Disease relevance of Lhb

• An analysis of NGFI-A-deficient mice derived from embryonic stem cells demonstrated female infertility that was secondary to LH-beta deficiency [1].
• To further explore the role of gonadotropins in promoting amyloidogenesis, M17 neuroblastoma cells were treated with the gonadotropin luteinizing hormone (LH) at concentrations equivalent to early adulthood (10 mIU/ml) or post-menopause/andropause (30 mIU/ml) [2].
• Epidemiological support for a role of LH/GnRH in AD is evidenced by a reduction in neurodegenerative disease among prostate cancer patients a group known to GnRH agonists [3].
• In humans, increased LH secretion also occurs in infertility and polycystic ovarian syndrome, often concomitant with adrenocortical dysfunction [4].
• Thus, besides polycystic ovaries, the bLHbeta-CTP mice provide a useful model for studying human disorders related to elevated LH secretion and adrenocortical hyperfunction [4].

Psychiatry related information on Lhb

• LH is known to cross the blood-brain barrier, receptors for LH are most concentrated in the hippocampus, that region of the brain most vulnerable to Alzheimer's disease (AD) and LH is significantly elevated in both the serum and the pyramidal neurons of AD subjects [3].
• We tested the effects of icv GALP infusions on LH release, locomotor activity, motor control, and body weight regulation in adult ovariectomized female mice hormonally primed with estradiol benzoate and progesterone [5].

High impact information on Lhb

• Minimal data has been accumulated so far involving human mutations in the FSH beta, LH beta, or the gonadotropin receptor genes [6].
• Follicle stimulating hormone (FSH) is a member of the glycoprotein hormone family that includes luteinzing hormone (LH), thyroid stimulating hormone, and chorionic gonadotropin [6].
• Rare inactivating mutations that produce distinctive phenotypes of isolated LH or FSH deficiency have been discovered in gonadotropin subunit genes [7].
• In addition, there is a common polymorphism in the LHbeta subunit gene with possible clinical significance as a contributing factor to pathologies of LH-dependent gonadal functions [7].
• NGFI-A apparently influences female reproductive capacity through its regulation of LH-beta transcription [1].

Chemical compound and disease context of Lhb

• We have previously shown that early growth response (Egr) 1-deficient mice exhibit female infertility, reflecting a luteinizing hormone (LH) beta deficiency [8].
• Previously, it was shown that female LHbetaCTP mice are infertile due to anovulation, develop granulosa cell tumors, and undergo precocious puberty from elevated LH and steroid hormones that fail to completely repress the alpha-subunit promoter [9].
• Biologically active luteinizing hormone (LH) in Klinefelter's syndrome: response to gonadotropin-releasing hormone (GnRH) and effects of testosterone undecanoate [10].
• These findings indicate that LH isoforms may regulate kidney growth in the male mouse both directly as a renotropin stimulating hyperplasia and indirectly as a gonadotropin via testicular androgen, producing cellular hypertrophy [11].

Biological context of Lhb

• Egr1 regulates luteinizing hormone beta subunit (LHbeta) gene expression in the pituitary gland [12].
• A steroidogenic factor-1 binding site is required for activity of the luteinizing hormone beta subunit promoter in gonadotropes of transgenic mice [13].
• By transient transfection assay in pituitary-derived GH3 cells, it was seen that Egr-1 increases promoter activity of region -207/+5 of the rat LHbeta gene promoter through action at both Egr-1 sites [14].
• NAB coactivation requires the conserved NCD2 protein domain, previously implicated in NAB corepression, is strictly dependent upon EGR binding to the LHbeta proximal promoter and is independent of EGR activation domains [15].
• Interaction between SF-1 and this putative response element in the bovine LH beta promoter was confirmed by electrophoretic mobility shift assays [13].

Anatomical context of Lhb

• However, following gonadectomy, INH(-/-)-LH-CTP mice develop large, sex steroid-producing adrenal tumors that arise from the x zone, indicating a growth-promoting effect of high levels of LH on the adrenal cortex in the absence of ovarian tumors [16].
• This paper presents functional characterization of a L beta T2 gonadotrope cell line generated by tumorigenesis in transgenic mice carrying the rat LH beta-subunit regulatory region linked to the SV40 T-antigen oncogene [17].
• 3) In contrast to the thecal layer, granulosa cell populations in FSHbeta knockout mice do not accumulate LH receptor mRNA [18].
• These data show for the first time that Ca/CaMK II activation plays an important role in the transmission of GnRH signals from the plasma membrane to the LH subunit genes [19].
• Luteinizing hormone (LH) released from anterior pituitary gland and human chorionic gonadotropin released from placenta (hCG) can upregulate the uterine Cox2 gene expression [20].

Associations of Lhb with chemical compounds

• These data were corroborated by assessing plasma levels of the respective peptide and steroid hormones. alphaERKO and alphabetaERKO females exhibited increased pituitary Cga and Lhb expression and increased plasma LH levels, whereas both were normal in betaERKO [21].
• Although activins and inhibins regulate follicle-stimulating hormone (FSH) synthesis, no factor has been identified that exclusively regulates luteinizing hormone (LH) synthesis [1].
• Due to decreased levels of LHbeta, female Egr1-deficient mice are anovulatory, have low levels of progesterone, and are infertile [12].
• This dose of T, however, had little effect on LH in mice with a blank pellet in the AH [22].
• In mice treated with melatonin the physiological dose of T significantly reduced the concentrations of LH in blood and pituitary (P less than 0.05) [22].

Physical interactions of Lhb

• Steroidogenic factor-1 and early growth response protein 1 act through two composite DNA binding sites to regulate luteinizing hormone beta-subunit gene expression [14].
• We have previously demonstrated the ability of SF-1 to bind to and transactivate the rat LHbeta gene promoter acting at a consensus gonadotrope-specific element (GSE) located at position -127 [14].
• Embryonic expression of the luteinizing hormone beta gene appears to be coupled to the transient appearance of p8, a high mobility group-related transcription factor [23].
• Furthermore, we report that NAB-activated promoters such as LHbeta contain EGR consensus sites that are fewer in number and lower in binding affinity than those found at NAB-repressed promoters such as basic fibroblast growth factor [15].
• Complete recovery of testicular LH binding was obtained by daily administration of prolactin (500 micrograms/mouse) when given simultaneously from day 9 of PCA treatment [24].

Regulatory relationships of Lhb

• Addition of MIS to LbetaT2 cells stimulates the activity of the rat LHbeta gene promoter with as little as 1 microg/ml and in a dose-dependent manner [25].
• Thus, Egr-1 is a likely transcriptional mediator of GnRH-induced signals for activation of the LHbeta gene [26].
• LH promotes the amyloidogenic processing of the amyloid-beta precursor protein in vitro, and the antigonadotropin leuprolide acetate decreases amyloid generation in mice [3].
• These data demonstrate that both ERalpha and ERbeta are involved in inhibiting LH levels at times of estrogen-negative feedback in vivo [27].
• We also explored whether the MC4 receptor participates in tonic stimulation of steroid-induced LH and PRL surges [28].

Other interactions of Lhb

• Ovariectomy led to increased amounts of FSH-beta but not LH-beta messenger RNA, which suggested a pituitary defect [1].
• These results elucidate a novel level of redundancy between Egr4 and Egr1 in regulating LH production in male mice [12].
• These cells synthesize alpha-subunit and gonadotropin-releasing hormone (GnRH) receptor, yet are not fully differentiated in that they do not synthesize the beta-subunits of luteinizing hormone (LH) or follicle-stimulating hormone (FSH) [29].
• Stimulation of luteinizing hormone beta gene promoter activity by the orphan nuclear receptor, steroidogenic factor-1 [30].
• The absence of detectable transcripts for alpha-subunit, TSH beta-subunit, or LH beta-subunit by in situ hybridization confirmed that ablation was complete [31].

Analytical, diagnostic and therapeutic context of Lhb

• Sequence analysis of the rat luteinizing hormone beta-subunit (LH beta) gene promoter revealed the presence of a consensus GSE at -127 to -119 (TGACCTTGT) [30].
• Castration increased LH levels [32].
• A sensitive in vitro bioassay, based upon testosterone production by mechanically dispersed mouse Leydig cells, was employed to assess LH biological activity [33].
• Levels of immunoreactive LH (RIA-LH) and basal testosterone (T) concentrations were determined by a double antibody radioimmunoassay technique [33].
• Pituitary mRNA expression levels of luteinizing hormone-beta (LHbeta), PRL and GH were quantified using real-time TaqMan RT-PCR [34].

References