Effects of Growth Hormone on Cognition and Cerebral Metabolism in Adults With Growth Hormone Deficiency

Eligibility screening: Diagnosis of GHD will be based on standard testing, including a
blunted GH response to stimulation with glucagon provocation, defined as GH <3 microgram/l.
Subjects with adult-onset GH deficiency will be included if they are age 18-65 years old,
naive to GH replacement therapy, in good general health, and on stable thyroid,
glucocorticoid (at replacement doses) and gonadal replacement therapy for at least 6 weeks
prior to study initiation. Patients with history a Major Depression will be excluded.

Baseline: Qualifying subjects will be admitted to the CTRU for the following: Weight, body
mass index, waist/hip ratio, menstrual cycle history on female subjects and vital signs.
Initial clinical laboratory assessments will include IGF-1, a complete blood count, liver
function tests, free T4, and a serum pregnancy test for women. Subjects will undergo 3 hours
of neuropsychological testing when attention, working memory, executive function and verbal
memory will be assessed with the Wechsler Adult Intelligence Scale III and Wechsler Memory
Scale (WMS III). Quality of life and mood will be quantified through the Quality of Life
Scale, Hamilton Rating Scale for Depression and the Quality of Life Assessment of Growth
Hormone Deficiency in Adults (Qol AGHDA). After a lunch break, the patients will undergo a 1
hour MRI scan. Resting images will be obtained, and thereafter simple letters, words or
pictures will be projected to subjects while in the scanner. The subjects will be asked
simple questions relating to these stimuli.

Randomization and treatment: Following completion of the baseline measurements, study
participants will be randomized in a double blind fashion to receive either active treatment
with GH or placebo for a period of 16 weeks. GH dosages will be increased incrementally over
the first 6 weeks. At 16 weeks, all subjects randomized to placebo will be switched to GH in
an open label fashion with dose schedules based on the above titration. Subjects initially
randomized to GH will continue to receive GH with their endocrinologist without further
follow up for the study.

For efficacy measures, neuropsychological testing and fMRI will be performed at baseline and
at 16 weeks, and, for subjects initially randomized to placebo, repeat studies will be
performed at 32 weeks.

Safety monitoring will include assessment of changes in thyroid and adrenal status, as well
as changes in liver function.

Inclusion Criteria:

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

- Age 18-65 years old

- Both men and women

- Naive to GH replacement therapy

- Diagnosis of Growth Hormone deficiency, adult onset

- Good general health

- Normal thyroid, adrenal or gonadal function, or stable thyroid, glucocorticoid (at
replacement doses) and gonadal replacement therapy for at least 3 months prior to
study initiation. If subjects are receiving transdermal testosterone, attainment of
mid-normal serum values will be considered adequate. If subjects are on intramuscular
testosterone, attainment of mid-normal serum testosterone at mid-injection cycle will
be considered adequate

Exclusion Criteria:

- Pregnancy (positive pregnancy test) prior to enrollment in the study

- Any other condition that the investigator believes would pose a significant hazard to
the subject if Growth Hormone therapy was initiated

- Idiopathic Growth Hormone Deficiency

- DSM IV diagnosis of Major Depressive Disorder with or without psychotic features,
Bipolar II Disorder with or without psychotic features in a major depressive episode

- Current use of psychotropic medications

- History of moderate to severe brain injury

- Clinically significant cardiovascular disease

- Anemia with hct<30

- Renal insufficiency with creatinine >2.0

- Recent history of excessive alcohol use

- Participation in another simultaneous medical investigation or trial

- Active neoplasm

- Prader Willi Syndrome

- History of brain radiation

- Chemotherapy, past or present use

- History of head or eye injury involving persistent metal fragments, and implanted
electrical device (such as a heart pacemaker)