Leydig-Cell Tumors Caused by an Activating Mutation of the Gene Encoding the Luteinizing Hormone Receptor

Liu, Guoquan; Duranteau, Lise; Carel, Jean Claude; Monroe, Jason A.; Doyle, Daniel A.; Shenker, Andrew

doi:10.1056/nejm199912023412304

Cited by 249 publications

(147 citation statements)

References 32 publications

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“…Analysis of the major signaling pathways in HEK and COS-7 cells demonstrated that YHR, rat D556H LHR and human D578H LHR increased the basal levels of cAMP and were unresponsive to exogenous hCG (Wu et al, 1996;Liu et al, 1999;Angelova et al, 2002). The level of constitutive activity exhibited by YHR and D556H LHR are similar (Fig.…”

Section: In Vitro Bioactivity Of D556h Lhr and Yhrmentioning

confidence: 77%

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Constitutively active luteinizing hormone receptors: Consequences of in vivo expression

Meehan¹,

Narayan²

2007

Molecular and Cellular Endocrinology

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Activating mutations in the luteinizing hormone receptor (LHR) gene are one of the most common mutations found in the gonadotropin receptor genes. Human males with these mutations exhibit precocious puberty while females do not have an obvious phenotype. To better understand the pathophysiology of premature LHR activation, transgenic mice have been generated with an activating mutation in LHR and a genetically engineered ligand-activated LHR. This review will summarize the major findings obtained with these two genetically modified mouse models and briefly discuss the similarities and differences between them and with the human phenotype.

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Section: In Vitro Bioactivity Of D556h Lhr and Yhrmentioning

confidence: 77%

“…Females with the activating mutations do not have an apparent phenotype. A particularly potent activating somatic mutation (D578H) has been identified in boys with testicular adenomas wherein the mutation is limited to the adenoma and not the surrounding normal tissue (Liu et al, 1999;Canto et al, 2001;Richter-Unruh et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Constitutively active luteinizing hormone receptors: Consequences of in vivo expression

Meehan¹,

Narayan²

2007

Molecular and Cellular Endocrinology

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“…Interestingly, activating mutations of G i2 have been found in a subset of ovarian sex cord stromal tumors and adrenal cortical tumors (Lyons et al, 1990). In addition, an activating somatic mutation of the LHR gene, with preferential stimulation of inositol trisphosphate production, has been shown to be associated with human Leydig cell tumors (Liu et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…There are also data showing that ovarian stimulation with gonadotropins is associated with an increased incidence of granulosa cell tumors (Willemsen et al, 1993). In addition, certain activating mutations of the LH receptor (LHR) gene have been shown to cause Leydig cell tumors in humans (Liu et al, 1999), while the results of in vitro studies have demonstrated that LH and FSH can stimulate the growth of human ovarian carcinoma cells (Simon et al, 1983;Wimalasena et al, 1992). In line with these results, a modest clinical response has been observed in the treatment of certain types of ovarian cancer with gonadotropin-releasing hormone (GnRH) analogs (Adelson and Reece, 1993).…”

Section: Introductionmentioning

confidence: 99%

High levels of luteinizing hormone analog stimulate gonadal and adrenal tumorigenesis in mice transgenic for the mouse inhibin-α-subunit promoter/Simian virus 40 T-antigen fusion gene

et al. 2003

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Transgenic (TG) mice expressing the Simian virus 40 T-antigen under the control of the murine inhibin-a promoter (Inha/Tag) develop granulosa and Leydig cell tumors at the age of 5-6 months, with 100% penetrance. When these mice are gonadectomized, they develop adrenocortical tumors. Suppression of gonadotropin secretion inhibits the tumorigenesis in the gonads of intact animals and in the adrenals after gonadectomy. To study further the role of luteinizing hormone (LH) in gonadal and adrenal tumorigenesis, a double TG mouse model was generated by crossing the Inha/Tag mice with mice producing constitutively elevated levels of LH (bLHb-CTP mice). Our results show that in double TG mice (bLHb-CTP/Inha/Tag), gonadal tumorigenesis starts earlier and progresses faster than in Inha/Tag mice. Both ovarian and testicular tumors were histologically comparable with the tumors found in Inha/Tag mice. In addition, adrenal tumorigenesis was found in intact double TG females, but not in Inha/Tag females. Inhibin-a and LH receptor (LHR) were highly expressed in tumorigenic gonadal tissues, and the elevated LH levels were shown to be associated with ectopic LHR and high inhibin-a expression in the female adrenals. We conclude that in the Inha/Tag tumor mouse model, elevated LH levels act as a tumor promoter, advancing gonadal and adrenal tumorigenesis.

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“…Asp578Gly is one of the most common activating mutations found in the LH receptor gene (Shenker et al 1993, Laue et al 1995, while tyrosine (Tyr) or glutamate (Glu) at this position also cause precocious puberty (Laue et al 1995(Laue et al , 1996. However, Asp578His causes Leydig cells to undergo transformation and their increased growth results in adenoma formation (Liu et al 1999). Interestingly, this mutation appears only to occur somatically, i.e.…”

Section: Activating Lh Receptor Mutationsmentioning

confidence: 99%

An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms

Themmen¹

2005

Reproduction

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New information about mutations and polymorphisms in the genes for the gonadotrophins and their receptors has become available in the last few years. In this short review mutations and polymorphisms in gonadotrophins, their receptors and their patho-physiological effects and implications are discussed. An increasingly clear picture about the structure -function relationships of gonadotrophin action is emerging from the combining the types and the locations of the mutations with their phenotypic effects and the information about the crystal structure of these molecules.

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Leydig-Cell Tumors Caused by an Activating Mutation of the Gene Encoding the Luteinizing Hormone Receptor

Cited by 249 publications

References 32 publications

Constitutively active luteinizing hormone receptors: Consequences of in vivo expression

Constitutively active luteinizing hormone receptors: Consequences of in vivo expression

High levels of luteinizing hormone analog stimulate gonadal and adrenal tumorigenesis in mice transgenic for the mouse inhibin-α-subunit promoter/Simian virus 40 T-antigen fusion gene

An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms

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