TDSM- Testosterone Dose Response in Surgically Menopausal Women
Condition: Hysterectomy; Ovariectomy; Menopause; Testosterone Deficiency
Study type: Interventional

Summary: 
      TDSM will study the physiology of testosterone in women ages 21-60 who have had surgical
      menopause (uterus and both ovaries removed). Testosterone is commonly thought of as a "male
      hormone" thus being that it is the male's primary hormone. Women produce testosterone in much
      smaller amounts and despite this, testosterone still plays a significant role. Fifty percent
      of a women's testosterone is made in her adrenal glands (glands that sit on top of the
      kidneys) and fifty percent is made in her ovaries. When a woman has her ovaries removed it is
      thought that her testosterone levels decrease rapidly and significantly. This study will be
      examining testosterone's role in sexual function, general well being, muscle performance,
      cognitive function, carbohydrate metabolism and muscle and fat distribution.

      The study is 14 months long with weekly to monthly visits. The subjects will be placed on the
      estrogen patch for the duration of the study. They will also be given weekly injections of
      testosterone or placebo for 6 months. During the testosterone treatment phase the women will
      be separated into 5 groups. The groups include a dose of testosterone that is very low, low,
      medium, high and placebo. A placebo looks and feels similar to testosterone; however it does
      not have testosterone in it. We use this to test if the subject is having a response to the
      testosterone itself or the thought of receiving testosterone. Neither the subject nor the
      investigators will know the dose until the end of the study.
    

Detailed description: 
      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.
    

Intervention name(s): Testosterone
Intervention type(s): Drug
Intervention description(s): Testosterone ester
Intervention MeSH terms: Testosterone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: androgens; testosterone; testosterone deficiency; women; menopause; surgical Menopause; hysterectomy; oophorectomy; ovariectomy; sexual dysfunction; sexual function; muscle function; insulin sensitivity; body composition