title: Enhanced LH action in transgenic female mice expressing hCGbeta-subunit induces pituitary prolactinomas; the role of high progesterone levels.
abstract: The etiology of pituitary adenomas remains largely unknown, with the exception of involvement of estrogens in the formation of prolactinomas. We have examined the molecular pathogenesis of prolactin-producing pituitary adenomas in transgenic female mice expressing the human choriongonadotropin (hCG) beta-subunit. The LH/CG bioactivity is elevated in the mice, with consequent highly stimulated ovarian progesterone (P(4)) production, in the face of normal estrogen secretion. Curiously, despite normal estrogen levels, large prolactinomas developed in these mice, and we provide here several lines of evidence that the elevated P(4) levels are involved in the growth of these estrogen-dependent tumors. The antiprogestin mifepristone inhibited tumor growth, and combined postgonadectomy estradiol/P(4) treatment was more effective than estrogen alone in inducing tumor growth. Evidence for direct growth-promoting effect of P(4) was obtained from cultures of primary mouse pituitary cells and rat somatomammotroph GH3 cells. The mouse tumors and cultured cells revealed stimulation of the cyclin D1/cyclin-dependent kinase 4/retinoblastoma protein/transcription factor E2F1 pathway in the growth response to P(4). If extrapolated to humans, and given the importance of endogenous P(4) and synthetic progestins in female reproductive functions and their pharmacotherapy, it is relevant to revisit the potential role of these hormones in the origin and growth of prolactinomas.
authors.affiliation: Department of Physiology Turku Graduate School of Biomedical Science, University of Turku, FIN-20520 Turku, Finland.
authors.forename: Petteri
authors.initials: P
authors.lastname: Ahtiainen
authors.forename: Victoria
authors.initials: V
authors.lastname: Sharp
authors.forename: Susana B
authors.initials: SB
authors.lastname: Rulli
authors.forename: Adolfo
authors.initials: A
authors.lastname: Rivero-Müller
authors.forename: Veronika
authors.initials: V
authors.lastname: Mamaeva
authors.forename: Matias
authors.initials: M
authors.lastname: Röyttä
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D005260:Female; D007986:Luteinizing Hormone / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000097:blood*; D011388:Prolactin / Q000097:blood; D015175:Prolactinoma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018997:Chorionic Gonadotropin, beta Subunit, Human; D011374:Progesterone; D011388:Prolactin; D007986:Luteinizing Hormone; D051358:Cyclin-Dependent Kinase 4
references.citation: Endocrinology. 1998 Apr;139(4):1602-9
references.pmid: 9528940
references.citation: Science. 1966 Oct 21;154(3747):402-3
references.pmid: 4288164
references.citation: Endocrinology. 2002 Dec;143(12):4536-43
references.pmid: 12446580
references.citation: Arch Pathol Lab Med. 1983 Sep;107(9):488-91
references.pmid: 6309114
references.citation: Cancer Cell. 2006 Jun;9(6):459-71
references.pmid: 16766265
references.citation: Endocrinology. 1970 Mar;86(3):503-5
references.pmid: 5410438
references.citation: J Cell Sci Suppl. 1994;18:89-96
references.pmid: 7883799
references.citation: Front Horm Res. 2004;32:34-62
references.pmid: 15281339
references.citation: Endocrinology. 2002 Oct;143(10):4084-95
references.pmid: 12239120
references.citation: J Biol Chem. 2002 Sep 27;277(39):35819-25
references.pmid: 12121979
references.citation: J Endocrinol. 1973 Feb;56(2):309-14
references.pmid: 4703244
references.citation: J Mammary Gland Biol Neoplasia. 1998 Jan;3(1):63-72
references.pmid: 10819505
references.citation: Acta Endocrinol (Copenh). 1993 Jul;129 Suppl 1:1-5
references.pmid: 8396832
references.citation: J Biol Chem. 1996 Aug 23;271(34):20608-16
references.pmid: 8702807
references.citation: J Reprod Med. 1999 Dec;44(12 Suppl):1121-6
references.pmid: 10649822
references.citation: Cancer Res. 1985 Mar;45(3):1015-9
references.pmid: 2982481
references.citation: Endocr Relat Cancer. 2009 Mar;16(1):113-22
references.pmid: 18852162
references.citation: Nat Genet. 1998 Apr;18(4):360-4
references.pmid: 9537419
references.citation: J Biol Chem. 1982 Mar 10;257(5):2133-6
references.pmid: 7061411
references.citation: Hum Reprod. 1994 Jun;9 Suppl 1:63-8
references.pmid: 7962471
references.citation: Horm Metab Res. 2008 Apr;40(4):245-50
references.pmid: 18548383
references.citation: Nature. 1992 Sep 24;359(6393):295-300
references.pmid: 1406933
references.citation: Mol Cell Biol. 2004 Aug;24(16):7260-74
references.pmid: 15282324
references.citation: J Clin Endocrinol Metab. 2006 Dec;91(12):4769-75
references.pmid: 16968795
references.citation: Cell Cycle. 2008 Jan 1;7(1):71-80
references.pmid: 18196959
references.citation: Genes Dev. 1998 Sep 15;12(18):2899-911
references.pmid: 9744866
references.citation: Endocrinology. 2005 Nov;146(11):4917-25
references.pmid: 16123159
references.citation: Endocrinology. 1991 Jul;129(1):270-6
references.pmid: 1711463
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1034-9
references.pmid: 12552124
references.citation: Eur J Endocrinol. 2008 Sep;159(3):197-202
references.pmid: 18567667
references.citation: J Endocrinol. 1996 Nov;151(2):175-84
references.pmid: 8958777
references.citation: J Clin Endocrinol Metab. 2000 Jan;85(1):168-74
references.pmid: 10634382
references.citation: Endocrinology. 2001 Oct;142(10):4479-85
references.pmid: 11564713
references.citation: Adv Exp Med Biol. 1981;138:151-63
references.pmid: 7342713
references.citation: Oncogene. 2005 Nov 10;24(49):7301-9
references.pmid: 16007123
references.citation: J Endocrinol. 1989 Jun;121(3):409-17
references.pmid: 2547009
references.citation: J Clin Invest. 2002 Jan;109(2):277-83
references.pmid: 11805140
references.citation: Endocrinology. 1976 Dec;99(6):1482-9
references.pmid: 826392
references.citation: J Neuroendocrinol. 2001 Mar;13(3):302-9
references.pmid: 11207946
references.citation: Cancer Res. 1995 Nov 1;55(21):4892-8
references.pmid: 7585526
references.citation: Cancer Res. 1993 Apr 1;53(7):1546-9
references.pmid: 8453621
references.citation: EMBO J. 1998 Apr 1;17(7):2008-18
references.pmid: 9524123