, Mulder E, van der Molen HJ (1983) Cyproterone acetate prevents translocation of the androgen receptor in the rat prostate. Mol Cell Endocrinol 32:117–129
Callaway TW, Bruchovsky N, Rennie PS, Comeau T (1982) Mechanisms of action of androgens and antiandrogens: Effects of antiandrogens on translocation of cytoplasmic androgen receptor and nuclear abundance of dihydrotestosterone. Prostate 3:599–610
Childs GV, Lloyd JM, Unabia G, Gharib SD, Wierman ME, Chin WW (1987) Detection of luteinizing hormone B messenger ribonucleic acid (RNA) in individual gonadotropes after castration: use of a new in situ hybridization method with a photobiotinylated complementary RNA probe. Mol Endocrinol 1:926–932
Döhler KD, Coquelin A, Davis F, Hines M, Shryne JE, Gorski RA (1982) Differentiation of the sexually dimorphic nucleus in the preoptic area of the rat brain is determined by the perinatal hormone environment. Neurosci Lett 33:295–298
Döhler KD, Coquelin A, Davis F, Hines M, Shryne JE, Gorski RA (1984) Pre- and postnatal influence of testosterone proprionate and diethylstilbestrol on differentiation of the sexually dimorphic nucleus of the preoptic area in male and female rats. Brain Res 302:291–295
Gomez F, Monnier B, Lemarchand-Béraud T (1984) Foetal exposure to low doses of cyproterone acetate in the rat leads to functional endocrine abnormalities despite normal sexual morphogenensis. Acta Endocrinol 106:411–419
Gorski RA, Gordon JH, Shryne JE, Southam AM (1978) Evidence for a morphological sex difference within the medial preoptic area of the rat brain. Brain Res 148:333–346
Gorski RA, Jacobson CD (1982) Sexual differentiation of the brain. Front Horm Res 10:1–14
Harlan RE, Gordon JH, Gorski RA (1979) Sexual differentiation of the brain: Implications for neuroscience. In: Schneider DM (ed) Review of Neuroscience 4. Raven Press, New York, pp 31–71
Hines M, Davis FC, Coquelin A, Goy RW, Gorski RA (1985) Sexually dimorphic regions in the medial preoptic area and the bed nucleus of the stria terminalis of the guinea pig brain: A description and an investigation of their relationship to gonadal steroids in adulthood. J Neurosci 5:40–47
Huang JK, Bartsch W, Voigt KD (1985) Interactions of an antiandrogen (cyproterone acetate) with the androgen receptor system and its biological action on the rat ventral prostate. Acta Endocrinol 109:569–576
König JFR, Klippel RA (1974) The rat brain. A stereotaxic atlas of the forebrain and lower parts of the brain stem. RE Krieger, Huntington NY
Lloyd JM, Childs GV (1988) Differential storage and release of luteinizing hormone and follicle-releasing hormone from individual gonadotropes separated by centrifugal elutriation. Endocrinology 122:1282–1290
Matsumoto A, Arai Y (1980) Sexual dimorphism in wiring pattern in the hypothalamic arcuate nucleus and its modification by neonatal hormonal environment. Brain Res 190:238–242
Matsumoto A, Arai Y (1983) Sex difference in volume of the ventromedial nucleus of the hypothalamus in the rat. Endocrinol Jpn 30:277–280
Mittra I (1980) A novel “cleaved prolactin” in the rat pituitary: Part I. Biosynthesis, characterization and regulatory control. Biochem Biophys Res Comm 95:1750–1759
Morin A, Rosenbaum E, Tixier-Vidai A (1984) Effects of thyrotropin-releasing hormone on prolactin compartments in normal rat pituitary cells in primary culture. Endocrinology 115:2278–2284
Neumann F, von Berswordt-Wallrabe R, Elger W, Steinbeck H, Hahn JD, Kramer M (1970) Aspects of androgen-dependent events as studied by antiandrogens. Rec Prog Horm Res 26:337–410
Oetting WS, Walker AM (1986) Differential isoform distribution between stored and secreted prolactin. Endocrinology 119:1377–1381
Owens RE, Casanueva FF, Friesen HG (1985) Comparison between rat prolactin radioimmunoassay and bioassay values under different experimental and physiological conditions. Mol Cell Endocrinol 39:131–140
Parsons B, Rainbow TC, McEwen BS (1984) Organizational effects of testosterone via aromatization on feminine reproductive behavior and neural progestin receptors in rat brain. Endocrinology 115:1412–1417
Rossi GL, Probst D, Panerai AE, Cocchi D, Locatelli V, Müller EE (1979) Ultrastructure of somatotrophs of rats with median eminence lesions: Studies in basal conditions and after thyrotropin-releasing hormone stimulation. Neuroendocrinology 29:100–109
Rossi GL, Bestetti G (1983) Technical aspects in the study of pathologic lesions in the hypothalamus of the rat. In: Jones TC, Mohr U, Hunt RD (eds) Endocrine system: monographs on pathology of laboratory animals. Springer, Berlin Heidelberg New York Tokyo, pp 311–316
Shah GN, Hymer WC (1989) Prolactin variants in the rat adenohypophysis. Mol Cell Endocrinol 61:97–107
Sinha YN, Gilligan TA (1981) Identification of a less immunoreactive form of prolactin in the rat pituitary. Endocrinology 108:1091–1094
Tarttelin MF, Gorski RA (1988) Postnatal influence of diethylstilbestrol on the differentiation of the sexually dimorphic nucleus in the rat is as effective as perinatal treatment. Brain Res 456:271–274
Traish AM, Muller RE, Wotiz HH (1985) Interaction of cyproterone acetate with rat prostatic androgen receptors. Steroids 45:247–262
Wallis M, Daniels M, Ellis SA (1980) Size heterogeneity of rat pituitary prolactin. Biochem J 189:605–614
Weinstein LA, Landis DMD, Sagar SM, Millard WJ, Martin JB (1984) Cysteamine depletes prolactin (PRL) but does not alter the structure of PRL-containing granules in the anterior pituitary. Endocrinology 115:1543–1550
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Rossi, G.L., Bestetti, G.E., Reymond, M.J. et al. Morphofunctional study of the effects of fetal exposure to cyproterone acetate on the hypothalamo-pituitary-gonadal axis of adult rats. Exp Brain Res 83, 349–356 (1991). https://doi.org/10.1007/BF00231158
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00231158