The Genetics of Polycystic Ovarian Syndrome

Polycystic Ovary Syndrome (PCOS) is one of the most common endocrine disorders in women. Its
marked phenotypic variability, puzzling list of associated conditions, and hence potential
risk to a woman's health over her lifecycle clearly remain a clinical investigational,
genetic, and therapeutic challenge. To a great extent, this variability can be attributed to
the marked genetic and environmental heterogeneity of the populations studied. We plan to
address many of these long-term clinical research obstacles by delineating the genetic basis
of PCOS in a unique investigational venue, the Icelandic population. Studying the Icelandic
population has the following advantages: a) the population's relative genetic and
environmental homogeneity; b) the remarkably rich genealogic database; and c) the centralized
healthcare information. In this unusual venue, clustering of large numbers of PCOS families
with known relationships is possible. Their relative homogeneity and genealogic
characteristics can reduce genetic variance and hence be used to map the genetic basis for
PCOS more efficiently than in more heterogeneous populations. As the genes responsible for
PCOS emerge, this protocol will also determine phenotype/genotype correlations in Iceland,
contrasting them with US women, and assess their long-term medical consequences.

Each female subject will be asked to arrive fasting in the morning. Women with PCOS will be
asked to arrive at least 10 days from their last menstrual period, while women with regular
menstrual cycles will be seen within the first 14 days after their menstrual period starts.
All subjects will be asked to fill out an extensive questionnaire. Subjects will then undergo
further history, physical exam and laboratory exams. Blood will be drawn at baseline for DNA
(the material in the cell that holds the genes), fasting blood glucose and insulin, HbA1C,
total and fractionated cholesterol, triglycerides, testosterone, androstenedione, DHEAS, SHBG
and 17-OH Progesterone. Additional blood will be drawn at 10 and 20 minutes for measurement
of LH and FSH, which are pulsatile. An oral glucose tolerance test will be optional. A
standardized transvaginal ultrasound will be performed to look at the ovaries in all female
subjects. This can be done over the abdomen with a full bladder if the patient prefers.

Male family members will also undergo a history, physical and laboratory exams in an
identical manner to that of their female family members with the addition that specific
notice of their hair distribution will be made. PCOS subjects who are on oral contraceptives
or other hormonal medication may have cholesterol, insulin, glucose, triglycerides and HbA1C
labs drawn, whereas subjects on insulin sensitizing agents will not have any blood drawn for
these tests. These subjects will undergo an ultrasound and DNA sampling.

All hormone blood samples from Icelandic and Boston subjects will be examined in Boston. All
DNA testing will be performed in the Genotyping Core of deCODE, a company in Iceland.
Therefore, all DNA samples from Iceland and Boston will be analyzed in Iceland. The Boston
blood samples will be coded and sent to the DeCODE genotyping facility. The investigators in
Boston will retain the link between the code and the subject information in a locked area in
the office. The names of subjects will not be disclosed to deCODE.

Inclusion Criteria:

- Inclusion Criteria-PCOS Probands: 1) Aged 18 yrs or above 2) Oligomenorrhea or
amenorrhea (<9 menses/yr); 3) clinical and/or biochemical evidence of
hyperandrogenemia; 4) normal TSH and prolactin <25 ng/mL; 5) on no hormonal or insulin
sensitizing medication for at least 3 months and have not taken Provera for at least
ten days prior to enrollment. If the subject has previously had hormone levels drawn
and processed in the Reproductive Endocrine Laboratory, it is not necessary to
discontinue hormonal or insulin sensitizing medication.

A second group of PCOS probands with a documented diagnosis of PCOS will also be recruited.
These subjects will meet all of the criteria above except that they will be on hormonal
medication.

Inclusion Criteria-Female Unaffected Relatives: 1) Aged at 18 yrs or above; 2) Regular
menstrual cycles 21-35 days or history of regular menstrual cycles in the past if
menopausal; 3) no clinical or biochemical evidence of hyperandrogenism; 4) normal TSH and
prolactin <25 ng/mL; 5) on no hormonal or insulin sensitizing medication for at least 3
months.

Inclusion Criteria-Male Relatives: 1) Aged 18 yrs or above; 2) normal TSH and prolactin <25
ng/mL; 5) on no hormonal or insulin sensitizing medication for at least 3 months.

Inclusion Criteria-Control Subjects: All control subjects will meet the criteria outlined
for the female unaffected relatives. In Iceland, control subjects will be recruited from
the Icelandic national registry, matched by age and sex to PCOS subjects and their family
members. They will otherwise be recruited at random. In Boston, control subjects will be
recruited from email and newspaper listings.

Exclusion Criteria:

- Exclusion Criteria PCOS Probands: Subjects will not have 1) late onset congenital
adrenal hyperplasia as defined by a fasting 17OH progesterone level <200 ng/mL or a
cortrosyn stimulated 17 OH progesterone level <500 ng/mL.

Exclusion Criteria (Female unaffected relatives): None. Exclusion Criteria Male Relatives:
None. Exclusion Criteria-Control Subjects: Control subjects chosen at random will be
excluded if they are already participating in the study as a PCOS subject or are a first
degree family member of the PCOS subject.