Luteinizing Hormone Receptor Knockout (LuRKO) Mice and Transgenic Human Chorionic Gonadotropin (hCG)-Overexpressing Mice (hCG αβ+) Have Bone Phenotypes

Yarram, S. J.; Perry, Mark; Christopher, T. J.; Westby, Keith; Brown, Nathan; Lamminen, Tarja; Rulli, Susana B.; Zhang, F.-P.; Huhtaniemi, Ilpo; Sandy, JR; Mansell, JP

doi:10.1210/en.2003-0036

Cited by 47 publications

(34 citation statements)

References 26 publications

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“…Taken together these data indicated that all effects found on bone density in the WT and the two genetically modified mouse models could be explained by modifications of gonadal activity. Most conspicuously, the increase in BMD seen in hCGαβ+ females was totally abolished and reversed to the same low level as in ovariectomized WT females, despite the persistent elevation of hCG in TG females (Yarram et al, 2003). It is apparent that ovarian estrogen production was the main factor determining BMD in these models.…”

Section: Bone Phenotypes Of Lurko and Hcg Tg Micementioning

confidence: 81%

“…Letters ns in the hCGαβ+ ovx bar denotes that significant differences between the WT ovx and hCGαβ+ ovx groups were not found. Modified from Yarram et al (2003).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, serum progesterone concentration was 40-100-fold and testosterone 3-8 fold elevated in adult hCGβ+ females (Rulli et al, 2002). Clear extragonadal phenotypes were also observed: the females developed obesity, pituitary macroprolactinomas, mammary gland adenocarcinomas, and their bone density was elevated (Rulli et al, 2002;Yarram et al, 2003) (see below). However, all the extragonadal phenotypes of the hCGβ+ females were abolished by gonadectomy, indicating that ovarian hyperstimulation A c c e p t e d M a n u s c r i p t and abnormal gonadal hormone production, rather than direct extragonadal hCG effects, was responsible for the extragonadal phenotypes observed in the hCGβ+ females ( Figs.…”

Section: Hcg Overexpressing Transgenic Micementioning

confidence: 96%

“…There are data on LHR expression in the bone based on Western blotting, immunolocalization and RT-PCR of mouse osteoblasts (Yarram et al, 2003). However, these studies were unable to show specific binding of iodinated hCG or hCG-stimulation of cAMP or phospohorylated ERK1/2, which findings left the functional significance of the positive findings open.…”

Section: Bone Phenotypes Of Lurko and Hcg Tg Micementioning

confidence: 99%

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Extragonadal LH/hCG action—Not yet time to rewrite textbooks

Pakarainen¹,

Ahtiainen²,

Zhang³

et al. 2007

Molecular and Cellular Endocrinology

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Please cite this article as: Pakarainen, T., Ahtiainen, P., Zhang, F.-P., Rulli, S., Poutanen, M., Huhtaniemi, I., Extragonadal LH/hCG action -not yet time to rewrite textbooks, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t AbstractGonadotropins are indispensable in both sexes in the regulation of gonadal sex steroid production and gametogenesis. In addition to their well established classical actions, numerous recent publications have indicated the presence and function of luteinizing hormone/chorionic gonadotropin receptors (LH/hCG-R) in a variety of extragonadal tissues. However, the physiological significance of such effects has remained unclear. We have generated two genetically modified mouse models, one with excessive production of hCG and the other with targeted disruption of LH/hCG-R gene, and used them to address the functions of LH and hCG.Numerous gonadal and extragonadal phenotypes were found in the models with the two extremes of LH/hCG action. However, when the extragonadal effects were scrutinized in greater detail, they all appeared to arise through modification of gonadal function, either through enhanced or inhibited response to LH/hCG stimulation. Hence, further evidence is needed before the extragonadal LH/hCG-R expression can be considered functionally significant.

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Section: Bone Phenotypes Of Lurko and Hcg Tg Micementioning

confidence: 81%

“…Letters ns in the hCGαβ+ ovx bar denotes that significant differences between the WT ovx and hCGαβ+ ovx groups were not found. Modified from Yarram et al (2003).…”

Section: Discussionmentioning

confidence: 99%

Section: Hcg Overexpressing Transgenic Micementioning

confidence: 96%

Section: Bone Phenotypes Of Lurko and Hcg Tg Micementioning

confidence: 99%

See 2 more Smart Citations

Extragonadal LH/hCG action—Not yet time to rewrite textbooks

Pakarainen¹,

Ahtiainen²,

Zhang³

et al. 2007

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

show abstract

“…Transgenic mice over-expressing LH but with silenced receptors did not show cognitive impairment in the Ymaze task suggesting receptor-mediated effect of LH on these behaviors (Casadesus et al, 2007). However, LH can exert some of its affects via mechanisms independent of the LH receptor and traditional downstream signaling mechanisms (West and Cook, 1992;Yarram et al, 2003). Whether or not these receptor-independent effects play a roll in this system is yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-β levels in female rats

Berry

Tomidokoro

Ghiso

et al. 2008

Hormones and Behavior

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Numerous studies have suggested that estradiol (E) improves spatial memory as female rats with E perform better than those without E. However there is an inverse relationship between E and luteinizing hormone (LH) levels and LH could play a role. We examined whether treatment with the LH homologue human chorionic gonadotropin (hCG), would impair spatial memory of adult Etreated female rats. In the Object Location Memory Task, ovariectomized (ovxed) rats treated with E and either a single high dose (400IU/kg) or a lower repeated dose of hCG (75 IU/kg hourly for 8 hours) showed spatial memory disruption compared to ovxed rats treated with estradiol alone. Impairment was attributed to memory disruption as performance improved with shortened delay between task exposure and testing. Tests on another spatial memory task, the Barnes maze, confirmed that hCG (400IU/kg) can impair memory: although E + veh treated animals made significantly fewer hole errors across time, E + hCG treated did not. In humans, high LH levels have been correlated with Alzheimer's Disease (AD). Because brain amyloid-beta (Aβ) species have been implicated as a toxic factor thought to cause memory loss in AD, we analyzed whether hCG-treated animals had increased Aβ levels. Levels of Aβ from whole brains or hippocampi were assessed by Western Blot. hCG treatment to E-implanted females significantly increased soluble Aβ40 and Aβ42 levels. These results indicate that high levels of LH/hCG can impair spatial memory, and an increase in brain Aβ species may account for the memory impairment in hCG-treated rats.

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Reproductive Hormones and Longitudinal Change in Bone Mineral Density and Incident Fracture Risk in Older Men: The Concord Health and Aging in Men Project

Hsu

Cumming

Seibel

et al. 2015

Journal of Bone and Mineral Research

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The objectives of this study were to examine relationships between baseline levels of reproductive hormones in older men and (1) change in bone mineral density (BMD) over 5 years and (2) incident fractures over an average of 6 years' follow-up. A total of 1705 men aged 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005)(2006)(2007), 2 years follow-up (2007)(2008)(2009), and 5 years follow-up (2010-2013). At baseline, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by immunoassay. Hip BMD was measured by dual X-ray absorptiometry (DXA) at all three time-points. Fracture data were collected at 4-monthly phone calls and verified radiographically. Statistical modeling was by general estimating equations and Cox model regression. Univariate analyses revealed inverse associations for serum SHBG, FSH, and LH and positive association for E1 but not DHT or E2 with BMD loss at the hip across the three time points. Serum levels of SHBG (b ¼ -0.071), FSH (b ¼ -0.085), LH (b ¼ -0.070), and E1 (b ¼ 0.107) remained significantly associated with BMD loss in multivariate-adjusted models; however, we were unable to identify any thresholds for accelerated BMD loss according to reproductive steroids. Incident fractures (all, n ¼ 171; hip, n ¼ 44; and nonvertebral, n ¼ 139) were all significantly associated with serum SHBG, FSH, and LH levels in univariate models but none remained significantly associated in multivariate-adjusted model. Serum T, DHT, E2, and E1 levels were not associated with incident fractures in univariate or multivariate-adjusted analyses. In older men, lower serum SHBG, FSH, and LH and higher E1 levels protected against loss of BMD without increasing fracture rate. This means these reproductive variables may be considered as novel biomarkers of bone health during male aging.

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Luteinizing Hormone Receptor Knockout (LuRKO) Mice and Transgenic Human Chorionic Gonadotropin (hCG)-Overexpressing Mice (hCG αβ+) Have Bone Phenotypes

Cited by 47 publications

References 26 publications

Extragonadal LH/hCG action—Not yet time to rewrite textbooks

Extragonadal LH/hCG action—Not yet time to rewrite textbooks

Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-β levels in female rats

Reproductive Hormones and Longitudinal Change in Bone Mineral Density and Incident Fracture Risk in Older Men: The Concord Health and Aging in Men Project

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