Document Detail

Transgenic models to study gonadotropin function: the role of follicle-stimulating hormone in gonadal growth and tumorigenesis.
MedLine Citation:
PMID:  10379885     Owner:  NLM     Status:  MEDLINE    
The role of FSH in gonadal tumorigenesis and, in particular, in human ovarian cancer has been debated. It is also unclear what role the elevated FSH levels in the inhibin-deficient mouse play in the gonadal tumorigenesis. To directly assess the role of FSH in gonadal growth, differentiation, and gonadal tumorigenesis, we have generated both gain-of-function and loss-of-function transgenic mutant mice. In the gain-of-function model, we have generated transgenic mice that ectopically overexpress human FSH from multiple tissues using a mouse metallothionein-1 promoter, achieving levels far exceeding those seen in postmenopausal women. Male transgenic mice are infertile despite normal testicular development and demonstrate enlarged seminal vesicles secondary to elevated serum testosterone levels. Female transgenic mice develop highly hemorrhagic and cystic ovaries, have elevated serum estradiol and progesterone levels, and are infertile, mimicking the features of human ovarian hyperstimulation and polycystic ovarian syndromes. Furthermore, the female transgenic mice develop enlarged and cystic kidneys and die between 6-13 weeks as a result of urinary bladder obstruction. In a complementary loss-of-function approach, we have generated double-homozygous mutant mice that lack both inhibin and FSH by a genetic intercross. In contrast to male mice lacking inhibin alone, 95% of which die of a cancer cachexia-like syndrome by 12 weeks of age, only 30% of the double-mutant male mice lacking both FSH and inhibin die by 1 yr of age. The remaining double-mutant male mice develop slow-growing and less hemorrhagic testicular tumors, which are noted after 12 weeks of age, and have minimal cachexia. Similarly, the double-mutant female mice develop slow-growing, less hemorrhagic ovarian tumors, and 70% of these mice live beyond 17 weeks. The double-mutant mice demonstrate minimal cachexia in contrast to female mice lacking only inhibin, which develop highly hemorrhagic ovarian tumors, leading to cachexia and death by 17 weeks of age in 95% of the cases. The milder cachexia-like symptoms of the inhibin and FSH double-mutant mice are correlated with low levels of serum estradiol and activin A and reduced levels of aromatase mRNA in the gonadal tumors. Based on these and our previous genetic analyses, we conclude that elevated FSH levels do not directly cause gonadal tumors. However, these results suggest FSH is an important trophic modifier factor for gonadal tumorigenesis in inhibin-deficient mice.
T R Kumar; G Palapattu; P Wang; T K Woodruff; I Boime; M C Byrne; M M Matzuk
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  13     ISSN:  0888-8809     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  1999 Jun 
Date Detail:
Created Date:  1999-08-03     Completed Date:  1999-08-03     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  851-65     Citation Subset:  IM    
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
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MeSH Terms
Crosses, Genetic
Follicle Stimulating Hormone / genetics*,  metabolism
Gene Expression Regulation
Hemorrhage / genetics
Infertility, Female / genetics
Infertility, Male / genetics,  pathology
Inhibins / blood,  genetics*,  metabolism
Metallothionein / genetics
Mice, Mutant Strains
Mice, Transgenic
Ovarian Neoplasms / genetics*,  pathology
Ovary / growth & development*,  pathology
Peptides / blood,  genetics
Polycystic Ovary Syndrome / genetics
Seminal Vesicles / pathology
Steroids / blood
Testicular Neoplasms / genetics*,  pathology
Urinary Tract / abnormalities
Wasting Syndrome / genetics
Grant Support
Reg. No./Substance:
0/Oligopeptides; 0/Peptides; 0/Steroids; 0/activin B; 104625-48-1/Activins; 137833-32-0/myelopeptides; 57285-09-3/Inhibins; 9002-68-0/Follicle Stimulating Hormone; 9038-94-2/Metallothionein

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