Genes, Androgens and Intrauterine Environment in PCOS
BACKGROUND Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in
premenopausal women, affecting 7-10% of this population. This syndrome is characterized by
hyperandrogenism, chronic anovulation and, frequently, obesity. Hyperandrogenemia seems to
be a consistent reproductive phenotype in male relatives as well as female relatives of PCOS
women. This phenotype appears to have a genetic basis in PCOS families and shows significant
linkage and association with a marker locus on chromosome 19p in the region of the insulin
receptor (allele 8 of D19S884.). This allele is also recently found to be associated with a
metabolic phenotype in PCOS probands and their brothers, including increased post-challenge
glucose levels, apparent defects in insulin secretion, especially in response to
sulfonylurea, and accelerated weight gain with age (unpublished date). Therefore, allele 8
status in PCOS probands and their family members can identify the reproductive and metabolic
abnormalities.
Many epidemiologic studies showed a plausible link between low birth weight and chronic
metabolic disorders manifested as hypertension, diabetes and obesity later in life,
suggestive of an early fetal programming. There is evidence to support fetal origin of PCOS.
Female rhesus monkeys that were exposed to excess androgen in utero, were born smaller for
gestational age. These animals had many of the reproductive features of PCOS, including
increased LH levels, irregular ovulation, polycystic ovaries and functional ovarian
hyperandrogenism. Similarly, in retrospective cohort studies, girls with elevated adrenal
androgen levels or with PCOS were significantly smaller for gestational age at birth than
reproductively normal control girls, suggestive of a possible fetal origin for some features
of PCOS in human studies. Molecular mechanism for fetal programming is not clearly
understood, but permanent changes in gene expression caused early insult may be a factor.
HYPOTHESIS These observations have led to a new hypothesis for the etiology of PCOS; genetic
variation resulting in hyperandrogenemia leads to many of the reproductive and metabolic
features of PCOS later in life. We will directly test the hypothesis that there is an excess
androgen production in female offspring of women with PCOS. Further, we will test whether
A8(+) female offspring have more profound changes in these parameters (increased androgen
and/or decreased insulin levels in fetal life and in infancy) compared to A8(-) female
offspring.
Observational
Observational Model: Case Control, Time Perspective: Prospective
Estradiol Level in Female Offspring
The blood that were analyzed were taken from cord blood and not from the offspring.
One time sampling from the cord blood
No
Andrea E Dunaif, MD
Principal Investigator
Chief, Division of Endocrinology, Metabolism and Molecular Medicine
United States: Federal Government
P50HD44405
NCT00364949
January 2003
July 2012
Name | Location |
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Northwestern University School of Medicine | Chicago, Illinois 60611 |