TDSM- Testosterone Dose Response in Surgically Menopausal Women

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT00494208
First received: June 28, 2007
Last updated: April 30, 2013
Last verified: January 2009
  Purpose

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.


Condition Intervention
Hysterectomy
Ovariectomy
Menopause
Testosterone Deficiency
Drug: Testosterone

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Testosterone Dose Response in Surgically Menopausal Women

Resource links provided by NLM:


Further study details as provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

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

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

Enrollment: 270
Study Start Date: January 2009
Study Completion Date: December 2009
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1 Drug: Testosterone
Testosterone ester
Active Comparator: 2 Drug: Testosterone
Testosterone ester
Active Comparator: 3 Drug: Testosterone
Testosterone ester
Active Comparator: 4 Drug: Testosterone
Testosterone ester
Active Comparator: 5 Drug: Testosterone
Testosterone ester

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.
  Eligibility

Ages Eligible for Study:   21 Years to 60 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00494208

Locations
United States, Massachusetts
Boston University Medical Center
Boston, Massachusetts, United States, 02118
Sponsors and Collaborators
Investigators
Principal Investigator: Shalender Bhasin, MD Boston Univeristy Medical Center
Study Director: Shehzad Basaria, M.D. Boston University
  More Information

No publications provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier: NCT00494208     History of Changes
Other Study ID Numbers: U54 HD041748
Study First Received: June 28, 2007
Last Updated: April 30, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
androgens
testosterone
testosterone deficiency
women
menopause
surgical Menopause
hysterectomy
oophorectomy
ovariectomy
sexual dysfunction
sexual function
muscle function
insulin sensitivity
body composition

Additional relevant MeSH terms:
Testosterone
Testosterone enanthate
Testosterone undecanoate
Testosterone 17 beta-cypionate
Methyltestosterone
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Anabolic Agents

ClinicalTrials.gov processed this record on September 16, 2014