Baseline Sexual Function, Cognitive Function, Body Composition and Muscle Parameters and Pharmacokinetics of Transdermal Testosterone Gel in Women With Hypopituitarism

The ovaries and the adrenal glands contribute to the daily production of 300 micrograms of
testosterone in healthy, menstruating women. The physiologic role of testosterone in women,
however, remains poorly understood. Previous studies of testosterone supplementation,
largely in surgically or naturally menopausal women, have reported improvements in
subjective measures of sexual function, sense of well being, and variable changes in markers
of bone formation and resorption. However, many of these previous studies used
supraphysiologic doses of testosterone, and insensitive assays for the measurement of total
and free testosterone levels that lacked precision and accuracy in the low range prevalent
in women. The effects of testosterone in women on body composition, muscle performance and
physical function have not been studied. Therefore, the clinical significance of androgen
deficiency in women remains unclear. Thus, we do not know whether physiologic testosterone
replacement of women with androgen deficiency can produce clinically meaningful improvements
in sexual and cognitive functions, fat-free mass, and muscle performance, without virilizing
side effects.

Women with hypopituitarism represent an excellent model to study the effects of physiologic
replacement as these patients have severely diminished androgen production from both the
adrenal glands and the ovaries. Estrogen administration, by increasing sex hormone binding
globulin (SHBG) in these women leads to further reduction in free testosterone
concentrations. In fact, a recent study demonstrated very low levels of total and free
testosterone, dehydroepiandrosterone sulfate (DHEAS), its parent steroid
dehydroepiandrosterone (DHEA), and androstenedione in women with hypopituitarism. Therefore,
it is postulated that many women with hypopituitarism suffer from decreased libido, altered
body composition, and impaired quality of life, symptoms possibly related to androgen
deficiency. However, these parameters have not been properly studied in a well-defined group
of women with hypopituitarism. These baseline studies are needed prior to undertaking a
study on treating women with hypopituitarism with a testosterone preparation.

Prior to investigating testosterone replacement in a large study of women with
hypopituitarism, we must first determine in this pilot study the amount and interval of
testosterone administration.

Currently, the only FDA-approved drug for testosterone in women is Estratest, which contains
methyl testosterone, a compound that when given orally is associated with liver toxicity in
animals and humans. Until recently, most hypogonadal men received biweekly intramuscular
injections of testosterone. This regimen gives variable serum testosterone levels depending
on the time of the blood sampling compared to the time of injection. Many male hypogonadal
patients now receive their testosterone replacement via either transdermal testosterone gel
or patch, with much more uniform serum testosterone levels. We have chosen transdermal
testosterone gel for use in this study for several reasons:

1. Recent studies have shown that stable, reproducible levels of serum testosterone can be
obtained irrespective of application site in hypogonadal men. No skin irritation (which
can be problematic with the testosterone patch) was observed.

2. Graded Double-blinded dosing can easily be implemented.

Thus, we will use transdermal testosterone gel as it provides predictable and physiologic
levels of testosterone.

Inclusion Criteria:

- Women age 18-55

- Hypopituitarism with documented central adrenal and gonadal deficiencies. Serum
testosterone level of < 20 ng/dl or free testosterone <1.5 pg/ml on conjugated equine
estrogen replacement

- No other significant medical condition

- Weight between 80 and 150% of ideal body weight

- Able to provide informed consent

- All races and ethnicities

- All patients regardless of marital status and relationship status

Exclusion Criteria:

- Physical disabilities that would prevent them from participating in the study

- Current use of testosterone or other androgenic steroids. Patients who are taking
testosterone, DHEA or other androgen precursors will discontinue these
medications/supplements three months prior to the study.

- Significant cardiopulmonary disease, renal disease (creatinine > 1.5 mg/dL), diabetes
mellitus, uncontrolled hypertension, malignancy (other than basal cell skin
carcinoma) or major psychiatric disease. Patients with depression or anxiety on a
stable dose of medication will be allowed to enroll.

- Current abuse of illicit drugs or heavy ethanol use

- History of breast or uterine cancer

- Those with significant liver function abnormalities defined as SGOT, SGPT or alkaline
phosphatase value of greater than one and one-half times the upper limit of normal in
our Clinical Pathology Laboratory or serum bilirubin levels of greater than 2 mg/dl
will be excluded.

- Those with history of hyperandrogenic disorders such as hirsutism and polycystic
ovary disease will be excluded. These conditions are rare in women with
hypopituitarism. Testosterone administration to these patients may exacerbate the
underlying disorder.

- Women who are pregnant, seeking to become pregnant in the next 6 months, or breast
feeding

- Those who have previously experienced intolerance to other transdermal systems

- Drugs known to alter testosterone production such as Megace or ketoconazole

- Patients with untreated hyperprolactinemia or active Cushing's disease. Patients with
treated prolactinoma or Cushing's disease will be allowed to participate in the
study.

- Hematocrit > 50%

- Male sex

- Not willing to answer all questions on surveys