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Genes, Androgens and Intrauterine Environment in PCOS

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Polycystic Ovary Syndrome

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Trial Information

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sulfonylurea, and accelerated weight gain with age (unpublished date).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

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

Inclusion Criteria

Probands who meet the following criteria will be enrolled:

Menses < 6 per year without confounding meds Not taking confounding medications at the
time of hormone analysis, willing to be off confounding medications for required washout
period, or able to provide documentation of hyperandrogenemia (without hyperprolactinemia
or evidence of non-classical adrenal hyperplasia) with past laboratory tests during a time
when not taking confounding medications Total Testosterone >58 ng/dl or bioavailable
testosterone >15 ng/dl Prolactin <25 ng/ml Baseline 17-OHP <3 ng/ml (and stimulated 17-OHP
<10 ng/ml if subject is studied on-site)

Control women who meet the following criteria will be enrolled:

History of completely regular menstrual cycles. No history of hirsutism or alopecia.
Control women will have a blood sample obtained 3-6 months after they have stopped
lactating and resumed regular menses to ensure that they have normal T, uT and DHEAS

Any pregnant woman who develops gestational diabetes will be excluded from the analysis.

To exclude disorders associated with insulin resistance, control subjects will have no
personal history of hypertension or hypertriglyceridemia and no first-degree relative with
Type 2 DM

Exclusion Criteria:

- history of gestational diabetes mellitus, eclampsia, pre-eclampsia or any medical
disorders complicating their pregnancies.

Type of Study:


Study Design:

Observational Model: Case Control, Time Perspective: Prospective

Outcome Measure:

Estradiol Level in Female Offspring

Outcome Description:

The blood that were analyzed were taken from cord blood and not from the offspring.

Outcome Time Frame:

One time sampling from the cord blood

Safety Issue:


Principal Investigator

Andrea E Dunaif, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Chief, Division of Endocrinology, Metabolism and Molecular Medicine


United States: Federal Government

Study ID:




Start Date:

January 2003

Completion Date:

July 2012

Related Keywords:

  • Polycystic Ovary Syndrome
  • Polycystic Ovary Syndrome
  • PCOS
  • Pregnant
  • Cord Blood
  • Polycystic Ovary Syndrome



Northwestern University School of Medicine Chicago, Illinois  60611