Abstract
Purpose
Estrogenic symptoms of liver disease patients including biliary tract disorder with high frequency is observed in clinical cases. However, the origin of 17β-estradiol which is abundant enough to cause symptoms remains uncertain. In male rats, it has been reported that the parietal cells which have an abundance of aromatase-synthesized 17β-estradiol, and a part of 17β-estradiol secreted into the portal vein, may flow into the systemic circulation under a pathophysiological condition of the liver including bile duct ligation (BDL). The aim of this study is to reveal the origin of 17β-estradiol increment in female rats and to investigate the effect of BDL on the ovary during the estrus cycle.
Methods
Wistar female rats were used, and the common bile duct was ligated twice and transected completely at 7 days before termination. Serum portal venous and arterial 17β-estradiol levels, Cyp19a1 expressions, aromatase protein levels, and estrogen receptor (ER) α levels in the liver were measured during the estrus cycle.
Results
Both arterial and portal venous 17β-estradiol levels increased 2.9 times at proestrus and maintained constant levels during the cycle. The expression of Cyp19a1 and aromatase protein in the stomach maintained constant levels, and significantly decreased during the estrus cycle in the ovary. Hepatic ERα protein and Esr1 expressions decrease by BDL in all stages.
Conclusions
These results suggest that the increment of serum 17β-estradiol levels in obstructive cholestasis induced by BDL is derived from 17β-estradiol secreted from the parietal cells in females as well as males.
Similar content being viewed by others
References
Carbone M, Mells GF, Pells G, Dawwas MF, Newton JL et al (2013) Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology 144:560–569
Farrell GC, Cooksley WG, Powell LW (1979) Drug metabolism in liver disease: activity of hepatic microsomal metabolizing enzymes. Clin Pharmacol Ther 26:483–492
Kawata S, Imai Y, Inada M, Tamura S, Miyoshi S et al (1987) Selective reduction of hepatic cytochrome P450 content in patients with intrahepatic cholestasis. A mechanism for impairment of microsomal drug oxidation. Gastroenterology 92:299–303
George J, Murray M, Byth K, Farrell GC (1995) Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 21:120–128
Hutterer F, Denk H, Bacchin PG, Sckenkman JB, Schaffner F et al (1970) Mechanism of cholestasis. 1. Effect of bile acids on microsomal cytochrome P-450 dependent biotransformation system in vitro. Life Sci II 9:877–887
Mackinnon AM, Simon FR (1974) Reduced synthesis of hepatic microsomal cytochroma P450 in the bile duct ligated rat. Biochem Biophys Res Commun 56:437–443
Chen J, Murray M, Liddle C, Jiang XM, Farrell GC (1995) Downregulation of male-specific cytochrome P450s 2C11 and 3A2 in bile duct-ligated male rats: importance to reduced hepatic content of cytochrome P450 in cholestasis. Hepatology 22:580–587
Setchell KD, Rodrigues CM, Clerici C, Solinas A, Morelli A et al (1997) Bile acid concentrations in human and rat liver tissue and in hepatocyte nuclei. Gastroenterology 112:226–235
Chen J, Robertson G, Field J, Liddle C, Farrell GC (1998) Effects of bile duct ligation on hepatic expression of female-specific CYP2C12 in male and female rats. Hepatology 28:624–630
Alvaro D, Alpini G, Onori P, Franchitto A, Glaser S et al (2002) Effect of ovariectomy on the proliferative capacity of intrahepatic rat cholangiocytes. Gastroenterology 123:336–344
Alvaro D, Alpini G, Onori P, Perego L, Svegliata Baroni G et al (2000) Estrogens stimulate proliferation of intrahepatic biliary epithelium in rats. Gastroenterology 119:1681–1691
Alvaro D, Alpini G, Onori P, Franchitto A, Glaser SS et al (2002) Alfa and beta estrogen receptors and the biliary tree. Mol Cell Endocrinol 193:105–108
Baird DT, Horton R, Longcope C, Tait JF (1969) Steroid dynamics under steady-state conditions. Recent Prog Horm Res 25:611–664
de Jong FH, Hey AH, van der Molen HJ (1974) Oestradiol-17 beta and testosterone in rat testis tissue: effect of gonadotrophins, localization and production in vitro. J Endocrinol 60:409–419
Dorrington J, Armstrong DT (1995) Follicle-stimulating hormone stimulates estradiol-17β synthesis in cultured Sertori cells. Proc Natl Acad Sci USA 72:2677–2681
Erickson GF, Hsueh AJW (1978) Stimulation of aromatase activity by follicle-stimulating hormone in rat granulose cells in vivo and in vitro. Endocrinology 102:1275–1282
Fukuda S, Terakawa N, Sato B, Imori T, Matsumoto K (1979) Hormonal regulation of activities of 17β-ol-dehydrogenases, aromatase, and 4-ene-5α-reductase in immature rat ovaries. J Steroid Biochem 11:1421–1427
Ueyama T, Shirasawa N, Mtasuzawa M, Yamada K, Shelangouski M et al (2002) Gastric parietal cells: potent endocrine role in secreting estrogen as a possible regulator of gastro-hepatic axis. Endocrinology 143:3162–3170
Ueyama T, Shirasawa N, Ito T, Tsuruo Y (2004) Estrogen-producing steroidogenic pathways in parietal cells of the rat gastric mucosa. Life Sci 74:2327–2337
Kobayashi H, Yoshida S, Sun YJ, Shirasawa N, Naito A (2013) Gastric estrogen increases pituitary estrogen receptor α and prolactin mRNAs during the different pathological conditions of the liver. Endocrine 43:170–183
Kobayashi H, Yoshida S, Sun YJ, Shirasawa N, Naito A (2013) Postnatal development of gastric aromatase and portal venous estradiol-17β levels in male rats. J Endocrinol 218:117–124
Kobayashi H, Yoshida S, Sun YJ, Shirasawa N, Naito A (2013) Gastric E2 and liver ERα correlate to serum E2 in the cholestatic male rat. J Endocrinol 219:39–49
Kobayashi H, Yoshida S, Sun YJ, Shirasawa N, Naito A (2014) Changes of gastric aromatase and portal venous 17β-estradiol during the postnatal development and estrus cycle in female rats. Endocrine 46:605–614
Izawa M, Inoue M, Osaki M, Ito H, Harada T et al (2008) Cytochrome P450 aromatase gene (CYP19) expression in gastric cancer. Gastric Cancer 11:103–110
Hori T, Ide M, Miyake T (1968) Ovarian estrogen secretion during the estrous cycle and under the influence of exogenous gonadotropins in rats. Endocrinol Jpn 15:215–222
Yoshinaga K, Hawkins RA, Stocker JF (1969) Estrogen secretion by the rat ovary in vivo during the estrous cycle and pregnancy. Endocrinology 85:103–112
Brown-Grant K, Exley D, Naftolin F (1970) Peripheral plasma oestradiol and luteinizing hormone concentrations during the oestrous cycle of the rat. J Endocrinol 48:295–296
Shaikh AA (1971) Estrone and estradiol levels in the ovarian venous blood from rats during the estrous cycle and pregnancy. Biol Reprod 5:297–307
Dupon C, Kim MH (1973) Peripheral plasma levels of testosterone, androstenedione, and oestradiol during the rat oestrous cycle. J Endocrinol 59:653–654
Butcher RL, Collins WE, Fugo NW (1974) Plasma concentration of LH, FSH, prolactin, progesterone and estradiol-17beta throughout the 4-day estrous cycle of the rat. Endocrinology 94:1704–1708
Hawkins RA, Freedman B, Marshall A, Killen E (1975) Oestradiol-17 beta and prolactin levels in rat peripheral plasma. Br J Cancer 32:179–185
Waxman DJ (1988) Interactions of hepatic cytochrome P450 with steroid hormones: regioselectitivity and stereospecificity of steroid metabolism and hormonal regulation of rat P450 enzyme expression. Biochem Pharmacol 37:71–84
Mode A, Wiersma-Lasson E, Ström A, Zaphiropoulos PG, Gustaffson JÅ (1989) A dual role of growth hormone as a feminizing and masculinizing factor in the control of sex-specific cytochrome P450 enzymes in rat liver. Endocrinology 120:311–317
Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R et al (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1–42
Livak KJ, Schmitten TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)). Method 25:402–408
Van Thiel DH, Gavaler JS, Zajko AB, Cobb CF (1985) Consequences of complete bile-duct ligation on the pubertal process in the male rat. J Pediatr Gastroenterol Nutr 4:616–621
Dueland S, Reichen J, Everson GT, Davis RA (1991) Regulation of cholesterol and bile acid homoeostasis in bile-obstructed rats. Biochem J 280:373–377
Thiesson HC, Jensen BL, Bistrup C, Ottosen PD, McNeilly AD et al (2007) Renal sodium retention in cirrhotic rats depends on glucocorticoid-mediated activation of mineralocorticoid receptor due to decreased renal 11beta-HSD-2 activity. Am J Physiol Regul Integr Comp Physiol 292:R625–R636
Marr W, White JO, Elder MG, Lim L (1980) Nucleo-cytoplasmic relationships of oestrogen receptors in rat liver during the oestrous cycle and in response to administered natural and synthetic oestrogen. Biochem J 190:17–25
Lax ER, Tamulevicius P, Müller A, Schriefers H (1983) Hepatic nuclear estrogen receptor concentrations in the rat—influence of age, sex, gestation, lactation and estrous cycle. J Steroid Biochem 19:1083–1088
Chico Y, Fresnedo O, Botham K, Lacort M, Ochoa B (1996) Regulation of bile acid synthesis by estradiol and progesterone in primary cultures of rat hepatocytes. Exp Clin Endocrinol 104:137–144
MacGeoch C, Morgan ET, Gustafsson J-Å (1985) Hypothalamo-pituitary regulation of cytochrome P-45015b apoprotein levels in rat liver. Endocrinology 117:2085–2092
Zaphiropoulos PG, Mode A, Ström A, Möller C, Fernandez C et al (1988) cDNA cloning, sequence, and regulation of a major female-specific and growth hormone-inducible rat liver cytochrome P-450 active in 15b-hydroxylation of steroid sulfates. Proc Natl Acad Sci USA 85:4214–4217
Ozawa M, Takahashi K, Akazawa KH, Takashima T, Nagata H et al (2011) PET of aromatase in gastric parietal cells using 11C-vorozole. J Nucl Med 52:1964–1969
Cho LY, Yang JJ, Ko KP, Ma SH, Shin A et al (2012) Genetic susceptibility factors on genes involved in the steroid hormone biosynthesis pathway and progesterone receptor for gastric cancer risk. PLoS One 7:e47603
Acknowledgments
We acknowledged to Mr. Nathan Strenge (Tokai University Yamagata Senior High School) for his suggestions and critically reading the manuscript. This work was supported by the Life Science Laboratory Research Grant (Grant Numbers K12G05, K13G05) and the Yuki Plan of Yamagata University (Grant Number DAY0010).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures were performed in accordance with the institutional guidelines, and approved by the animal research ethical committee at Yamagata University.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Kobayashi, H., Yoshida, S., Sun, YJ. et al. 17β-Estradiol in the systemic circulation derives mainly from the parietal cells in cholestatic female rats. J Endocrinol Invest 39, 389–400 (2016). https://doi.org/10.1007/s40618-015-0374-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40618-015-0374-8