title: An investigation into pituitary gonadotrophic hormone synthesis, secretion, subunit gene expression and cell structure in normal and mutant male mice.
abstract: To investigate brain-pituitary-gonadal inter-relationships, we have compared the effects of mutations that perturb the hypothalamic-pituitary-gonadal axis in male mice. Specifically, serum and pituitary gonadotrophin concentrations, gonadotrophin gene expression, and gonadotroph structure and number were measured. Follicle-stimulating hormone (FSH)β knockout (FSHβKO), FSH receptor knockout (FSHRKO), luteinising hormone (LH) receptor knockout (LuRKO), hypogonadal (hpg), testicular feminised (tfm) and gonadectomised mice were compared with control wild-type mice or heterozygotes. Serum levels of LH were similar in FSHβKO, FSHRKO and heterozygote males despite decreased androgen production in KO males. As expected, there was no detectable FSH in the serum or pituitary and an absence of expression of the FSHβ subunit gene in FSHβKO mice. However, there was a significant increase in expression of the common α and LHβ subunit genes in FSHRKO males. The morphology of FSHβKO and FSHRKO gonadotrophs was not significantly different from controls, except that the subpopulation of granules consisting of an electron-dense core and electron-lucent 'halo' was not observed in FSHβKO gonadotrophs and the granules were smaller in diameter. In the gonadotrophin-releasing hormone deficient hpg mouse, gonadotrophin mRNA and hormone levels were significantly lower compared to control mice and gonadotrophs were correspondingly smaller, with less abundant endoplasmic reticulum and reduced secretory granules. In LuRKO, tfm and gonadectomised mice, hyperstimulation of LHβ and FSHβ mRNA and serum protein concentrations was reflected by subcellular changes in gonadotroph morphology, including more dilated rough endoplasmic reticulum and more secretory granules distributed adjacent to the plasma membrane. In summary, major differences in pituitary content and serum concentrations of the gonadotrophins LH and FSH have been found between normal and mutant male mice. These changes are associated with changes in transcriptional activity of the gonadotrophin subunit genes and are reflected by changes in the cellular structure and secretory granule architecture within the gonadotroph cells.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Abel
authors.forename: H M
authors.initials: HM
authors.lastname: Charlton
authors.forename: I
authors.initials: I
authors.lastname: Huhtaniemi
authors.forename: P
authors.initials: P
authors.lastname: Pakarinen
authors.forename: T R
authors.initials: TR
authors.lastname: Kumar
authors.forename: H C
authors.initials: HC
authors.lastname: Christian
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D015870:Gene Expression; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D010902:Pituitary Gland / Q000378:metabolism*; D010907:Pituitary Hormones / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D010907:Pituitary Hormones
keywords: FSH; LH; anterior pituitary; gonadotrophs; ultrastructure
references.citation: Nature. 1970 Sep 19;227(5264):1217-9
references.pmid: 5452809
references.citation: Endocrinology. 1980 Jan;106(1):390-7
references.pmid: 6985587
references.citation: Somatic Cell Genet. 1983 Nov;9(6):757-70
references.pmid: 6581542
references.citation: Endocrinology. 1998 Jun;139(6):2765-73
references.pmid: 9607783
references.citation: Reproduction. 2005 Sep;130(3):293-302
references.pmid: 16123236
references.citation: Reprod Suppl. 2003;61:463-76
references.pmid: 14635955
references.citation: Reproduction. 2002 Aug;124(2):267-77
references.pmid: 12141940
references.citation: Recent Prog Horm Res. 1999;54:455-84; discussion 485
references.pmid: 10548887
references.citation: Recent Prog Horm Res. 1980;36:53-88
references.pmid: 6774388
references.citation: Endocrinology. 1991 Jan;128(1):459-66
references.pmid: 1986939
references.citation: Endocrinology. 2012 Nov;153(11):5105-18
references.pmid: 22989628
references.citation: Biol Reprod. 2000 Apr;62(4):886-94
references.pmid: 10727257
references.citation: Endocrinology. 1980 May;106(5):1442-50
references.pmid: 6988207
references.citation: J Endocrinol. 1986 Apr;109(1):35-44
references.pmid: 3517215
references.citation: J Mol Endocrinol. 2004 Apr;32(2):467-80
references.pmid: 15072552
references.citation: Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8606-10
references.pmid: 1924321
references.citation: Endocrinology. 2004 Jan;145(1):318-29
references.pmid: 14551232
references.citation: J Endocrinol. 1982 Dec;95(3):321-30
references.pmid: 6816887
references.citation: Mol Endocrinol. 2004 Apr;18(4):925-40
references.pmid: 14701939
references.citation: Endocrinology. 2005 Feb;146(2):596-606
references.pmid: 15514086
references.citation: Nature. 1977 Sep 22;269(5626):338-40
references.pmid: 198666
references.citation: Science. 1986 Dec 12;234(4782):1372-8
references.pmid: 3097822
references.citation: Reproduction. 2004 Jul;128(1):43-52
references.pmid: 15232063
references.citation: Endocrinology. 1972 Oct;91(4):910-5
references.pmid: 5065813
references.citation: Nat New Biol. 1971 Jul 7;232(27):5-7
references.pmid: 5284427
references.citation: Endocrinology. 1993 Apr;132(4):1687-91
references.pmid: 8462469
references.citation: Histochemistry. 1991;96(4):285-93
references.pmid: 1723974
references.citation: Endocrinology. 2003 Jan;144(1):138-45
references.pmid: 12488339
references.citation: Endocrinology. 2000 May;141(5):1795-803
references.pmid: 10803590
references.citation: Mol Endocrinol. 2001 Sep;15(9):1505-16
references.pmid: 11518799
references.citation: Genes Dev. 1995 Aug 15;9(16):2007-19
references.pmid: 7544315
references.citation: Annu Rev Biochem. 1981;50:465-95
references.pmid: 6267989
references.citation: J Endocrinol. 1973 Sep;58(3):357-62
references.pmid: 4743527
references.citation: Mol Endocrinol. 1989 Nov;3(11):1748-56
references.pmid: 2514347
references.citation: J Neuroendocrinol. 2007 Aug;19(8):605-13
references.pmid: 17620102
references.citation: Mol Endocrinol. 2001 Nov;15(11):1906-17
references.pmid: 11682622
references.citation: Results Probl Cell Differ. 2008;46:117-43
references.pmid: 18193176
references.citation: Mol Endocrinol. 2001 Jan;15(1):172-83
references.pmid: 11145748
references.citation: Biol Reprod. 2002 Apr;66(4):966-75
references.pmid: 11906915
references.citation: Nat Genet. 1997 Feb;15(2):201-4
references.pmid: 9020850
references.citation: Nature. 1975 Dec 18;258(5536):620-2
references.pmid: 1207739
references.citation: Endocrinology. 1984 Jul;115(1):106-13
references.pmid: 6329642