The Effect of Dipeptidyl Peptidase 4 Inhibition on Growth Hormone Secretion in Women With Polycystic Ovarian Syndrome

Thirty-four obese (BMI ≥ 30 kg/m2) females (18-40 years old) with PCOS will participate in
this randomized, double-blind, placebo-controlled crossover study. The use of oral
contraceptives or metformin will be discontinued at least 30 days prior. In females
experiencing monthly cycles, the outpatient visit will take place during the mid-luteal phase
of the participant's menstrual cycle and the inpatient visit will take place during the late
follicular phase.

Subjects will be randomized to treatment order (sitagliptin 100 mg daily vs placebo) using a
block randomization algorithm with a block size of two. The dose of sitagliptin was chosen as
it is currently the FDA-recommended dose of sitagliptin for type 2 diabetic patients with
unimpaired renal function. Subjects will receive standardized dietary counseling throughout
the study; visits will be standardized to the menstrual cycle when possible. Subjects will
take each therapy for one month; a minimum one month wash-out will separate study treatments.
Side effects and compliance with study medication will be assessed at each visit in the CRC.

Each subject will undergo one outpatient visit and one inpatient visit during each treatment.
On each study day, subjects will report fasting to the CRC in the morning having abstained
from exercise that morning. On each study day, subjects will receive an intravenous catheter.
Subjects will undergo an oral glucose tolerance test (OGTT) during the outpatient study
visit. During the inpatient study visit, endothelium-dependent and -independent vasodilation
will be assessed using flow-mediated dilation technique with ultrasound. Standardized meals
will be provided at lunch and dinner. Body composition will be determined in the afternoon.
At 8 PM overnight frequent sampling for venous GH will begin every 10 minutes for 12 hours to
determine overnight GH secretion.

Inclusion Criteria:

- Females, age 18-40 years

- BMI ≥ 30 kg/m2

- Diagnosis of polycystic ovary syndrome defined by 2003 Rotterdam criteria as meeting
two out of the three below criteria :

- Oligomenorrhea or amenorrhea

- clinical or biochemical evidence of hyperandrogenism (hirsutism and/or documented
upper normal or elevated serum testosterone in the absence of exogenous hormone
therapy or Metformin)

- documented history of polycystic ovaries on ultrasound examination

Exclusion Criteria:

- Smoking

- Type 1 or Type 2 Diabetes Mellitus, as defined by a fasting glucose of 126 mg/dL or
greater at the time of screening visit or the use of anti-diabetic medication

- Hypertension, as defined by an untreated seated SBP greater than 150 mmHg and/or an
untreated DBP greater than 95 mmHg at the time of screening visit or the use of
anti-hypertensive medication

- History of reported or recorded hypoglycemia (plasma glucose < 70 mg/dL)

- Pregnancy and/or Breast-Feeding (Negative serum pregnancy test will be confirmed at
screening visit and every study visit.)

- Surgical menopause, defined as s/p total hysterectomy including bilateral
salpingo-oophorectomy

- Use of transdermal or oral contraceptive therapy. The use of these contraceptives must
be discontinued at least 8 weeks prior to study initiation.

- The use of insulin sensitizers, specifically Metformin or thiazolidinediones must be
discontinued 8 weeks prior to study initiation.

- Anemia defined as hematocrit <35% at screening visit

- Cardiovascular or cerebrovascular disease, including history of myocardial infarction,
history of congestive heart failure, history of stroke

- Pulmonary Hypertension

- Abnormal thyroid hormone levels (TSH), prolactin, or morning 17 hydroxyprogesterone at
the time of screening visit

- Impaired renal function, defined as eGFR <60 mL/min/1.73M2

- Impaired hepatic function (AST or ALT > 2 X upper limit of normal range)

- Treatment with an investigational drug in the 1 month preceding the study

- Allergy to any of the medications used in this protocol

- Regular work of a night-shift or unusual schedule which may disrupt circadian rhythm.

- Personal or Family History (defined as first degree relative) of Pancreatic Cancer

- Personal history of Pancreatitis or known pancreatic lesions

- Coagulopathy as defined by history

- Regular NSAID use, including but not limited to, naproxen, ibuprofen, and aspirin

- Mental conditions rendering the subject unable to understand the nature, scope, and
possible consequences of the study

- Inability to comply with the protocol, e.g., uncooperative attitude, inability to
return for follow-up visits, and unlikelihood of completing the study

- Any underlying or acute disease requiring regular medication that could possibly pose
a threat to the subject or make implementation of the protocol or interpretation of
the study results difficult