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27
- 30 May 2005
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POLYCYSTIC
OVARY SYNDROME (PCOS): GENOMIC AND GENETIC
STRATEGIES TO ELUCIDATE A COMPLEX DISEASE
Jerome F Strauss, III, MD,
PhD
Center for Research on Reproduction &
Women’s Health
University of Pennsylvania Medical Center
Philadelphia, PA 19104
USA |
The underlying pathophysiology of polycystic ovary
syndrome (PCOS), the most common endocrine disorder
of women of reproductive age, remains poorly understood.
There has also been an on-going debate over disease
phenotypes. The biochemical evidence for involvement
of multiple organ systems in PCOS including hyperandrogenemia
of ovarian origin, elevated adrenal androgen production,
insulin resistance and abnormal pancreatic beta-cell
function raises several important questions: Is
PCOS many diseases, or do the factors that influence
reproductive function also impact different cell
types simultaneously, resulting in the multi-system
PCOS phenotype? Are the metabolic abnormalities
detected in different cells the result of a shared
intrinsic defect, or are they the consequence of
exposure to an altered endocrine state? Nearly fifty
percent of sisters of women diagnosed with PCOS
had elevated total or bioavailable testosterone
levels, suggesting that hyperandrogenemia is a dominant
trait. Freshly isolated theca cells collected from
ovaries of PCOS women studied in short term culture
and propagated PCOS thecal cells grown through multiple
population doublings display greater steroidogenic
activity than theca cells collected from normal
ovaries.
The increased steroidogenic activity is due to
increased transcription of genes encoding steroidogenic
enzymes as reflected by enhanced promoter activities
in cultured PCOS theca cells and increased levels
of steroidogenic enzyme mRNAs in thecal tissue.
Moreover, the elevated androgen production by theca
cells appears to provoke stromal hyperplasia. The
stromal cells produce growth factor binding proteins
which may contribute to follicular maturation arrest.
To define the genes that are differentially expressed
in PCOS theca cells and to identify new candidate
genes that may contribute to the etiology of PCOS,
we compared gene expression profiles of normal and
PCOS theca cells using Affymetrix oligonucleotide
microarray chips. Our analysis revealed that PCOS
theca cells have a gene expression profile that
is distinct from normal theca cells. Included in
the cohort of genes with increased mRNA abundance
in PCOS theca cells was the transcription factor,
GATA6 and the regulator of the AKT/protein kinase
B (PKB) signaling pathway, cAMP-GEF-II. Changes
in cAMP-GEF-II and other genes increase the sensitivity
of theca cells to insulin activation of AKT/PKB.
We demonstrated that GATA6 increased the expression
of enzymes involved in androgen biosynthesis, providing
a functional link between altered gene expression
and intrinsic abnormalities in PCOS theca cells.
The elevation of GATA6 and cAMP-GEF-II in PCOS theca
cells appears to be the result of increased mRNA
half-life, which may be controlled by a gene on
chromosome 19p13.2, a locus shown to be linked to
PCOS in our genetic studies. ELAVL1, a gene that
encodes and RNA binding protein that regulates mRNA
stability is located in this region. Our analyses
have:
1. defined a stable molecular phenotype of PCOS
theca cells;
2. suggested new mechanisms for excess androgen
synthesis by PCOS theca cells; and
3. identified candidate genes that may be involved
in the genetic etiology of PCOS and its metabolic
phenotype.
List
of abstracts from the 3rd International Conference
on the Female Reproductive Tract
