• Physical Function [ Time Frame: 14 months ] [ Designated as safety issue: No ]
  

• Muscle mass [ Time Frame: 14 months ] [ Designated as safety issue: No ]
  
• Lipids, glucose, HOMA [ Time Frame: 14 months ] [ Designated as safety issue: No ]
  

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.