Ovarian stimulation and granulosa-cell tumour

Willemsen, W.N.P.; Kruitwagen, Roy F.P.M.; Bastiaans, L.A.; Rolland, R.; Hanselaar, A. G. J. M.

doi:10.1016/0140-6736(93)91071-s

Cited by 127 publications

(34 citation statements)

References 12 publications

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“…This is supported by epidemiological findings showing an increased incidence of ovarian cancer after menopause, when circulating gonadotropin levels are elevated (Wise et al, 1996). 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).…”

Section: Introductionsupporting

confidence: 69%

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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Section: Introductionsupporting

confidence: 69%

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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“…3D), indicating that stimulation of granulosa and other stromal cells by LH-CTP was tumorigenic. Gonadotropin hyperstimulation has been suggested as a mechanism for tumor formation in ovaries transplanted to the spleen in ovariectomized rats (25), in women undergoing ovarian stimulation for treatment of infertility (26), and in ovaries of inhibin-deficient mice (27). The tumors observed in each of these examples include granulosa cell and other stromal cell tumors.…”

Section: Methodsmentioning

confidence: 99%

Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors.

Risma

Clay

Nett

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

298

192

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Hypersecretion of luteinizing hormone (LH) is implicated in infertility and miscarriages in women. A lack of animal models has limited progress in determining the mechanisms of LH toxicity. We (7)], it is difficult to devise protocols for chronic administration of exogenous LH that mimic endogenous pulse patterns of LH. To circumvent this limitation, we report a transgenic mouse model in which elevated hormone levels are maintained chronically, without requiring multiple injections,The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. supraphysiologic dosing, or dampening of the hypothalamicpituitary-gonadal axis.We utilized a two-pronged approach to achieve elevated levels of serum LH. (i) Increased secretion of hormone from the pituitary was achieved by expression of an LH(3 subunit transgene, targeted to the pituitary by a previously characterized bovine a-subunit promoter (8,9). (ii) The LH,B transgene was modified to encode a peptide extension that we proposed would slow the elimination of LH from the serum. This peptide is normally found at the C terminus of the 3 subunit of human chorionic gonadotropin (hCG) (hCG,B) and is referred to as the C-terminal peptide (CTP) (10). The CTP is thought to be a major determinant of the serum t,'2 of hCG and has been shown to increase the til2 of FSH 2-to 3-fold when fused to its (3 subunit (11). Accordingly, we constructed a transgene with the coding region of bovine (b) LH,B fused in-frame to the coding region of CTP (bLH3-CTP). MATERIALS AND METHODSConstruction of the bLH3-CTP Transgene. The bLH,B-CTP minigene was engineered by a two-step PCR. (i) A short fragment containing the C terminus of bLH,B (30 bp) fused in-frame to the CTP (last 87 bp of the hCGj3 gene) was generated. (ii) This fragment was lengthened to contain the entire bLHf3 cDNA fused in-frame to the CTP. This fusion gene was utilized for transfection experiments but was modified to contain the first intron of bLH3 for the transgene construct. The resulting insert was ligated into a BSK-plasmid already containing the bovine a-subunit promoter (positions -315 to +45) and the simian virus 40 late polyadenylylation signal. Transgenic mice were generated by microinjecting the bLH3-CTP insert into fertilized oocytes as described (12). Mice were genotyped by PCR analysis of tail DNA using primers specific to the a-subunit promoter and (3-subunit gene.Analysis of t,,2. Recombinant bLH and bLH-CTP heterodimers were generated by stably cotransfecting CHO cells with viral expression vectors containing the bovine a-subunit gene and either the bLH( or bLH,3-CTP genes as described (13). Serum-free medium was collected and ammonium sulfate-precipitated or concentrated with an Amicon ultrafiltration cell. Female rats were pretreated with 50 ,tg of antide (Sigma) in 20% (vol/vol) propylene glycol, injected subcutaneously 2 h prior to hormone injections t...

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“…Although some limited studies suggest that there is no correlation between fertility drug treatments and ovarian cancer (3,4), several case reports suggest that there may be a link (5)(6)(7). With the use of these drugs increasing, it is important to assess their long-term impact on the ovary.…”

mentioning

confidence: 99%

Luteinizing hormone induction of ovarian tumors: Oligogenic differences between mouse strains dictates tumor disposition

Keri

Lozada

Abdul‐Karim

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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The use of fertility drugs has continued to grow since their introduction in the 1960s. Accompanying this increase has been the speculation that repetitive use of these drugs can cause ovarian tumors or cancer. We recently reported that transgenic mice with chronically elevated luteinizing hormone (LH), an analog of which is commonly used in fertility regimens, develop granulosa cell (GC) tumors. In this report we show that LH induction of these tumors is highly dependent on genetic background. In CF-1 mice, chronically elevated LH invariably causes GC tumors by 5 months of age. However, in hybrid mice generated by crossing CF-1 males with C57BL͞6, SJL, or CD-1 females, elevated levels of this same hormone cause a completely different phenotype resembling a luteoma of pregnancy. We also show that three genes likely control these alternative hormonal responses. This clinical correlate of elevated LH reveals remarkably distinct, strain-dependent, ovarian phenotypes. In addition, these results support the rare incidence of GC tumors in the human population, and suggest that the ability of certain fertility drugs to cause ovarian tumors may depend on an individual's genetic predisposition.

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Ovarian stimulation and granulosa-cell tumour

Cited by 127 publications

References 12 publications

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

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

Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors.

Luteinizing hormone induction of ovarian tumors: Oligogenic differences between mouse strains dictates tumor disposition

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