TDSM- Testosterone Dose Response in Surgically Menopausal Women

In healthy women the primary hormones produced by the ovaries are estrogens and progesterone,
but they also produce testosterone both before and after menopause. Although normal blood
levels of testosterone in women are much lower than in men, testosterone is thought to have
important physiologic effects in women, particularly on muscle function, body composition,
sexual function and cognitive function. When women require bilateral oophorectomy (removal of
ovaries), they subsequently have a significant drop in serum testosterone levels. They also
frequently experience a decreased sense of well being, and decreased sexual function.

While treatment with testosterone and other androgens has been widely promoted for women with
low serum levels, there is little available data on the effects of such treatment
particularly when given in physiologic doses (doses resulting in normal blood levels for
women). Studies that have demonstrated benefits of testosterone in women have often used
doses of testosterone which resulted in higher than normal serum testosterone levels. At such
doses, testosterone and other androgens can produce virilizing side effects such as increased
facial and body hair, acne, increased size of the clitoris and changes in the voice.

It is not known whether physiologic testosterone replacement can provide the benefits seen
with higher doses in women with androgen deficiency without the limiting, virilizing side
effects. It has been assumed that testosterone dose-response relationships are different in
women than in men, and that clinically significant effects on psycho-sexual function, body
composition, muscle performance, cognitive function, and other health-related outcomes can be
achieved at testosterone doses and concentrations that are substantially lower than those
required to produce similar effects in men; however, these assumptions have not been tested
rigorously.

Therefore, the primary objective of this study is to establish testosterone dose-response
relationships in surgically menopausal women with low testosterone concentrations for a range
of androgen-dependent outcomes, including sexual function, fat-free mass, thigh muscle
strength and leg power, several domains of neurocognitive function, plasma lipids,
apolipoproteins and lipoprotein particles, and insulin sensitivity.

The secondary objective is to determine the range of testosterone doses and subsequent plasma
testosterone concentrations that are associated with improvements in sexual, physical and
neurocognitive functions and that can be safely administered to women without significant
adverse effects on hair growth, voice, sebum production, clitoral size, and cardiovascular
risk factors.

Hypotheses

1. Testosterone administration in surgically menopausal women with low testosterone
concentrations is associated with dose- and concentration-dependent improvements in
sexual function and sexual activity scores, specific domains of cognitive function,
fat-free mass, thigh muscle strength, and leg power.

2. Testosterone dose-response relationships are different for different androgen dependent
processes. While some domains of sexual function are normalized by testosterone
concentrations at the upper end of the normal range for healthy, young women,
significant gains in fat-free mass, thigh muscle strength and power would require higher
testosterone doses than those required to induce changes in sexual function.

Inclusion Criteria

- Medically stable, ambulatory, surgically menopausal women, 21-60 years of age, who
have undergone bilateral salpingo-oophorectomy and hysterectomy at least 6 months
before study entry

- Serum total testosterone concentrations less than 31 ng/dL or free testosterone less
than 3.5 pg/ml (less than the median for healthy, young women

- Able to understand and give informed consent.

- The women will have been on a stable regimen of transdermal estrogen replacement for
at least three months. Those who are not on estrogen replacement or are taking a
different mode of estrogen replacement will be included only if they are willing to
switch to transdermal estradiol patch (see below).

- A normal PAP smear (if subject has a cervix) and mammogram in the preceding 12 months.

Exclusion Criteria:

- Significant depression, as assessed by Beck's Depression Scale.

- Any acute or chronic illness, malignant disease or fever of known or unknown origin
will be excluded.

- Poorly controlled diabetes mellitus (hemoglobin A1c greater than 8.5%)

- Uncontrolled hypertension defined as blood pressure of greater than 160/100

- Severe obesity defined as body mass index of greater than 40 kg/m2

- Current or recent (last 6 months) users of illicit drugs (which may affect appetite,
food intake, metabolism, and/or compliance with the protocol)

- Any one planning to initiate a weight-reduction diet in the subsequent six months

- Alcohol or drug dependence currently or in the preceding 6 month.

- Significant liver function abnormalities, defined as SGOT, SGPT or alkaline
phosphatase value of greater than three times the upper limit of normal in our
Clinical Pathology Laboratory or serum bilirubin levels of greater than 1.5 mg/dl will
be excluded.

- History of breast, ovarian, endometrial or cervical cancer

- History of hyperandrogenic disorders such as hirsutism, grade 2 or 3 acne, and
polycystic ovary disease. Testosterone administration to these patients may exacerbate
the underlying disorder.

- Intolerance to other transdermal formulations

- Women with abnormal PAP smears or mammograms will not be included unless they have
been evaluated by their gynecologists and breast and uterine/cervical cancers have
been excluded by appropriate tests.

- Women with dementia as assessed by the mini-mental state examination

- Women with depression, assessed by Beck's Depression Scale.

- Those with disabilities that would prevent them from participating in strength testing
(e.g., amputation of limbs, blindness, severe arthritis, neurologic disorders such as
Parkinson's disease, stroke, or myopathy).

- Women with any heart disease, including angina, congestive heart failure, or history
of myocardial infarction or coronary artery angioplasty or bypass surgery in the
previous year will be excluded.

- Subjects planning to initiate a weight-reduction diet in the subsequent six months

- Other Medications. Women who have received in the preceding three months drugs known
to affect testosterone production or metabolism such as ketoconazole, Megace, and/or
anabolic/androgenic steroids will be excluded. We will also exclude women who are
taking or have taken in the past three months medication that include sexual
dysfunction (e.g., spironolactone, SSRIs, GnRH agonists). Women who are using any
medication, device or dietary supplement known to enhance sexual function will not be
included. Women receiving thyroid hormone replacement therapy may participate in the
study only if they have been on a stable replacement dose of L-thyroxine for at least
three months.

- Intolerance to estrogen products or skin patches

- Undiagnosed vaginal or vulvar bleeding

- History of deep vein thrombosis, pulmonary embolism, or other thromboembolic disorder