Low Dose Growth Hormone in Obese PCOS Women

The study will be a double-blinded cross-over study. Thirty subjects will be screened for
eligibility initially, and the first 12 eligible subjects will be enrolled. Six subjects
will be randomized to receive the low GH dose (0.1 mg/day) treatment and 6 subjects to
receive Placebo treatment for 12 weeks, exchanging their treatment for a further 12 weeks
after a 4-week washout period. The study drugs will be stored at the Oregon Health and
Science University (OHSU) Research Pharmacy and following randomization, the subjects will
be taught by our Endocrine Nurses to self-administer the subcutaneous GH and Placebo
injections using Nutropin/Placebo vials and insulin syringes into the abdomen at 2200h.
Randomization for treatment assignment will be performed by an investigator not directly
involved in the patients' recruitment, treatment and follow-up care. The randomization
process will be performed by computerized pre-assigned random codes by blocks, stratified by
age and examined for possible differences in body mass index. During their in-patient stay
at the Oregon Clinical and Translational Research Institute (OCTRI) at OHSU, subjects will
only be allowed to eat the food provided to them by the OCTRI.

Initial Screening Assessment (outpatient)

The following assessments will be performed:

- Written informed consent

- Demographics (demographic information including the subject's birth date, and race)

- Physical exam and medical history

- Previous/significant medical history

- Concomitant medication review

- Vital signs, e.g., pulse and blood pressure measurements

- Height and weight

- Laboratory findings, e.g. CBC, electrolytes, and fasting glucose levels

- Visit 1, Baseline Assessment for the First Treatment Phase (in-patient)

The following is a description of the assessments that will be performed after consent is
obtained:

- Physical exam and medical history

- Vital signs, e.g., pulse and blood pressure measurements

- Height and weight

- Waist circumference measurement

- Concomitant medication review

- Urine pregnancy test

- Fasting blood assessments, e.g., hemoglobin, glucose, insulin, C-peptide, serum total
and free IGF-I, IGFBP-3, C-reactive protein, non-esterified fatty acids (NEFAs),
testosterone, albumin, sex hormone binding globulin and androstenedione

- A 3-hour one-step hyperinsulinemic euglycemic clamp

- MRS and DEXA scans

- Cortisol clearance rate assessments

- Fat biopsy

- Randomization to GH or Placebo

- Teach GH or Placebo self-administration

- Visit 2, Final Assessment for the First Treatment Phase (Week 12 +/- 1 week)
(outpatient)

The following is a description of the assessments that will be performed at the end of the
first treatment phase with either GH or Placebo. Subjects will also be monitored for safety
with the collection of the following:

- Physical exam and medical history

- Vital signs, e.g. pulse and blood pressure measurements

- Height and weight

- Waist circumference measurement

- Concomitant medication review

- Adverse event recording

- Urine pregnancy test

- Fasting blood assessments, e.g. hemoglobin, glucose, insulin, C-peptide, serum total
and free IGF-I, IGFBP-3, C-reactive protein, adiponectin, ghrelin, non-esterified fatty
acids (NEFAs), testosterone, albumin, sex hormone binding globulin and androstenedione

- A 3-hour one-step hyperinsulinemic euglycemic clamp

- MRS and DEXA scans

- Cortisol clearance rate assessments

- Fat biopsy

Washout Period and Crossover After the first treatment phase with GH or Placebo, the
subjects will have a 4-week washout period and the treatment will be crossed over for
another 12-week treatment phase with either GH or Placebo. During this time, the subjects
will be advised to maintain a stable diet and weight.

Visit 3, Baseline Assessment for the Second Treatment Phase (Week 16 +/- 1 week) (as
outpatient)

The following is a description of the assessments that will be performed:

- Physical exam and medical history

- Vital signs, e.g., pulse and blood pressure measurements

- Height and weight

- Waist circumference measurement

- Concomitant medication review

- Adverse event recording

- Urine pregnancy test

- Fasting blood assessments, e.g. hemoglobin, glucose, insulin, C-peptide, serum total
and free IGF-I, IGFBP-3, C-reactive protein, adiponectin, ghrelin, non-esterified fatty
acids (NEFAs), testosterone, albumin, sex hormone binding globulin and androstenedione

- Treatment exchanged to Placebo or GH

- Visit 4, Final Assessment for the Second Treatment Phase (Week 28 +/- 1 week) (as
inpatient)

The following is a description of the assessments that will be performed at the end of the
second treatment phase with either GH or Placebo. Subjects will also be monitored for safety
with the collection of the following:

- Physical exam and medical history

- Vital signs, e.g. pulse and blood pressure measurements

- Height and weight

- Waist circumference measurement

- Concomitant medication review

- Adverse event recording

- Urine pregnancy test

- Fasting blood assessments, e.g., hemoglobin, glucose, insulin, C-peptide, serum total
and free IGF-I, IGFBP-3, C-reactive protein, adiponectin, ghrelin, non-esterified fatty
acids (NEFAs), testosterone, albumin, sex hormone binding globulin and androstenedione

- A 3-hour one-step hyperinsulinemic euglycemic clamp

- MRS and DEXA scans

- Cortisol clearance rate assessments

- Fat biopsy

- Because of the potentially long duration of Visits 1, 2 and 4, the studies can
either be divided into two separate admissions upon prior arrangement or can be
done all at once with one admission, depending on the subject's wishes and
schedule.

Inclusion Criteria:

- Ability to provide written informed consent and comply with study assessments for the
full duration of the study.

- Age 21 to 45 years

- Body mass index between 30 to 40 kg/m2

- Diagnosis of PCOS with underlying insulin resistance (assessed by HOMA at screening
visit) and/or other features that characterizes the metabolic syndrome such as
hypertension ( > 130/85 mmHg), abdominal obesity (waist circumference > 88 cm), and
acanthosis nigricans

- Diagnosis of normal or impaired glucose tolerance (WHO criteria)

- Stable body weight for at least 6 months prior to study entry (body weight deviating
+/- 5 kg from previously recorded weight > 6 months ago)

- Normal thyroid, renal and hepatic function

- Able to self administer daily GH/Placebo injections

Exclusion Criteria:

- Inability to comply with study requirements

- Body mass index < 30 kg/m2 and > 40 kg/m2 (patients with body mass index > 40 kg/m2
are excluded because they will not fit into the MRS scanner)

- Untreated hypothyroidism or hyperthyroidism

- Anemia from any cause

- Known diabetes mellitus

- Patients with an increased risk of venous thrombosis or previous history of recurrent
venous thrombosis

- Patient on any insulin-sensitizers (e.g., Metformin, Rosiglitazone, Pioglitazone)
within 30 days of screening assessment

- Patient on any anti-androgens (e.g., Spironolactone, Cyproterone acetate, Flutamide,
Finasteride) within 30 days of screening assessment

- Patient with other concurrent illnesses

- Pregnant (positive pregnancy test) prior enrollment in the study or planning to
conceive whilst participating in the study

- Emotional/social instability likely to prejudice study completion

- Previous history of known malignancy

- Recurrent or severe unexplained hypoglycemia

- Known or suspected drug/alcohol abuse

- Patient with any metals in the body

- Any other condition/s that the investigator believes would pose a significant hazard
to the subject if the investigational therapy were initiated

- Participation in another simultaneous medical investigation or trial